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									Chapter 5. PROSTATE CANCER

Chapter 10. PROSTATE CANCER .......................................................................... 2
 I. INTRODUCTION................................................................................................... 2
 II. ANATOMY AND PHYSIOLOGY ...................................................................... 3
 III. NATURAL HISTORY OF PROSTATE DISEASE ........................................ 3
 IV. BASIC SCIENCE OF PROSTATE CANCER ............................................... 3
     (i) Introduction .................................................................................................... 3
     A Genetics of Prostate Cancer ....................................................................... 4
     B. Stromal Epithelial Interaction in Prostate Cancer................................ 8
     C. Molecular Markers of Prostate Cancer. ................................................ 15
     D Future Directions ......................................................................................... 21
 V. PREVENTION OF PROSTATE CANCER .................................................... 22
     Introduction ....................................................................................................... 22
     Dietary & Natural Therapies .......................................................................... 22
     Pharmacological............................................................................................... 24
     Conclusion ......................................................................................................... 25
 VI. DIAGNOSING PROSTATE CANCER .......................................................... 25
     A. Introduction .................................................................................................. 25
     B. Making Decisions about whether or not to diagnose Prostate
     cancer.................................................................................................................. 26
     Supporting Patient Choice about Testing for Prostate cancer ........... 26
     C. Digital Rectal Examination ....................................................................... 29
     D. Prostate-specific Antigen (PSA) ............................................................. 29
     E. Prostatic Fluid .............................................................................................. 33
     F. Prostate Needle Biopsies .......................................................................... 33
     G. Histologic Analysis .................................................................................... 34
 VII. PROSTATE CANCER TREATMENT OPTIONS....................................... 41
     A. Introduction .................................................................................................. 41
     B. Pre-treatment decision-making ............................................................... 42
     C. Clinical staging ............................................................................................ 44
     D. Management Options ................................................................................. 48
     E. Sexuality and prostate cancer ................................................................. 49
 VIII. RADICAL RETROPUBIC PROSTATECTOMY (RRP) ........................... 51
     A. Preoperative Consultation and Care ..................................................... 52
     B. Operative Technique .................................................................................. 53
     C Nerve-sparing prostatectomy ................................................................... 53
     D. Pelvic Lymphadenectomy ........................................................................ 57
 IX. RESULTS OF RADICAL RETROPUBIC PROSTATECTOMY ............... 58
     A. Disease-free Recurrence and Survival .................................................. 58
 X. COMPLICATIONS OF RADICAL RETROPUBIC PROSTATECTOMY . 60
     A. Incontinence ................................................................................................. 60
     B. Impotence (& sexual dysfunction – see section VII. E) .................... 61
     C. Bleeding......................................................................................................... 62
     D. Infection ......................................................................................................... 62
     E. Visceral Injuries ........................................................................................... 62
     F. Deep vein thrombosis, pulmonary embolus & other problems ...... 63
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    XI. TREATMENT OF POST-PROSTATECTOMY RECURRENCES ............ 63
      Adjuvant radiotherapy .................................................................................... 63
      Salvage radiotherapy ...................................................................................... 64
    XII. RADIOTHERAPY ........................................................................................... 65
      A. Introduction .................................................................................................. 65
      B. Stratification of risk of progression & metastases ............................ 65
      C. External Beam Radiotherapy ................................................................... 65
      D. Brachytherapy ............................................................................................. 67
      E. Defining biochemical failure (BF) after radiotherapy ........................ 68
      F. Management of local failure after radiotherapy .................................. 70
      G. Quality of life issues in prostate cancer radiotherapy ..................... 71
    XIII. SYSTEMIC THERAPIES .............................................................................. 71
      A. Hormonal Therapy ...................................................................................... 72
      B. Chemotherapy ............................................................................................. 76
      C Bisphosphonates ......................................................................................... 77
      D Bone-seeking radio-isotopes.................................................................... 78
      E. Emerging Therapies: Vaccines in Prostate cancer............................ 78
    XVII. CONCLUSIONS ........................................................................................... 87
    References ............................................................................................................. 87



Chapter 10. PROSTATE CANCER
              Acknowledgments: Hema Samaratunga, Chris Schmidt, Mark Frydenberg, John
              Yaxley for their guidance and advice in preparation of this document and to the
              authors of the previous edition Mitchell H Sokoloff, William B Isaacs, and Leland
              WK Chung.

I. INTRODUCTION
              Prostate Cancer is an increasingly common diagnosis in Western societies and in
              those emulating Western lifestyles and diets. In the year 2001 there were estimated
              to be 198,100 new cases and almost 31,900 deaths attributable to this condition in the
              United States (1). Approximately one in seven American men will be diagnosed with
              prostate cancer during their lifetime, making it the most common solid tissue cancer
              in the United States.
              Despite advances in prevention and early detection, refinements in surgical
              technique and improvements in adjuvant radio-therapy and chemotherapy, the
              ability to cure many patients with prostate cancer remains elusive. However,
              mortality rates are changing. Baade et al recently reviewed international trends in
              prostate cancer mortality and reported significant reductions in prostate-cancer
              mortality in the UK, USA, Austria, Canada, Italy, France, Germany, Australia and
              Spain with downward trends in the Netherlands, Ireland and Sweden (2).
              Detection of this disease earlier, as a consequence of introduction of the prostate
              specific antigen (PSA) blood test, has been acknowledged by the NCI as one factor
              contributing to lowering the mortality rate over the past few years (3-6). The use of
              PSA testing has been estimated to provide a diagnostic lead-time of up to 10 years
              (7-11). In the mid to late 1980s only one third of prostate cancers were diagnosed at
              curable stages compared with today when 80% are staged clinically as

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      organ-confined and potentially curable (12-14). Unfortunately, however, even when
      the tumour is thought to be localized, up to 25% of men have non-localised disease
      which declares itself subsequently (15).
      Since curative therapies are directed to localised tumours (3,4,7,16), extending
      effective but non-invasive treatments to include both primary and secondary lesions
      remains a major goal and challenge. Once prostate cancer metastasizes, apart from
      causing loss of life, its toll is often considerable with regard to morbidity from both
      the disease itself and administered therapies.
      As a result of increasing numbers of men having their prostate cancers diagnosed
      earlier, more patients are now eligible for treatment with curative intent. Improved
      surgical and radiation-based treatments have been developed so that the prognosis
      of a man diagnosed today with prostate cancer is better than ever before.

II. ANATOMY AND PHYSIOLOGY
      The term "prostate", originally derived from the Greek word prohistani which
      means "to stand in front of," has been attributed to Herophilus of Alexandria who
      used the term in 355 B.C.E. to describe the small organ located in front of the bladder
      (17). The prostate gland is a small firm organ, about the size of a chestnut, located
      below the bladder and in front of the rectum. The urethra, the channel through
      which urine is voided, passes from the bladder and through the prostate and penis.
      The primary function of the prostate gland, which contracts with ejaculation, is to
      provide enzymes to maintain the fluid nature of seminal fluid and to nourish sperm
      as they pass through the the prostatic and penile urethra to outside the body.

III. NATURAL HISTORY OF PROSTATE DISEASE
      Traditionally, prostate cancer was considered a disease of "older men." As such, it
      was generally accepted that "men never died from prostate cancer, they died of other
      conditions with prostate cancer." Consequently, treatment was conservative and
      directed toward palliation and prevention of the emergence of debilitating and
      painful sequelae. In addition, diagnosis was generally made on the basis of
      palpating a rock-hard and nodular prostate on digital rectal exam [DRE] or by
      symptoms and signs of primary or secondary tumors, such as urinary obstruction,
      back pain, nerve root or, less commonly, spinal cord compression. Almost invariably,
      most tumors had already disseminated at the time of diagnosis and, therefore, were
      incurable. It was in the mid-1980s, with the introduction of the PSA blood test that
      prostate cancer began to be diagnosed earlier and in younger men.
      Although methods of diagnosis and treatment of localized disease have become
      well-established, the management of prostate cancer remains controversial due to its
      variable biologic course, imprecision with clinical staging and limitations in
      prediction of the clinical outcome of patients with both organ-confined and
      locally-invasive disease - not to mention the morbidity associated with all currently
      established treatments. It is sobering to muse that, were the unwanted effects of
      diagnosis and treatment insignificant, the dilemma of whether or not to treat would
      not be an issue.

IV. BASIC SCIENCE OF PROSTATE CANCER
      (i) Introduction
      As described in the previous section the prostate consists of two major cellular types,
      the stroma and the epithelium. The stromal component is comprised of smooth

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        muscle cells, fibroblasts and endothelial cells; 5 cell sub-types, basal epithelium,
        secretory epithelium, transit amplifying cells, neuroendocrine cells and stem cells,
        constitute the epithelium Prostate cancer is non-regulated proliferation primarily of
        the epithelium. A number of factors may contribute to dedifferentiation and
        proliferation of epithelial cells, including aberrations in surrounding stromal cells
        via cytokines and growth factors secreted by both stromal and epithelial cell types
        (18,19).
        To date, the exact triggers for development of prostatic adenocarcinoma have not
        been elucidated, although epidemiological studies have shown links to both
        environmental (discussed subsequently) and genetic contributors. A variety of
        growth factors and cytokines have been shown to influence the growth rate and
        development of prostatic cancers, and a number of proteins and genes have been
        identified whose regulation and/or function are altered between malignant and
        benign states. Several of these proteins and genes have been flagged as potential
        biomarkers and therapeutic targets for prostate cancer.
        This chapter will provide an overview of the current literature, and will discuss
        factors that contribute to the development and progression of PCa, as well as the
        potential of new biomarkers for diagnosing and treating this disorder.

        A Genetics of Prostate Cancer
        Genetic aberrations, whether inherited or acquired, are universally associated with
        cancer development, growth, and progression. Several cancer types, such as breast,
        renal and colorectal, have been shown to have a familial component (20). In an effort
        to identify important genetic determinants associated with hereditary prostate
        cancer, a number of research groups have employed different methodologies
        involving large-scale populations (epidemiology), families (with one or more
        affected individuals) and twins.

        (i) Epidemiology:
        Major genetic epidemiologic studies published in the last two decades support the
        notion that prostate cancer may exist as clusters in families. In the 1980s, a Utah
        Mormon genealogy study found that prostate cancer exhibited the fourth strongest
        degree of familial clustering after lip, melanoma, and ovarian cancers . Prostate
        cancer, interestingly, had a higher familial association than either colon or breast
        carcinoma, which are known to be predisposed by genetic or familial components. A
        later study, determined cancer pedigrees in 691 men with prostate cancer and 640
        spouse controls, and found a positive familial history of prostate cancer . They
        concluded that men with an affected father or brother were twice as likely to
        develop prostate cancer as men with no affected relatives. Although these studies
        strongly suggest that familial clustering of prostate cancer risk does exist, they did
        not address the underlying aetiological mechanisms. Indeed, familial clustering can
        reflect either shared environmental and lifestyle risk factors, or a genetic mechanism,
        or indeed both.
        In order to address the inherent difficulties in separating the inheritable and
        environmental causes of prostate cancer, the International Consortium for Prostate
        Cancer Genetics (ICPCG) was formed. In early 2005 they published a world-wide
        study of 1,233 families located in North America, Australia, and Europe. While the
        study included some families with Asian, Hispanic, Native American and
        African-American backgrounds, 1,166 of the 1,233 families were Caucasian. The
        researchers found 5 regions (5q12, 8p21, 15q11, 17q21 and 22q12) in human
        chromosomes that potentially could harbour cancer susceptibility genes. In addition,
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the authors flagged chromosomal regions which linked to families with 5 or more
affected members (22q12, 1q25, 8q13, 13q14, 16p13 and 17q21) and those which
corresponded with early onset of disease (less than 65 years; 3p24, 5q35, 11q22, and
Xq12) . While, to date, there are no known cancer susceptibility genes in these loci,
work is ongoing to refine the mapping of these regions to the gene level.

(ii) Twin Studies:
Twin studies compare the similarities (concordance rate) of a trait or traits, traced to
either monozygotic (MZ) or dizygotic (DZ) twins to dissect the relative genetic and
environmental influences of a disease. Several twin studies (although with limited
subject numbers) of prostate cancer reported higher concordance rates in MZ twins
compared to DZ twins, implicating a genetic contribution for prostate cancer.
Lichtenstein et al (2000) (24) analyzed Swedish, Finnish and Danish twin registries
and concluded that the recurrent risk in the twin of an affected man was 21.1% for
MZ and 6.4% for DZ. More recent mathematical modeling of genetic risk of a
number of cancers, by the same research group (25), found that the contribution of
genetic susceptibility to prostate, breast, and colorectal cancers was small to
moderate. Although these aforementioned studies clearly demonstrated a potential
genetic basis of prostate cancer, albeit low, for a portion of familial prostate cancers,
this rate is much lower than coeliac disease where strongly heritable components
were found in 75% of the MZ with 11% prevalence in first-degree relatives . The
significant differences in the contribution by the heritable element on the
development of prostate cancer, as opposed to coeliac disease, suggest the
importance of gene-environment interaction, which may be pivotal in prostate
carcinogenesis.

(iii) Gene Association Studies:
In addition to hereditary prostate cancer-associated genes, a number of studies have
focused on genetic components that may be associated with prostate cancer
development. Association studies are generally case-control studies based on the
comparison of frequencies of an allele in unrelated cases and normal controls. A
significant difference in allele frequency between cases and controls can be expected
if a particular allele harbours causal variations or if that allele is closely linked with
(or in close proximity to) a disease-causing mutation. These types of association
studies are susceptible to aetiological (genetic versus environmental), inheritance
(dominant, recessive, or X-linked), and locus heterogeneity, as well as allelic (same
gene but different mutations) and founder (same mutation in different genetic
background) heterogeneity. Despite these difficulties, association studies have
identified genes that may be associated with, or contribute to, prostate cancer
development and progression.

1. BRCA1 and BRCA2
BRCA1 and BRCA2 genes, linked to breast cancer development, have also been
examined in prostate cancer due to links between these cancers‟ aetiology, observed
through epidemiologic, biologic, and molecular studies (27, 28). Recent association
studies demonstrated an increase in the frequency of BRCA1 and BRCA2 mutations
in prostate cancer carriers . The most recent studies have shown that the rate of
prostate cancer diagnosis after age 60 in cases with a deleterious mutation in BRCA1
or BRCA2 was 5.2% compared with 1.9% of controls. . In addition, data reported
thus far show that mutations of BRCA1 and BRCA2 may increase the risk of prostate
cancer, particularly in the case of BRCA2 for early-onset disease. The contribution of


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        germ line mutations in these genes to familial clusters of prostate cancer needs to be
        more fully assessed.

        2. Androgen Receptor Pathway
        Androgens serve as a most important ligand for prostate cancer, stimulating growth
        via the androgen receptor action pathway. The androgen receptor action pathway,
        broadly defined, includes the androgen receptor, the 5-alpha-reductase gene and the
        various members of the cytochrome p450 family.
        Mutations within the AR gene are detected in 10 – 20% of prostate cancer specimens,
        with mutations more common in hormone escape than hormone sensitive
        specimens . The androgen receptor (AR) is comprised of three important domains:
        N-terminal transactivation domain, DNA binding domain, and C-terminal steroid
        binding domain. Mutations in the N-terminal transactivation domain include
        variations in the number of polymorphic triplet repeats located within this area of
        the gene . Several studies have suggested that AR genes with shorter repeat lengths
        may increase the risk of developing more aggressive prostate cancer, as the number
        of polyglycine repeats is inversely related to the ability of the AR to activate target
        genes . Mutations at the steroid-binding domain have been associated the
        promiscuous nature of AR which recognizes non-androgen ligands, such as
        oestrogen, progesterone, and anti-androgens as agonists that confer AR-induced
        gene transactivation and growth stimulatory activities (36). Overall, the increase in
        incidence of mutations and the variety of mutations observed in the AR in metastatic
        cancers, suggest that these regions of AR heterogeneity may be acquired through
        gene-environment interactions.
        Amplification or duplication of the AR gene has been associated with the transition
        from hormone sensitive to hormone refractory tumours. Edwards et al, (2003) (37)
        found that less than 5% of hormone sensitive prostate cancers contained more than
        one copy of the AR gene, compared with 20-30% of hormone resistant tumours. In
        80% of these cancers there was a corresponding increase in AR protein
        concentrations. However, it was the presence of the gene duplication and not just
        higher AR protein levels which significantly predicted poorer survival rates for
        patients in their study .
        Alterations in the 3-beta-hydroxysteriod dehydrogenase gene (also a member of the
        AR pathway) have also been strongly associated with hereditary prostate cancer .
        3-beta-hydroxysteroid dehydrogenase metabolises dihydrotestosterone to 3-alpha-
        and 3-beta-diol. Recently Guerini et al (2005) have found that 3-beta-diol does not
        bind androgen receptors but efficiently binds the estrogen receptor (ER-beta), and
        exerts an inhibitory effect on prostate cancer cells through the activation of ER-beta
        signaling. Subsequently, deletiorous mutations in the 3-beta-hydroxysteriod
        dehydrogenase gene are thought to confer a growth advantage to cancer cells.
        Although the androgen receptor pathway dominates in hormonal-tumour
        interactions in prostate cancer, other relationships are also operative. As well as
        oestrogens having an increasingly recognised role, the growth hormone
        secretagogue ghrelin and a preproghrelin isoform have been shown to be highly
        expressed in prostate cancer with activation via the protein kinase pathway (39).
        Both inhibin and activin subunits are known to be expressed in the normal prostate
        with the inhibin alpha subunit gene down regulated in prostate cancer with a loss of
        heterozygosity at the gene locus and methylation of the promoter (40).
        Overexpression of the activin betaC-subunit has been demonstrated to increase
        activin AC heterodimer levels, concomitantly reducing activin A levels and
        decreasing activin signaling in PC3 cells (41).
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(iv) Clinical and pathological characterization of hereditary Prostate
Cancer
To determine what differences might distinguish hereditary prostate cancer from its
sporadic counterparts, a number of clinical features of prostate cancer were
examined by Carter, et al. . Clinical stage at presentation, pre-operative PSA, final
pathologic stage, and prostate weight were examined in a series of approximately
650 patients divided among three categories. Individuals were classified as having
hereditary disease if 3 or more relatives were affected in a single generation, prostate
cancer occurred in each of 3 successive generations in either paternal or maternal
lineages, or 2 relatives were affected under the age of 65 years. For the other groups,
either no other family members were affected (sporadic disease), or other family
members were affected but not to the extent found in families classified as
hereditary. In summary, no unique clinical or pathological characteristics
distinguished hereditary prostate cancer in this group of patients. This parallel
between hereditary and sporadic prostate cancer extends to the incidence of
multifocality found in both of these categories.

(v) Other molecular changes in Prostate Cancer
While mutations or gene duplications have been associated with familial prostate
cancers, other molecular changes have been documented in the majority of prostate
tumours. Although the mechanisms behind these changes have not always been
elucidated, it is believed that changes in gene methylation patterns, gene expression
profiles and expression of non-coding mRNA‟s play important roles in cancer
development and progression.

1. Silencing of gene expression by CpG methylation
One of the mechanisms used by cells to alter gene expression is by conjugation of a
methyl group on certain cytosine residues in the gene promoter. In a normal cell this
may function to maintain cellular differentiation, but recent reports have described
several genes which are abnormally silenced, or activated, in many tumour types
including prostate cancer, by promoter methylation. . Lodygin et al, (2005) (43)
described many genes, including cell cycle regulating genes, angiogenesis inhibitors,
apoptosis inducing genes, growth factor receptors and transcriptional control genes
that are “switched off” in prostate cancer. The “switch” could be thrown into reverse
by treatment with 5-aza-2‟ deoxycytidine, a chemical that removes methyl groups
from cytosine residues. A study of 41 primary tumours from prostate cancer patients
found that frequencies of CpG methylation detected in the promoter region of a
selection of the above genes were as follows, GPX3 (Glutathione peroxidase –
detoxification), 93%; SRFP1 (Secreted frizzled-related protein 1 – signaling), 83%;
COX2 (cyclooxygenase 2 –signaling) 78%; DKK3 (Dickkopf homologue 3 – signaling)
68%; GSTM1(Glutathione S-transferase M1 - detoxification), 58% and KIP2/p57 (cell
cycle control), 56%.
The authors also found that methylation in some gene promoters did not always
equate to reduced transcription rates, and that some genes apparently “switched on”
after 5-aza-2‟ deoxycytidine treatment did not show detectable CpG methylation.
They concluded that silencing of genes by CpG methylation occurs at an early stage
of prostate cancer development. This may have implications for the use of certain
methylation events as diagnostic markers for prostatic disease (44).
Recently, global methylation in the chromosomes of prostate cancer cells has been
studied with specific antibodies that detect all CpG sites, both in gene promoters and
elsewhere in the chromosomes (45). Interestingly, the overall amount of methylation

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        in tumour cells was decreased when compared with benign cells from the same
        individuals. It was also noted that men with recurrent disease and/or positive
        surgical margins showed overall higher levels of methylation in their tumour cells
        compared with men with early stage, surgically curable disease (45). Brothman et al,
        (2005) (45) suggest that genomic hypermethlyation is associated with condensed
        DNA. Hypomethylation of these regions permits a reduction of DNA condensation
        and may result in chromosomal rearrangement and genetic instability. In addition
        they suggest that global DNA hypomethlyation precedes hypermethylation of
        specific gene promoters (such as GSTP1) in cancer development, and the balance
        between the two methylation states may be critical in determination of aggressive vs
        non-aggressive disease (45). However, whether CpG methylation is a cause or
        consequence of cancer remains to be shown.

        2. Non-coding mRNA’s:
        With the rise of microarray technologies, analyses of changes in multiple gene
        transcription rates have been described. Interestingly, some changes in the
        transcriptional output of the human genome points to the existence of a significant
        number of non-coding RNA transcripts, derived from intronic genomic regions,
        with some of these being oriented antisense relative to the protein-coding mRNA of
        the gene. To investigate the expression level of intronic messages in human tissues, a
        subset of approximately 2,000 totally intronic Expressed Sequence Tags (EST)
        clusters and 2,000 clusters from exonic segments of known genes, was selected for
        intronic microarray analysis. Hybridization of these intronic microarrays with 27
        prostate tumours and corresponding adjacent normal tissue revealed that in prostate
        cancer, the fraction of expressed messages arising from exonic or intronic transcripts
        were similar . Moreover, the expression levels of 23 intronic non-coding transcripts
        correlated (p value - 0.001) with the degree of prostate tumour differentiation. It has
        not been determined whether the expression of intronic antisense RNAs in tumours
        is a true mechanism of cancer disregulation or just reflects broad errors in promoter
        recognition/transcription initiation. However, regulatory elements have been
        identified for a number of non-coding RNA‟s, including DD3/PCA3 and PCGEM1 –
        see below.

        B. Stromal Epithelial Interaction in Prostate Cancer
        While a variety of genetic and environmental determinants may contribute to the
        cause of malignancy, cancer cells display similar phenotypes and modes of
        development such as changes in cell adhesion, attachment, migration and invasion.
        These phenotypes and the genes controlling them are in turn regulated by epigenetic
        factors, such as soluble proteins, steroids and growth factors released by immune
        cells and adjacent stromal cells (e.g. fibroblasts, smooth muscle cells, endothelial
        cells, and neuroendocrine cells) and alterations in the extracellular matrix (ECM)
        surrounding tumor epithelium .
        Reciprocal cellular interaction between stroma and epithelium is involved in foetal
        prostate development, post-natal prostate growth and maturation, maintenance of
        differentiation status, hormonal responsiveness, and the aging and senescence of
        prostate gland in adulthood ). During neoplastic progression, key phenotypic
        changes in prostate cancer cells are also modulated by a dynamic, two-way
        communication between tumour epithelium and various stromal cells, including
        fibroblasts, smooth muscle cells, vascular endothelium and bone-derived cells
        including osteoblasts . All of these cell types and the factors they secrete form the
        cell‟s microenvironment that can either enhance or repress cancer development and
        progression. One of the challenges in understanding carcinogenesis is determining
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how the tumour microenviroment interacts with genetic changes in the cells
themselves.

(i) AR-mediated cell communication
Experimental evidence using co-cultured human benign prostatic hyperplasia
(BPH)-derived stromal and epithelial cells indicate that the expression of AR, PSA,
and 5 alpha-reductase in epithelial cells relies on the inductive influence of
neighbouring stromal cells . Similarly, in co-cultured rat prostatic epithelial and
fibroblast cells, the androgen responsiveness of prostate epithelial cells can be
conferred by the presence of fibroblastic cells . Therefore the action of AR in prostate
development is mediated by the local stroma. In addition, oestrogens have been
shown to have a role in cancer development, yet the oestrogen receptor is
predominantly localized in stromal cells. . Animal models have demonstrated
prostatic cell proliferation occurs in androgen deficient mice due to exogenous
oestrogen. . In addition, elevated androgen levels in oestrogen deficient mice
induced prostatic hyperplasia . While neither of these hormones alone induced
prostate cancer, combined androgen and oestrogen therapy did evoke prostatic
dysplasia and adenocarcinoma. It is proposed, therefore, that both androgens and
oestrogens influence the process of prostate carcinogenesis .
The function of androgen ablation therapy (ABT) is to prevent activation of AR
regulated genes. Failure of ABT, as in hormonally resistant prostate cancer, was
logically linked to genetic modification of the AR, as described above. More recently
however, there has been recognition of the effect of post-translational modifications
on the AR . In 1998, Blok et al. demonstrated phosphylation of the AR in response to
binding by the ligand DHT (dihydrotestosterone). In addition to stabilizing the
active AR homodimers, this phosphorylation can influence AR mediated gene
activation . In vivo, phosphorylation of AR by MAPK (serine-threonine kinase) and
AKT (protein kinase B) sensitizes AR to low levels of DHT, allowing low levels of
androgens, or alternative steroids to induce translocation of the AR to the nucleus,
facilitating gene activation . MAPK has been shown to be activated in cell lines
derived from hormone-refractory tumours, and is correlated with advanced stage
and grade in prostate cancer . While the exact mechanism is not fully known,
transfection of cells with c-Ras (cell growth regulator; activated in many cancer
types), leads to increased activation of MAPK and development of hormone escape .
AKT can be activated via PI3 kinase pathway (involved in cell growth, adhesion and
migration in many tumours; (69), and specifically phosphorylates AR at Ser210 and
Ser790 (70)– see Figure 1
The control of AR function also involves interaction of the receptor with a number of
co-factors or proteins that bind either as part of a complex or directly to AR and
increase (co-activators) or inhibit (co-repressors) the transcriptional activity of the
AR.
Co-activators include CBP (CREB-binding protein), beta-catenin, ARA55 and
ARA70 which all act to alter ligand specificity of the AR . These mechanisms include
allowing the antiandrogens such as hydroxyflutamide (CBP, ARA70) and
bicalutamide (ARA70) to act as agonists and/or by permitting low concentrations of
adrenal androgens or oestradial to activate AR (ARA55, beta-catenin, ARA70; . Some
co-activators activate AR in the absence of ligands, such as SRC-1, SRC-3, p300,
Tip60, and c-Jun. C-Jun binds to the AR, promoting homodimerization and
subsequently activating AR dependent transcription initiation of downstream genes
(such as PSA) . SRC-1 and SRC-3 are members of the steroid receptor cofactor family,
which is commonly overexpressed in hormone-refractory prostate cancer. This

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        family of proteins normally facilitates AR transcriptional activity in the presence of
        androgens, however, phosphorylation of SRC-1 by MAPK (activated as discussed
        above), may be one mechanism by which SRC-1 activates AR in the absence of
        androgens. Tip60 is linked to the transcription activation activity of AR by inducing
        changes to AR acetylation. In cell line models, in the absence of androgens, p300 is
        required for Il-6 (see below) stimulated growth, and it has been proposed that p300
        plays an important role in the development of hormone refractory tumours .




        Figure 1. Phosphorylation of the androgen receptor (AR) by MAPK and AKT.
        Numerous signalling factors (intracellular and extracellular), involved in
        inducing cell growth and proliferation, stimulate the Ras pathway to activate
        MAPK. Subsequently, MAPK phosphorylates AR, enabling AR to form dimers,
        enhancing ARE (androgen response element) dependent gene expression.
        Similarly, intra- and extra-cellular factors inducing cell growth and migration and
        inhibiting cell adhesion activate the PI3 kinase pathway resulting in AKT
        dependent phosphorylation, dimerisation and activation of AR.

        A less well understood mechanism of AR co-activators involves movement of AR to
        the nucleus. In LNCaP cells, STAT3 binds ligand-free AR and facilitates its
        translocation to the nucleus, and it is via this mechanism that the STAT3/AR
        complex activates AR dependent genes (in the absence of androgens) in response to
        IL-6 stimulation .

        (ii) Soluble Factors in Cell signalling
        The mediation of stromal-epithelial interactions in the normal and malignant
        prostatic environment involves a number of soluble factors that can serve paracrine,
        autocrine or intracrine functions (72). Several soluble factors have been identified
        performing a variety of functions from angiogenesis, growth enhancement, and
        dedifferentiation. These are listed in Table 1 (72).
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Table 1. Most commonly cited soluble factor signaling pathways regulating
prostate growth and differentiation (from Chung et al., 2005 [19])


 Soluble Growth Factor                                                   Referen
                                                                         ces




 Name       Source      Receptor    Receptor    Function     Regulati
                                    Location                 on     at
                                                             Androge
                                                             n
                                                             Indepen
                                                             dent
                                                             Progressi
                                                             on




 VEGF       Epitheliu   VEGFR-1     Epitheliu   Angioge      Disease     van
            m,          ,2          m,          nic factor   prognosi    Moorsela
            stroma                  stroma                   s     neg   ar    RJ,
                                                             correlati   2002)
                                                             on




 bFGF       Stroma      FGF-2R      Epitheliu   Angioge      Disease     van
 (FGF-2)                            m,          nic factor   prognosi    Moorsela
                                    stroma                   s     pos   ar    RJ,
                                                             correlati   2002)
                                                             on




 HGF/SF     Stroma      c-met       Epitheliu   Stimulat     Disease     Knudsen
                                    m           es   cell    progressi   BS, 2004;
                                                growth       on    pos   Lail-Trec
                                                             correlati   ker    M,
                                                             on          1998




 TGF-beta   Epitheliu   TGF-beta    Stroma      Induces      Augment     Bachman
            m           I-III                   apoptosi     ed          ,    2004
                        receptors               s,           expressio   and 2005;
                                                increases    n      at   Yingling,
                                                angiogen     androge     2004
                                                esis         n
                                                stimulate    withdra

                                                                                   11
Chapter 10. PROSTATE CANCER




         Soluble Growth Factor                                                    Referen
                                                                                  ces


                                                         s stromal    wal
                                                         but
                                                         inhibits
                                                         epithelial
                                                         cell
                                                         growth




         IGF-I       Stroma      IGF-IR      Epitheliu   Stimulat     Up-regul    Djavan
                                             m,          es    cell   ation at    B, 2001;
                                             stroma      growth,      disease     Rubin,
                                                         blocks                   2003
                                                         apoptosi
                                                         s            Progressi
                                                                      on




         IL-6        Epitheliu   IL-6R,      Epitheliu   Promotes     Increasin   Edwards
                     m,          sIL-6R      m,          differenti   g    IL-6   , 2005a
                     stroma                  stroma      ation and    signaling   and    b;
                                                         apoptosi                 Hideshi
                                                         s                        ma.,
                                                         inhibitio    during      2005;
                                                         n            disease     Royuela
                                                                      progressi   M, 2004
                                                                      on




         (KGF)       Stroma      Gp130       Epitheliu   Stimulat     Stromal     Planz,
                                 KGF-R       m           es cell      KGF         1999 and
                                                                      expressio   2004
         (FGF-7)                                                      n
                                                         Growth       responde
                                                                      d      to
                                                                      androge
                                                                      n



        1. VEGF
        Recruitment of neovascular endothelial cells to proliferating cancer cells is thought
        to be required for the maintenance and stimulation of tumour growth, and is
        mediated by vascular endothelial growth factor (VEGF) and its receptors. VEGF has
        been shown to be secreted by both glandular and surrounding stromal cells, and

12
                                                      Chapter 10. PROSTATE CANCER


VEGF expression can be modulated by a number of treatments including androgen
ablation, finasteride, and thalidomide .

2. IL-6
High levels of IL-6 secretion from prostate fibroblasts, smooth muscle cells, and
tumour cells themselves, are thought to be a mechanism of ligand independent
activation of AR activation via the PI3K-Akt, STAT3 and MAPK pathways in PCa .
Interference with IL-6 signaling is a potential means of modulating the growth of
advanced prostate cancer. Importantly, IL-6 is secreted by bone marrow stromal
cells (BMSCs), and this secretion is further augmented by direct interaction between
tumour cells and BMSCs . Studies using an anti-IL-6 monoclonal antibody have
shown tumoricidal effects in a murine model

3. IGF-1
The insulin-like growth factor-I (IGF-I) pathway is involved with malignant
transformation in various tissues. In prostate cancer, it has been proposed that IGF-1
induces ligand-independent activation of the androgen receptor and enhances the
expression of matrix metalloproteinase-2 and urokinase plasminogen activator (see
next section, insoluble cell signalling). Progression to androgen independence has
also been linked to deregulation of the IGF-1-IGF-1-receptor axis (76). Manipulations
of the IGF axis have shown therapeutic potential, for example, antisense RNA to
IGF-I receptor inhibits prostate cancer proliferation and invasion, while increasing
IGF binding protein 3 expression induces cell death .

4. HGS/SF, EGF and bFGF
HGS/SF, EGF and bFGF are all members of a large family of heparin bound growth
factors. Hepatocyte growth factor/scatter factor (HGF/SF) and its receptor, the
c-met proto-oncogene, were shown to be predominantly expressed by localized and
metastatic prostate cancer. Experimental evidence suggests that HGF/SF and c-met
downstream signaling may regulate prostate cancer growth and metastasis through
enhanced IL-6, androgen receptor, extracellular matrix and integrin interaction .
Epidermal growth factor (EGF) its receptor (EGFR), and other family members,
erbB2/neu, erbB3 and erbB4, are known to have a role in prostate cancer
progression through their interactions with a broad spectrum of soluble factors and
their downstream converging signaling pathways (81, 82).

5. TGF-beta
Transforming growth factor beta type 1 is a ubiquitous cytokine originally named
for its ability to transform fibrolasts in culture (83). TGF-beta both inhibits the
growth of normal epithelial cells, but paradoxically can induce cancer cell
proliferation and promote an Epithelial to Mesenchymal transition (EMT). The
mammalian TGF-beta family has 3 subtypes, and can bind to three cell surface
receptors (type I, II and III). The type II receptor functions as a tumor repressor gene,
and absence of this receptor results in resistance to the growth inhibitory effects of
TGF-beta. This growth factor also stimulates angiogenesis, extracellular matrix
turnover and host immune surveillance, although the receptors mediating this
function have not been well defined (84). TGF-beta specific inhibitors have been
developed and have been proposed to have utility in treatment of progressive
prostate cancer .




                                                                                      13
Chapter 10. PROSTATE CANCER


        (ii) Insoluble factors and the Extracellular Matrix in Cell signalling
        At the stromal /tumor cell interface of adenocarcinomas, there is a noticeable
        derangement of Extracellular Matrix (ECM), due mainly to the activity of enzymes
        derived from the host stroma. (72). However, the mechanisms of this breakdown of
        ECM are unknown, and whether cancer cell invasion develops before or after
        interacting with host stroma, or whether stroma response is subject to reciprocal
        regulation by cancer cells remains undetermined. De Wever, and Mareel (2003)(86)
        suggest that the maintenance of epithelial homeostasis requires the participation of
        stroma, and therefore it is likely that stromal changes are subsequent to epithelial
        aberrations. ECM and its degradative products could signal to cancer cells through
        their cell surface integrin or non-integrin associated receptors. Subsequently, cell
        behaviours, such as cell polarity, secretion, adhesion, motility and invasion, and
        integrated cell functions, such as proliferation, differentiation and survival could be
        affected.

        1 Integrins
        Integrins are a family of heterodimeric, transmembrane receptors that mediate the
        attachment of cells to the surrounding ECM and function as sensors of the
        environment. Alterations in integrin expression and signaling have been implicated
        in many aspects of tumorigenesis and metastasis including cell survival, migration,
        and invasion. In prostate cancer, the progression from normal to metastatic cells is
        accompanied by changes in the repertoire of integrins expressed and up-regulation
        of key adhesion-dependent signaling pathways . Important mediators of Integrin
        signaling include the adhesion kinases FAK (focal adhesion kinase) PAK (p21
        activated kinase) and MAPK (a serine/threonine kinase) . Potentially, Integrins may
        have more complex roles by coordinating their actions with metalloproteinases and
        serine proteases, which together may increase cancer cell invasion and migration
        into secondary sites of cancer growth (72).

        2. FAK
        Overexpression and increased phosphorylation of FAK has been shown in a variety
        of tumours and these changes correspond to a malignant and metastatic phenotype .
        FAK has been shown to promote cell surface expression of metalloproteinases,
        particularly MT1-MMP. This results in activation of other MMP‟s – particularly
        MMP2 enabling ECM degradation and tumour cell invasion .

        3.MMP’s:
        Matrix metalloproteinases (MMPs) are involved in tumour invasion and metastasis
        in various malignancies. MMP-2 and MMP-9 are capable of digesting collagen type
        IV, a significant component of basement membranes, and have been implicated in
        prostate cancer progression and metastases ). Preliminary studies show the
        stimulation of protease induced receptors produced increased levels of MMP-2 and
        MMP-9 activity in prostate cancer cell lines, indicating their potential role in the
        metastasis of prostate cancer cells .
        A crucial role for MMP-9 has been demonstrated in the colonization of bone by
        prostate cancer cells . Net MMP-9 activity in bone tissues peaked 2 weeks after
        injection of prostate cancer cells (PC-3), coinciding with a wave of osteoclast
        recruitment. In vitro, co-culture of PC3 cells with bone tissue led to activation of
        pro-MMP-9 and increased in secreted MMP-9 activity. Activation of pro-MMP-9
        was prevented by metalloprotease inhibitors but not by inhibitors of other classes of


14
                                                   Chapter 10. PROSTATE CANCER


proteases. The authors concluded that their data suggested that osteoclast-derived
MMP-9 may represent a potential therapeutic target in bone metastasis .
MMP-2 has been implicated in initiation of metastases, that is in promoting the
movement of tumour cells from the primary lesion into the lymphatic or circulatory
systems , but does not appear to have a role in bone metasteses colonisation .
Recently inhibition of MMP-2 by genistin, a form of dietary soy, via MAPK and
TGF-beta, was demonstrated. This study suggested a physiological role for genestin
and confirmed epidemiological studies which demonstrated that dietary intake of
genisten was associated with lower rates of metastatic prostate cancer .

4. Urokinase Plasminogen activator
The plasminogen plasmin proteolytic cascade is a multi-functional pathway which
facilitates a spectrum of biological processes including ECM remodelling during
wound healing and tumour invasion, and metastasis. The urokinase-type
plasminogen activator (uPA) and its receptor (uPAR), initiate this cascade by
converting plasminogen to plasmin. Plasmin subsequently degrades a range of ECM
components and activates MMPs (see above) (95-98). Over expression of uPA or
uPAR is a feature of a number of malignancies, including prostate, and is correlated
with tumour progression and metastasis. In contrast, inhibition of expression of uPA
or uPAR or inhibition of uPA and uPAR interaction leads to a reduction in the
invasive and metastatic capacity of many tumors (96, 98-100).

5. Kallikreins
Kallikreins (KLKs) are highly conserved serine proteases that play key roles in a
variety of physiological and pathological processes . Possibly the best known KLK
with respect to prostate cancer is KLK3 or PSA. Recently, two other androgen
regulated KLK‟s have been shown to have altered expression in PCas, KLK2 and
KLK4 . The protein product of KLK2, (glandular kallikrein; hGK2) is secreted in
ejaculate, and like PSA has been shown to have a number of substrates (105). In
particular, KLK2 can proteolyse several IGFB‟s (IGFB-2, -3, -4 and -5) more
efficiently and at lower concentrations than PSA, and potentially may stimulate the
IGF axis. KLK4 may also play a role in the IGF axis by activating pro-PSA/KLK3
which induces IGF activity by cleaving IGFB-3. PSA (KLK3) also cleaves latent
pro-transforming growth factor-beta (TGF-beta) to active TGF, thereby regulating
prostatic cell growth and bone homeostatis.
In addition, it has also been suggested that PSA also plays a role in degradation of
laminin (the ECM glycoprotein), stimulating cell invasion through the ECM. Both
KLK2 and KLK4 can activate pro-uPA to active uPA, initiating the plasminogen
plasmin proteolytic cascade (see above). KLK2, can also inactivate plasminogen
activator inhibitor-1, repressing regulatory control of the plasminogen plasmin
proteolytic cascade. (105)
Overexpression studies have shown that KLK4 induces transcriptional repression of
E-cadherin, with associated increase in vimentin . Veveris-Lowe et al (2005) (106)
concluded that the loss of E-cadherin and associated increase in vimentin are
indicative of EMT and that KLK4, may have a functional role in the progression of
prostate cancer through promotion of tumour cell migration.

C. Molecular Markers of Prostate Cancer.
One of the challenges in diagnosing prostate cancer is the heterogeneity of the
disease phenotypically. As described above, alterations occur in cancer cells at many


                                                                                  15
Chapter 10. PROSTATE CANCER


        levels, both pre and post transcriptionally (in the genome and transcribed RNA),
        and post translational protein modifications (such as phosphorylations).
        The quest for reliable prostate cancer markers to identify cancer cells in blood, bone
        marrow, urine, prostatic tissue itself and semen, has embraced a number of
        candidate biomarkers in addition to PSA. Many methods have been used to identify
        potential markers for prostate cancer, including analysis of gene expression
        (microarrays and quantitative PCR) and protein marker (histopathology,
        Mass-spectrophotometry) changes between disease and non-disease states.
        Interestingly it has been noted that the genes, their transcription rates and
        subsequent proteins altered in prostate cancer can be grouped into a number of
        cellular pathways. These include cell adhesion, cell-cycle regulation, cell signaling,
        angiogenesis and apoptosis. Some of these proteins and genes have been discussed
        above, and therefore only their applicability as diagnostic/prognostic or therapeutic
        targets will be discussed in this section.

        Table 2. Summary of molecular aberrations in prostate Cancer (Modified from
        Quinn et al., European Journal of Cancer 41 (2005) 858–887 [107])


         Process                       Key molecules/markers          References




         Apoptosis                     p53, Bcl-2, Clusterin          Downing        SR, 2003
                                                                      Augustin, 2003; Rubio,
                                                                      2005; Scaltriti, 2004a;
                                                                      Scaltriti, 2004b




         Signal transduction           TGF-beta, KGF,          EGF,   Chung, 2005; Williams,
                                       Caveolins AR                   2005;    Yang;     2004
                                                                      Edwards, 2005a and b




         Cell cycle regulation         c-Myc,        p16INK4A,        Quinn, 2005; Epstein
                                       p27KIP1, pRb, apoptotic        2005; Verambally, 2002
                                       index, Ki67 p53, EZH2




         Cell    adhesion        and   E-cadherin,                    Quinn et al, 2005; Burger,
         cohesion                      alpha-catenin,                 2002; Haese A, 2005;
                                       delta-catenin,                 Kurek R, 2004; Lintula S,
                                       metalloproteinases,            2005; Steuber T, 2005;
                                       kallikreins, CD151             Stephenson et al, 1999;
                                                                      Ang, 2004




16
                                                    Chapter 10. PROSTATE CANCER




 Process                     Key molecules/markers        References


 Angiogenesis                VEGF, VEGF receptors,        Quinn et al, 2005; Burger,
                             nitric oxide, PSMA           2002; Chang, 2004




 Other Molecular Markers     AMACR;    DD3/PCA3;          Bussemakers,         1999;
                             pCGEM-1; Hepsin; PSCA        Landers, 2005; ; Schalken
                                                          et al., 2005; Kumar-Sinha,
                                                          2004;       Jiang,   2004;
                                                          Srikantan V, 2002; ;
                                                          Zhigang, 2005;



1. Cell Signalling markers
As previously discussed, cell-cell signaling is mediated by a number of soluble and
insoluble proteins and factors. These include growth factors, such as TGF-beta, EGF
and IGF, and cytokines such as Il-6. Several of these factors have utility as
biomarkers, such as TGF-beta and, as mentioned above, inhibitors to several of these
compounds have been developed (72).
Caveolins are major structural proteins of Caveolae, specialized plasma membrane
invaginations that are abundant in smooth muscle cells, adipocytes, and
endothelium, and act as regulators of signal transduction (108). In a number of
tumour models (including prostate) caveolin-1 has been implicated in oncogenic cell
transformation and subsequent metastasis. Studies on knock-out mice and in breast
cancer models, indicate that caveolin-1 normally functions as a negative regulator of
cell transformation and tumorigenesis. However, in prostate cancer caveolin-1 may
function as a tumour promoter, potentially via both genetic and post-translational
modifications (108). In addition, a recent study showed that c-Myc and caveolin-1
immunopositivity correlated positively with Gleason score (P = 0.0253) and positive
surgical margin (P = 0.0006). Yang (109) found that the combination of positive
c-Myc and caveolin-1 in patients with clinically confined prostate carcinoma was a
significant prognostic marker for disease progression after surgery.
As described above, changes in the androgen receptor have been long associated
with prostate cancer development. While alterations in the function of this gene
appear to be critical for cancer progression, these alterations occur at many levels,
both in the genome (such as point mutations) and also post transcriptional and
translational (ie at the RNA and protein levels (62, 63). Therefore using detection of
any one of these changes as a screening tool for prostate cancer has not yet been
shown to be practicable.

2. Cell Adhesion markers
Aberrant expression of cell-cell adhesion molecules (C-CAMs) is often associated
with the development of tumours. Decreased expression of many C-CAMs
including E-cadherin, have been associated with the progression of prostate cancer
and several other types of neoplasm (107). While CD44, another cell adhesion
molecule, has been associated with prostate cancer, there have been inconsistencies
                                                                                   17
Chapter 10. PROSTATE CANCER


        across the few studies as to the prognostic value of this marker . While the loss of
        these molecules may be useful in immuno-histopathologically- based diagnoses,
        molecular based profiling may depend more on overexpressed molecules. Therefore,
        the activity of MMP‟s 2 and 9, uPA and uPAR, and KLK2, 3 (PSA) and 4 (see above)
        in interfering with cell adhesion, may prove to be more relevant
        Both KLK2 mRNA and its protein product, hK2, have been examined for efficacy as
        stand alone biomarkers or in combinations with other known biomarkers such as
        PSA . Thus far none of the published studies has found KLK2 to be useful
        prognostically and it appears to have limited diagnostic value; only one study has
        found that KLK2 (measured by quantitative PCR) in combination with PSA
        distinguishes cancers from BPH . A recent study from China found that a functional
        C748T polymorphism in KLK2 may be associated with increased risk for developing
        prostate cancer. The frequency of the CC, CT and TT genotypes was 65.7%, 32.7%
        and 1.6% in patients with prostate cancer and 56.0%, 37.5% and 6.5%, respectively, in
        controls (p = 0.010). Therefore, C allele carriers (CC and CT genotypes) were at
        significantly higher risk for prostate cancer than TT homozygous subjects (p =
        0.002) .
        As noted previously, KLK4, has also been associated with prostate cancer (114). The
        KLK4 protein product, hK4, is the first member of the KLK family that is
        intracellularly localized , and KLK4 expression is regulated by androgens, oestrogen
        and progesterone in prostate cancer cells. In situ hybridization on normal and
        hyperplastic prostate samples indicated that KLK4 is predominantly expressed in
        the basal cells of the normal prostate gland and overexpressed in prostate cancer .
        Some cell adhesion associated molecules such as CD151, a member of the
        tetraspanin family which interacts with integrins (see above), may prove to be
        relevant prognostically. CD151 plays a role as a link between extracellular matrix
        and intracellular structures, and increased protein levels of CD151 in well and
        moderately differentiated prostate cancers correlate with disease relapse subsequent
        to radical prostatectomy (115)

        3. Markers of apoptosis
        Apoptosis or programmed cell death is part of cell growth and cycling in normal
        and benign cells. In cancers, key regulators of apoptosis can be pro-apoptotic or
        anti-apoptotic such as p53 and Bcl-2 respectively, show abnormal function and
        expression. While there are many genes and proteins which fall into this category,
        many are also cell cycle regulators (such as p21 and p16) and will be discussed
        below.
        The pro-apoptotic protein p53 regulates transcription of genes required for G1-phase
        growth arrest of cells in response to DNA damage. Mutant p53 protein accumulation
        in malignant cell nuclei has been shown to be a poor prognostic indicator in several
        human carcinomas including breast, lung and colorectal (107). Mutations in p53
        have been shown to be a common event in early stage, organ-confined prostate
        cancer and the loss of p53 function via expression of viral or cellular oncoproteins
        also seems common (116). A number of studies have reported that p53 nuclear
        accumulation in  20% of tumour cells is adversely prognostic (117). Although using
        p53 as a diagnostic marker has been debated due to the heterogeneity of expression
        within tumours, Quinn et al (2000 & 2005) (107, 117), propose that p53 has great
        potential as a prognostic marker as metastatic, recurrent and androgen resistant
        cancers show higher number of cells with p53 immunoreactivity compared with
        primary tumours.


18
                                                     Chapter 10. PROSTATE CANCER


Bcl-2 was initially identified as an apoptosis-inhibiting proto-oncogene in B-cell
lymphomas. Its value as a diagnostic marker is unclear with some groups showing
that only limited numbers of prostatic tumours express Bcl-2 (118, 119). However,
other researchers have shown correlation with Bcl-2 and poor prognostic outcomes,
with increased numbers of high-grade and metastatic tumours having Bcl-2
immunoreactivity . Also Bcl-2 overexpression in tumours has been associated with
resistance to radiotherapy (123). Subsequently many scientists are looking at Bcl-2
inhibitors (such as transgenes, and antisense RNA oligonucleotides) as a means of
sensitizing Bcl-2 expressing tumours to chemo and radiotherapies (125).
Another study showed that testosterone-repressed prostate message-2 (TRPM-2),
also known as clusterin or sulfated glycoprotein-2, was elevated following androgen
withdrawal in both normal and malignant tissues . In prostate adenocarcinoma,
TRPM-2/clusterin expression may be useful as both a diagnostic and prognostic
marker, with increased TRPM-2/clusterin protein expression evident in prostate
cancer (96%) compared with BPH (73%) and normal prostate epithelium (17%) . Pins
et al (2004) (129) indicated that TRPM-2/clusterin immunoreactivity in stromal cells
surrounding the tumour epithelium predicted PSA relapse but staining within the
primary tumour epithelium was not prognostic. The anti-apoptotic function of
TRPM-2/clusterin is well documented, both by overexpression studies and through
the activities of TRPM-2/clusterin specific inhibitors (124). However, some studies
have shown pro-apoptotic functions of TRPM-2/clusterin in PC-3
androgen-independent prostate cancer cells. Cells overexpressing an intracellular,
non secreted form of TRPM-2/clusterin showed signal-independent nuclear
localization of the protein - leading to G2-M phase blockade followed by
caspase-dependent apoptosis (127, 131). While TRPM-2/clusterin is an attractive
target for theraputics, caution is warranted as it seems to have a number of functions
in cell cycle and apoptosis, with the nuclear form (nClu) being proapoptotic while
the secreted form (sClu) has prosurvival effects (131).

4. Cell cycle Regulators as markers
Genetic aberrations in the control of progression in the cell cycle are present in most
human cancers (107). There are many molecules involved in this process whose
expression is altered in prostate cancer, including the cyclin family, RBp
(retinoblastoma protein), p16, p21, p27, p53, Smad4, FHIT, and PTEN/MMAC1.
Increased expression of p16 and p21 has been associated with poorer prognostic
outcomes, and while loss of RBp and p27 may also have some prognostic value,
further studies are warranted (107, 110).
Strong expression of EZH2, a catalytic subunit of the polycomb repressor complex 2,
in clinically localized prostate cancer is related to poor prognosis . EZH2 is also
overexpressed in hormone refractory prostate cancers (133). Regulation of EZH2 is
controlled by the E2F3 transcription factor and recently Foster (2004) (134) showed
that nuclear expression of E2F3 in 20% or more of prostate epithelial cells is also an
indicator of an unfavourable clinical outcome.

5. Markers of Angiogenesis
As discussed above, angiogenesis or blood vessel growth is an essential factor in
cancer growth and progression (135). A key component in angiogenesis, VEGF, is
highly expressed in most prostate cancers and has value prognostically (107). A
number of VEGF and VEGF-R antibodies and peptide antagonists have been
developed with the specific goal of targeting the neovasculature and growing cancer
cells. This targeting pathway may become highly important since hypoxia is a
known important factor that induces VEGF production .
                                                                                    19
Chapter 10. PROSTATE CANCER


        Another molecule whose expression has been associated with angiogenesis is PSMA
        (prostate-specific membrane antigen) which is expressed by both tumor epithelium
        and tumour associated endothelial cells and neovasculature (137). A number of
        researchers, (138-140)have made a series of antibodies against the external domain of
        this protein, which have been used both pre-clinically and clinically for the diagnosis
        and therapy of prostate cancer. Chromosomal localization of PSMA gene, however,
        is controversial. It has been mapped to two regions, chromosome 11p11-12 and
        11q14 and it has been proposed that a PSMA-like gene may exist in one of the two
        chromosomal regions through the process of gene duplication. Our research group
        has shown that a specific PSMA transcript has applicability as a biomarker for
        prostate cancer, particularly when used in combination with other gene transcripts
        (such as DD3/PCA3) (143, 144). PSMA may function as a ligand internalising
        receptor, an enzyme playing a role in nutrient uptake, and a peptidase involved in
        signal transduction in prostate epithelial cells (145).

        6 Other molecular markers
        A number of other gene transcripts have been identified which may have utility as
        diagnostic and prognostic markers that do not fit into the catergories discussed
        above. These include Hepsin a transmembrane serine protease, AMACR,
        (alpha-methylacyl-CoA racemase), PSCA (prostate Stem cell antigen) and the
        non-coding RNA‟s DD3 and PCGEM-1.
        Hepsin, a type II transmembrane serine protease is differentially expressed in
        prostate cancer compared with normal and BPH affected prostate tissue (144, 146).
        Interestingly, in-vitro studies in prostate cell lines found that Hepsin overexpression
        had growth inhibitory effects . More recently a model for Hepsin and tumour
        progression was found when the soluble form of Hepsin was found to activate HGF
        (hepatocyte Growth Factor) . Potentially, antagonists to Hepsin and subsequently
        HGF activation could be useful therapeutically.
        Alpha-methylacyl-CoA racemase (AMACR) overexpression in prostate and other
        cancer tissues has been well characterized at both the mRNA and protein levels
        (151-153). This enzyme functions in the peroxisomal beta oxidation of
        branched-chain fatty acid molecules and has been implicated in the link between
        high meat high fat diets and the increased incidence of prostate cancer observed by
        many epidemiological studies (154). AMACR immunohistochemistry is being used
        in conjunction with normal Haemotoxylin and Eosin staining to aid in the diagnosis
        of prostate cancer histologically (128, 155, 156). As with many of the markers already
        mentioned clinicians are finding that using AMACR in conjunction with other
        prostatic markers gives better diagnostic results than AMACR alone (J153, 157).
        Molinie (2004)(157) showed that basal cells of normal prostatic glands stained with
        p63 in 100% of cases, while carcinomas had a p63-/AMACR+ profile, PIN were
        p63+/AMACR+, and benign lesions were p63+/AMACR-. Recently a number of
        splice variants of the AMACR transcript have been described which may be relevant
        for strategies targeting AMACR expression such as RNA antisense oligonucleotides
        (158).
        PSCA was identified as a cell surface antigen expressed by prostate cancer cells and
        is regulated by the androgen receptor ). It is central to the development of the
        prostate gland and could provide a new diagnostic and therapeutic target for PCa
        (161). PSCA overexpression has more recently been shown in pancreatic and
        urothelial tumor models (162-164) and has been proposed as a target antigen with
        immuno-based therapeutics (165, 166).


20
                                                      Chapter 10. PROSTATE CANCER


DD3/PCA3 was identified by differential display technology in 1999 as a
non-coding RNA highly specific to prostate cancer . Subsequently a number of
researchers have confirmed the over-expression of DD3 (144,168) in a number of
different cohorts. More recently the uPM3 (Bostwick) test has utilized this detection
of this RNA in a PCR based assay in urines of prostate cancer patients. Two
independent studies showed significant improvements in detecting cancer
compared with the use of PSA alone (169, 170). Tinzl (2004)(169) reported 82%
sensitivity, 76% specificity for the uPM3 assay compared to 98% sensitivity, 5%
specificity, for tPSA (at a cutoff of 2.5 ng/ml). In the tPSA categories <4, 4-10 and >10
ng/ml sensitivity was 73%, 84% and 84% and specificity was 61%, 80% and 70%,
respectively (169). The Canadian-based study (170) sampled 517 patients
undergoing biopsy at five centres, for which 86% had an assessable sample. The
overall uPM3 sensitivity and specificity in this sample group was 66% and 89%,
respectively. Once again, in the tPSA categories <4, 4-10 and >10 ng/ml, the
sensitivity of the uPM3 assay was 74%, 58% and 79% with specificity of 91%, 91%
and 80% respectively. The positive predictive value of uPM3 was 75% compared
with 38% for total PSA. (170).
PCGEM1, also a putative non-coding RNA was also identified by differential
display analysis of paired normal and prostate cancer tissues, with subsequent
Northern blot analysis of tissues showing that PCGEM1 was expressed exclusively
in the human prostate. In-situ analysis showed tumor associated overexpression in
84% of prostate cancer patients while reverse transcription PCR assays revealed
tumour-associated overexpression in 56% of patients . Interestingly PCGEM1
over-expression has been shown to be significantly higher in prostate cancer cells of
African-American men than in Caucasian-American men (P=0.0002). In addition,
„normal‟ prostate epithelial cells from prostate cancer patients with a family history
of prostate cancer also displayed increased PCGEM1 expression (P=0.0400). A
physiological role for PCGEM1 in cell growth regulation has been suggested, with
cells transfected with PCGEM1 displaying cell proliferation and an increase in
colony formation .

D Future Directions
Recently the focus of some studies has changed from identification of individual
markers to utilising combinations of known prostate cancer-specific markers as
predictors of disease recurrence after treatment with curative intent (172, 173). In our
laboratory we have investigated the utility of using combinations of biomarkers in a
PCR based diagnostic assay for prostate cancer. We found that using a combination
of Hepsin, DD3 and PSMA allowed us to distinguish 100% of prostate tumour from
BPH tissues (144). As with diagnosis, it has been proposed that a number of genes
can be used to build a “fingerprint” of an aggressive tumour . The challenge
remaining is how to apply this information in biologically relevant samples such as
serum, ejaculate and urine sediments.
With the development of methods that allow large scale gene expression profiling,
such as microarrays and quantitative RT-PCR, the list of genetic alterations in
prostate cancer cells has increased dramatically. Now the same technology is being
applied to proteins (proteomics). These advances in technology should allow the
scientist to determine that genetic changes translate into the proteome and identify
post-translational modifications which are biologically significant in cancers.
Although this chapter has attempted to summarise the current literature, this area of
science is ever-expanding and subsequently there are many other biomarkers for
prostate canceer, and other cancers which may be relevant in PCa, that were not

                                                                                      21
Chapter 10. PROSTATE CANCER


        discussed. Over the past decade there has been an explosion of research into the
        basic science of prostate cancer. Consequently, we are developing new paradigms
        for understanding the natural history of the disease as well as creating novel
        approaches to therapy. Later in this chapter, some of these advances will be
        discussed in further detail.
        Currently, surgery and radiation therapy are the conventionally accepted primary
        treatment modalities for localized prostate cancer. However, with the advent of new
        molecular-based therapies, combination therapy using surgery and/or radiation
        with these novel agents has been proposed as a method of improving therapeutic
        outcomes. More importantly, molecular-based therapies are being studied in phase I,
        II, and II trials in men with advanced and hormone-refractory prostate cancer, for
        which no curative therapies currently exist.

V. PREVENTION OF PROSTATE CANCER
        Introduction
        Predisposition to any cancer can be considered in terms of environmental and
        extrinsic factors, such as foods and interventions, and intrinsic or inherent
        susceptibility related to the person‟s genes apportioned at conception. For prostate
        cancer in particular, many people hold strong opinions regarding various strategies
        to avoid contracting it and for treatment of the condition, very often without any
        clear evidence of beneficial effect. It should be borne in mind that many advocated
        supplements and unconventional therapies are expensive and, although some
        ultimately may be proven to be of benefit, many will not and some may be harmful.

        Dietary & Natural Therapies
        (i) Dietary fat and animal meat
        A body of epidemiological data links high meat consumption and a diet rich in
        saturated fats with an increased risk of prostate cancer. (175-177). As stated in the
        previous section, alpha-methylacyl-CoA racemase (AMCR), an enzyme involved in
        oxidation of fatty acid molecules, has been implicated in the link between high fat
        diets and prostate cancer (154).
        Fatty acids in dietary fats can be divided into essential and non-essential with the
        former consisting of omega-6 (linoleic acid derived) and omega-3 fatty acids (which
        are linolenic acid in origin). Current evidence suggests that omega-3 fatty acids offer
        a protective role. (178, 179).
        Mutagens in cooked meats and fat, which include heterocyclic amines and
        polycyclic aromatic hydrocarbons, are known to be activated by cytochrome p450
        and N-acetyl transferase enzymes in the prostate to produce an increase in markers
        of dietary stress. (180). These, in turn, generate reactive oxygen species (ROS)
        leading to mutation of DNA base pairs and oncogene expression. Another mode of
        action invoked is degradation of omega-6 fatty acids via the arachidonic acid
        pathway production of prostaglandin and lipoxygenase products which, in addition
        to resulting in inflammation, are known to decrease apoptosis, stimulate
        proliferation and induce angiogenesis. (181-184).

        (ii) Lycopene
        The relevance of the anti-oxidant lycopene, an isomer of β-carotene, has been reported
        in relation to various cancers, including prostate, in a number of epidemiological studies.
        Lycopene, which is the carotenoid responsible for the red colour in tomatoes is thought to
22
                                                          Chapter 10. PROSTATE CANCER


have a protective effect as an inverse relationship has been observed between tomato intake or
blood lycopene level and the risk of cancer. (180, 185, 186)

(iii) Selenium & vitamin E
The essential micronutrient selenium is present in water and food, especially seafood, meats
and Brazil nuts. In countries with selenium-poor soils such as New Zealand, locally produced
foodstuffs may be low in selenium content. A number of epidemiological studies have
reported an increased risk of prostate and other cancers with selenium deficiency and,
conversely, a reduced incidence of prostate cancer with selenium supplementation. (187,
188).
Selenium is a component of many proteins, such as glutathione peroxidase which is a key
enzyme in surveillance against oxidative stress, involved in maintenance of genomic stability.
(189). In addition to an effect in reducing tumour initiation, selenium is considered to have an
inhibitory effect in relation to progression by blocking cell-cycle arrest through
down-regulation of CDK1, CDK2 and cyclin A and activation of p19/INK4d and p21/WAF1.
(190). Gianduzzo et al (2003) (191) demonstrated in a randomised, controlled trial that oral
selenium supplementation resulted in significantly higher levels of this compound in prostatic
tissue removed at transurethral resection of the prostate (TURP). Importantly, these
investigators also found that blood and prostate levels correlated poorly, suggesting that
peripheral blood measurements are a poor indicator of prostatic selenium content (191).
Vitamin E is present in a wide range of foods which include vegetables, vegetable oils, nuts
and egg yolks. Through its most active form, α-tocopherol, vitamin E causes G1 cell-cycle
arrest via cell regulatory proteins D1, D3 and E and cdk2 and cdk4. (190) In the
Alpha-Tocopherol, Beta-Carotene study in the United States, a one-third reduction in prostate
cancer incidence and a 40% reduction in prostate cancer deaths were reported in men taking
vitamin E (The Alpha-Tocopherol, Beta Carotene Cancer Prevention Study Group, 1994)
Currently, 2 large prevention studies are in progress to evaluate selenium and vitamin E
supplementation. SELECT (Selenium and Vitamin E Cancer Prevention Trial) is American
based and APPOSE (Australian Prostate cancer Prevention Trial Using Selenium) are
expected to produce results in the next few years (180, 192).

(iv) Soy products/isoflavones/green tea
Dietary differences between people living in Asian countries and those in the West correlate
with marked differences in prostate cancer incidence. However, with adoption of western
dietary patterns, there is an increase incidence of diseases of affluence, such as diabetes
mellitus, breast, colorectal and prostate cancer (193). These traditional differences have been
attributed to the high content of soy, tofu and isoflavinoids in many traditional asian diets.
(194, 195).
The major isoflavone components of soy, including genistein, daidzein and their metabolites,
have been shown to inhibit benign and malignant prostatic epithelial cell growth,
down-regulate androgen-related genes and reduce tumour growth in some animal models
(190). Huang et al (2005) (94) reported inhibition of MMP-2 by genistein via MAPK and
TGF-beta. This study suggested a physiological role for genestin and confirming
epidemiological studies which demonstrated that dietary intake of genisten was associated
with lower rates of metastatic prostate cancer . deVere-White et al (2005)(196) very recently
presented their experience with GCP, a proprietary nutritional supplement, the major
constituents of which are genestine and diadzin. The preparation functions as a tyrosine kinase
inhibitor and facilitates entry of prostate cancer cells into apoptosis. For13 men on active
surveillance for their prostate cancer, six months of GCP resulted in a lowering of PSA; the
trial is ongoing (196).
Dalais et al (2004)(197) studied 29 men diagnosed with prostate cancer and scheduled to
undergo RRP who were randomized to one of three groups; soy (high phytoestrogen), soy and
linseed (high phytoestrogen), or wheat (low phytoestrogen) in the form of specially prepared
breads. Their findings indicated that a daily diet containing four slices of a bread rich in soy
                                                                                             23
Chapter 10. PROSTATE CANCER


        grits favourably influenced the PSA level and the free/total PSA ratio in patients with prostate
        cancer, providing supportive evidence for epidemiological studies claiming that men who
        consume high phytoestrogen diets have a reduced risk of prostate cancer development and
        progression (197).
        Schröder et al (2005) (198) reported on 49 patients with rising serum PSA levels after
        radical prostatectomy (n = 34) or radiotherapy (n = 15) who participated in a
        randomised, double-blind, placebo-controlled crossover study of a dietary
        supplement of soy, isoflavones, lycopene, silymarin and antioxidants as main
        ingredients. The soy-based dietary supplement delayed PSA progression in a
        significant fashion with a 2.6 fold increase in the PSA doubling time from 445 to 1150
        days for the supplement and placebo periods (198).
        An integral part of most asian diets, green tea has had many benefits accorded to it,
        often through association with other dietary components. In terms of its affect on
        inhibiting prostate cancer development, it is thought to provide a benefit through
        the presence of polyphenols (also present in red wine) which induce apoptosis and
        inhibit proliferation via WAF1/p21 cell- cycle effects (190)

        Pharmacological
        (i) COX-2 Inhibition
        Continuous use of Nonsteroidal anti-inflammatory drugs (NSAIDs), in particular
        aspirin, has been reported to reduce the likelihood of development of several
        malignancies, including prostate cancer (199). Indeed, aspirin and other NSAIDs
        have been considered to decrease the risk of developing prostate cancer by 24-66%
        (200-2002)
        Non-selective NSAIDS such as aspirin inhibit both cyclooxygenase (COX-1 & COX-2)
        enzymes with the COX-2 isoform believed to be the relevant one in terms of prostate
        cancer development. COX-2 converts arachidonic acid to prostaglandin so both
        non-specific and specific COX-2 inhibitors act at this site, although some specific
        COX-2 inhibitors may have other actions as well. Specific COX-2 inhibition by
        celecoxib and nimesulide has been reported to reduce expression of several
        androgen-inducible genes, repress androgen-receptor mediated activation of PSA
        and hK2 promoter activity and repress androgen receptor protein expression. (203).
        Cost implications aside, the recent reporting of previously unappreciated serious
        side-effects with two prominent COX-2 inhibitors, rofecoxib and celecoxib, have
        resulted in some reluctance to change from using NSAIDS to selective COX-2
        inhibitors for prostate cancer prophylaxis.

        (ii) Finasteride
        Based on the observations that androgens are necessary for the development of
        prostate cancer and that men with a congenital deficiency of the 5-α-reductase type 2
        enzyme do not develop prostate cancer, a 7-year randomised, controlled trial with the drug
        finasteride was undertaken with 18 882 men who were >55 years, had a normal prostate on
        digital rectal examination and a PSA of <3 ng/ml.
        The study was ended 15 months prematurely because the end-point had been reached and
        continuing the trial would not have changed the outcome. Men who received finasteride,
        which inhibits conversion of testosterone to dihydrotestosterone (DHT) by targeting the
        5-α-reductase type 2 enzyme, had a prostate cancer prevalence reduction of 24.8% (24.4% to
        18.4%. However, the prevalence of Gleason 7-10 tumours was higher in the finasteride arm
        (6.4% versus 5.1%) although 98% of the tumours were clinically localised. (204). Klein et al
        (2005) (205) have questioned the validity of the conclusion in relation to the rate of

24
                                                                   Chapter 10. PROSTATE CANCER


      clinically-significant prostate cancer detection in this trial. They present a model of risk and
      benefit that estimates the potential influence of histological artefact (due to
      finasteride-induced effect on prostatic epithelial appearances) in the assignment of excess risk
      for high-grade disease and possible overdetection bias introduced by finasteride-induced
      volume reduction in prostates for the treated patients (205).
      A further industry-sponsored study, the REDUCE (Reduction by DUtasteride in prostate
      cancer Events) trial is in progress. In this randomised, controlled study involving 8 000 men
      with PSA values between 2 and 10 ng/ml dutasteride, which inhibits both isoforms of the
      5-α-reductase enzyme, is being used in the treatment arm. All patients in this trial are being
      biopsied at least twice during the study unlike the finasteride study in which prostatic biopsies
      were recommended if the annual PSA (adjusted for the effect of finasteride) exceeded 4 ng/ml
      or if the digital rectal examination was abnormal.
      Recent research suggests that inhibition of the irreversible action of 5α-reductase to convert
      testosterone to the more transcriptionally active dihydrotestosterone may have untoward
      effects in relation to prostate cancer. Dihydrotestosterone in turn is hydroxylated to 3α-diol
      and 3β-Adiol which do not bind to the androgen receptor but have a strong affinity for
      oestrogen receptors, the result of which is thought to have a direct effect on prostate
      development and homeostasis (206). The binding of 3β-Adiol to oestrogen receptor beta (ERβ)
      induces expression of the cell adhesion molecule E-cadherin, loss of which is associated with
      a more aggressive phenotype in prostate cancer cells (38).

      Conclusion
      The genesis of prostate cancer is multifactorial, with changes arising over a considerable
      period of time. Consequently, with respect to preventative or ameliorating measures, it is
      axiomatic that these should be implemented early and sustained for longer rather than shorter
      duration if their beneficial effects are to be maximised.

VI. DIAGNOSING PROSTATE CANCER
      A. Introduction
      Indisputably, early detection and treatment of prostate cancer are more effective than ever
      before with a consistent decline in mortality rates in many Western countries (2). However,
      this statement does not accomodate the fact that many men continue to die with prostate
      cancer and that the consequences of this tumour and its treatments may contribute
      significantly to the demise of many of these men, both directly and indirectly. Albertsen et al
      (207, 208) estimated that, for conservative treatment, men with moderately and poorly
      differentiated tumours lost approximately 4-5 years and 6-8 years of life, respectively,
      compared with those with well-differentiated tumours whose life-expectancies were little
      different to age-matched controls (207, 208).
      This problem of identifying patients with the more aggressive cancers is relevant to men of all
      ages, consistent with the findings of Parker et al (2001) (209) who concluded in their
      meta-analysis that age is not a significant prognostic factor in contemporary clinical practice
      (209). Using the SEER database, Lu-Yao and Yao (1997) (210) found that the
      disease-specific 5 year survival for poorly differentiated tumours was 63-69% (210).
      Albertsen et al (2005) (211), reporting on 767 men diagnosed between 1971 and 1984 and
      treated without curative intent, found that, for low-grade prostate cancers (Gleason 2-4), men
      have a minimal risk of dying from prostate cancer during 20 years of follow-up. Those with
      Gleason scores of 5 or 6 have an intermediate risk of prostate cancer being the cause for their
      demise but patients with high-grade prostate cancers (Gleason 8-10) have a high probability
      of dying from prostate cancer within 10 years of diagnosis (211).
      The zeal to diagnose and treat must be tempered by realisation that neither detection nor
      therapeutic intervention may be in the best interests of many men. Establishing the right
      balance between the benefits and disadvantages of diagnosis and treatment is problematical
      and, consistent with the variation in the natural history of prostate cancer, it is not difficult for
                                                                                                        25
Chapter 10. PROSTATE CANCER


        the unwanted effects of intervention to be worse than the disease being treated. Of necessity, it
        is important to recognise that the risks of competing mortalities are very different for men of
        different ages. Based on Queensland data, Baade et al (2005) estimated that about 60% of men
        diagnosed in their 50s could be expected to die a premature death (ie, before reaching 80 years
        of age) from prostate cancer compared with corresponding rates of 50% and 38% for men
        diagnosed at 60 and 70 years. Thus, for a 50 year-old man, a diagnosis of prostate cancer is
        more likely to result in a premature death from prostate cancer than for men diagnosed in their
        70s (212). Hence, whether or not to diagnose the condition should be a carefully considered
        decision.

        B. Making Decisions about whether or not to diagnose Prostate
        cancer
        While prostate cancer is the most common male malignancy in the developed world and the
        second most common cause of cancer deaths, uncertainties remain about management
        practices at several points in the illness continuum. For example, owing to a lack of definitive
        data confirming that widespread screening for prostate cancer will reduce the death rate from
        this disease, population-based screening for prostate cancer in asymptomatic men is not
        currently recommended in most countries . Rather, it is suggested that men should be able to
        access PSA testing as long as they are fully informed of the pros and cons of testing.
        For those diagnosed with localised prostate cancer, further decisions present with three
        possible treatment options at a minimum: watchful waiting, radiation therapy, or RRP -
        extending more recently to include in some settings brachytherapy and laparoscopic and
        robotic surgery . Men who are diagnosed with advanced disease will also face difficult
        treatment decisions such as when to commence treatment and what method of hormonal
        ablation to select, each with various quality of life „trade-offs‟, to accept . In the setting in
        which no one treatment approach is clearly superior with regards to cancer cure and where
        quality of life outcomes differ markedly, the quality of patients‟ decision making about
        medical treatments is critical. As a result, strategies to assist in meaningfully considering
        prostate cancer treatment options, and the risks and benefits of these options in order to
        achieve high quality patient decisions, are essential .
        The approach that is considered to be optimal for achieving high quality patient decisions is
        shared decision making . Shared decision making is defined as a process carried out between a
        patient and his health care professional where both parties share information and the patient
        understands the risks and benefits of each treatment option, participates in the decision to the
        extent that he desires and makes a decision consistent with his preferences and values, or
        defers the decision to another time. Shared decision making may not be easy to achieve for all
        patients . For example, although many patients with cancer indicate a preference for sharing
        decision making with their clinicians, some, in the case of prostate cancer between 8% to 58%
        of men, prefer a passive decision making role where clinicians make treatment decisions on
        their behalf . However, clinicians still need to understand patients‟ preferences to ensure that
        they are making quality decisions on behalf of their patients. As well, there is often a gap
        between the clinical ideal of shared decision making and actual clinical practice where
        decision complexity and time constraints may make this approach difficult for both parties to
        achieve . There are, however, defined strategies and decision aids that can facilitate this
        process .

        Supporting Patient Choice about Testing for Prostate cancer
        Many groups advocate an informed decision-making process as an evidence-based approach
        and necessary precursor to screening for early prostate cancer . Others have suggested that
        informed decision-making on this health topic is also necessary as a medico-legal risk
        management strategy . While some researchers have suggested a set of information that needs
        to be communicated to men about this health decision , there are few explicit guidelines on
        this subject . Problematically, patients and clinicians do not agree on core content . It has been
        advised that, for any screening test, patients need to understand the purpose of the test, the
        likelihood of false-negatives and false-positives, the uncertainties and risks associated with
26
                                                           Chapter 10. PROSTATE CANCER


testing, significant medical, social or financial implications of testing and any possible
sequelae and follow up care plans (www.ipdas.ohri.ca).
Such information needs to be communicated to patients in a logical and balanced sequence in
order to promote better understanding and increased decisional control by men. One approach
that has been widely tested in primary care in Australia is the use of six decision steps (see
Table 1). Each decision step logically follows to prompt the clinician to overview important
health information, with tailoring suggested in Step 1 to ensure the discussion is consistent
with the patient‟s concerns. For example, for a man with a significant family history of
prostate cancer, this factor is likely to be central to the patient discussion . Men who
experience uncomplicated lower urinary tract symptoms (LUTS) often worry about prostate
cancer, so addressing this concern first may be priority . In this regard, resources for patients
that explain about male reproductive health problems such as urinary symptoms and sexual
dysfunction are available at www.andrologyaustralia.org1. As well, National Health and
Medical Research Council guidelines are available about the management of LUTS
(http://www.health.gov.au/nhmrc/publications/synopses/cp42syn.htm).

Table. Box 1: Six Decision Steps


 Six Decision Steps for Informed Choice about PSA Testing in Asymptomatic
 Men




 1. Identify the patient‟s main concern


 2. Explain where the prostate is and tests available to detect prostate cancer


 3. Discuss prostate cancer risk and risk factors


 4. Explain the pros and cons of early detection of prostate cancer


 5. Identify patient‟s personal preferences


 6. Support the patient‟s choice, and if requested implement a prostate cancer risk
 management plan




 Source: Steginga S, Pinnock C, Baade P. "The early detection of prostate cancer in
 general practice: supporting patient choice ", practice resource in “Supporting
 patients' choice about PSA testing in general practice” A collaborative project of
 the Queensland Cancer Fund. Brisbane, 2005



From this point, checking to ensure the patient has a basic understanding of both the
prostate and possible tests is needed and, given many men may be unaware of the

                                                                                              27
Chapter 10. PROSTATE CANCER


        location and function of the prostate gland, an anatomical diagram may be a useful
        teaching tool here. Next, a consideration of individual risk with regard to both the
        incidence and mortality of prostate cancer is needed. Communicating health risks
        effectively is a challenge in the provision of effective decision support. In general
        people find probabilities hard to understand, often estimate their level of risk
        incorrectly, and tend not to weigh up pros and cons in a systematic way when
        deciding about treatments . As well, population based statistics provide data about
        populations, not individuals, so risk communication needs to acknowledge this as a
        limitation and, where possible, refer to age-based risk estimates and relevant
        individual factors such as family history ).
        There are a number of communication strategies that have been suggested to help
        patients understand risk. These include
            1. using numbers as well as words to explain risk
            2. where possible providing the absolute risk or benefit
            3. using frequencies rather than single event probabilities
            4. using consistent denominators
            5. putting the risk into context by comparing it to other life events
            6. offering both the possible negative and positive outcomes to balance the
               message frame .
        However, a quality health decision goes beyond the simple transfer of information
        and includes consideration and incorporation of each patient‟s values and personal
        preferences . Thus, Step 5 in Box 1 prompts the clinician to discuss each man‟s
        individual preferences. A number of strategies can be used to do this, most
        commonly the use of a pros and cons exercise in which patients are encouraged to
        explicitly consider the factors that matter most to them personally in this decision,
        and the direction and leaning of their preferences either for or against each possible
        option. One approach to support this process for this health topic is the inclusion of a
        values table within a decision card (see Table 1). A decision aid that incorporates
        both the six decision steps and this values clarification exercise can be found on
        http://www.ncci.org.au/services/PSA_decision_card.pdf .

        Table 3. What is most important to you?


         FOR: Is this like you?                      AGAINST: Is this like you?




         I‟m concerned that I might get prostate     I think my chance of getting prostate
         cancer                                      cancer is low




         I want the best chance of finding it        I am not convinced             about   the
         early, if I do get it                       effectiveness of testing




28
                                                    Chapter 10. PROSTATE CANCER




 FOR: Is this like you?                      AGAINST: Is this like you?




 I‟m not interested in waiting for all the   I am more concerned about avoiding
 proof to be in                              treatment side effects, if there‟s no
                                             guarantee I‟d be reducing my risk of
                                             dying from prostate cancer




 I want to do everything possible to
 reduce my risk of dying from prostate
 cancer



Decision aids are also effective in supporting patients to make informed choices.
With regards to PSA testing, patient focussed decision aids have been found to be
effective in increasing men‟s knowledge about PSA testing and decreasing
decision-related distress , with a variable effect on actual testing behaviour.
A range of aids is freely available from the web ( www.prostatehealth.org.au 2;
www.cdc.gov/cancer/prostate3; www.cancerbacup.org.uk4).
Cancer helplines also often provide such information, for example, The Cancer
Council Australia Cancer Helpline on 13 11 20; the UK helpline on 0808 800 1234; the
USA Cancer Helpline on 1800 227 2345.

C. Digital Rectal Examination
Traditionally, palpation of the prostate by digital rectal examination (DRE) was the
manner by which a diagnosis of prostate cancer was suspected. In historical series,
up to 50% of palpable masses were attributable to prostate cancer (243, 244).
Although DRE by itself is a poor method for diagnosing this malignancy (245, 246),
it does still have an important diagnostic role as 25% of tumours are detected in men
with normal PSA levels (247). Unfortunately, when a prostate cancer is diagnosed
based on a palpable tumour, the risk of the patient already harbouring metastatic or
locally advanced malignancy is considerable (248-250). However, a PSA-based
prostate cancer detection strategy which omits DRE runs the low risk of missing
some curable cancers (251).

D. Prostate-specific Antigen (PSA)
PSA testing has revolutionized the detection of prostate cancer and monitoring of its
treatment. However, its application in early detection is contentious with attitudes
to population-based screening for prostate cancer in asymptomatic men varying
considerably. (252, 253)
In the US, PSA screening is currently recommended for all men older than 50 years
and advocated to begin at 45 years in those with first-degree relatives with prostate
cancer and African-American men because of their higher risk of contracting this
tumour.( 247, 254) Population screening is not currently recommended in most
Western countries (213) although case selection is widely practised with peer
                                                                                  29
Chapter 10. PROSTATE CANCER


        organisations endorsing the importance of informed patient participation in
        decision-making for diagnostic testing, as outlined above.

        Background to PSA as a screening test
        The FDA initially approved PSA testing in 1986 for monitoring the disease status of
        prostate cancer patients and, subsequently in 1994, it was endorsed as a screening
        method for prostate cancer (255). However, the benefits for screening in improving
        survival are yet to be proven (256). Fitzpatrick (255) summarised the state of the
        evidence for screening recently. Although the results from the Quebec trial
        published in 1999 (16) and the experience in the Tyrol compared with the rest of
        Austria (3) are encouraging, the results of two large randomised trials are awaited
        with considerable interest. The Prostate, Lung, Colorectal and Ovarian Cancer Study
        (PLCO) (n = 74 000) in the US and the European Randomised Study for Screening for
        Prostate Cancer (ERSPCC) ( n = 239 000) from Europe are both on-going with results
        from the PLCO study due in 2006 and those from the ERSPC trial in 2008. Whether
        these 2 studies demonstrate a benefit for screening in reducing mortality, and from
        prostate cancer in particular, it is unlikely that early detection will disappear which,
        currently, remains PSA-based. The topic is reviewed in BJU Int, volume 95
        supplement 3, 2005.

        Strengths, limitations and adaptations of PSA
        Although emergence of an abnormal PSA due to prostate cancer can precede the
        appearance of a palpable mass by as many as ten years (8, 10, 11), tumour-induced
        symptoms by 5-10 years and, on average, death by prostate cancer by 17 years (257),
        it must be remembered that PSA is not a test for prostate cancer (258, 259). An
        abnormal serum PSA merely indicates that something is likely to be awry in the
        prostate that includes cancer as one possibility.
        Contemporarily, the large majority of patients diagnosed with prostate cancer
        present with elevated serum PSA levels, mostly between 4-10 ng/ml, (260) in the
        absence of any other discernable abnormality. Although the prevalence of prostate
        cancer depends on the population examined, most men undergoing prostatic
        biopsies – usually the next step in elucidating the cause of an elevated PSA - have
        negative histology for cancer, even when >8 transrectal ultrasound (TRUS)-guided
        biopsies are taken,(261-263) with biopsies repeated if suspicion of an undetected
        malignancy is high.(260).
        In order to increase the likelihood of detecting prostate cancer earlier, a serum PSA
        „cut-off‟ of 3 ng/ml has been advocated. However, Lodding et al (1998) (251)
        reported that approximately 15% of prostate cancers detected by investigating a
        serum PSA level between 3 and 4 ng/ml had extraprostatic growth (251).
        Furthermore, for a PSA threshold of 3 ng/ml, the negative biopsy rate is increased
        which Hessels et al (2004) (264) considered to be 70-80% (264).
        Thompson et al (2005) (265) for the Prostate Cancer Prevention Trial, reported on a
        randomised, prostpective study of 18, 882 healthy men >55 years, PSA levels <3.0
        ng/ml and normal DREs followed for 7 years with annual DREs and serum PSA
        measurements conducted from 1993 to 2003 at 221 US centres. Biopsies were
        recommended for either a PSA >4.0 ng/ml or an abnormal DRE and for all
        participants at the end of 7 years. They concluded from their findings that there is no
        cutpoint of PSA with simultaneous high sensitivity and high specificity for
        monitoring healthy men for prostate cancer but rather a continuum of prostate
        cancer risk at all values of PSA (265).


30
                                                    Chapter 10. PROSTATE CANCER


In their analysis of 3,446 consecutive volunteers with a PSA level of 2.0-10.0 ng/ml
(free PSA 18% or less) screened in the Tyrol project who underwent 10 systematic
prostate biopsies and an additional five Doppler-enhanced targeted biopsies on the
basis of age-specific PSA reference ranges, Pelzer et al (2005) (266) focused on
findings of those patients with PSA levels <4 ng/ml. They found that more than one
third of prostate cancers were detected in 313 men with a PSA value of 2-3.9 ng/mL.
Of these 313 patients, 24% had a Gleason score of 7 or greater compared with 33% of
560 patients with a PSA value of 4.0-10.0 ng/mL (P = 0.004). In addition, the prostate
cancer cases with a low PSA level occurred in younger patients and at lower stages
with smaller prostate volumes (266).Aus et al (2005) (267) also found similarly in
their study of 5,855 men, 539 cases of whom had prostate cancer detected after a
median follow-up of 7.6 years. However, based on their finding that there was not a
single case of prostate cancer detected within 3 years in 2950 men (50.4% of the
screened population) with an initial PSA level <1 ng/ml, they concluded that
retesting intervals should be individualized on the basis of the PSA level, and that
the large group of men with PSA levels of <1 ng/ml can be safely scheduled for a
3-year testing interval (267). On the basis of an evaluation of their data from the
Rotterdam section of the ERSPC, Roobol et al concur that patients with a PSA of <1
ng/ml are at low risk of developing prostate cancer. They concluded that a strategy
of PSA screening every 8 years for men with a PSA level of <1.0 ng/ml would result
in a minimal risk of missing an aggressive cancer at a curable stage (268).

Table 4a. Age-based Ranges for PSA


 Age range                   50th percentile median       95th percentile upper
                                                          limit of normal




 40-49                       0.65                         2.0




 50-59                       0.85                         3.0




 60-69                       1.39                         4.0




 70-79                       1.64                         5.0




 Between 50th & 95th percentile, higher long-term risk of cancer


 PSA increases at ~3.3% pa – if rate of increase is greater, the risk of cancer is
 greater

                                                                                   31
Chapter 10. PROSTATE CANCER




         Age range                       50th percentile median           95th percentile upper
                                                                          limit of normal




         References: 11, 269-271



        Table 4b. Non-prostate cancer contributors to increases in PSA

              1.       Benign prostatic hyperplasia (BPH)

             2. Ejaculation (both free & total) up to 48 hours
             3. Bacterial infection of prostate
             4. Prostatic massage
             5. Instrumentation (including catheterisation) of prostatic urethra
             6. Prostatic biopsy




         #Finasteride lowers PSA levels by ~50%


         http://ncci.org.au/services/prostate_GPresources.htm



        As indicated in table 4(b), non-malignant causes can produce an elevated PSA (>4.0
        ng/ml): these include infection, benign prostatic hyperplasia [BPH] and ageing
        (endorsing age-based reference ranges) (272). Instrumentation of the prostate and
        urinary tract can also raise PSA levels (273). Certain drugs, such as finasteride can
        lower PSA values by approximately 50% (274, 275). Physical examination and
        symptomatology can help differentiate BPH and prostatitis from cancer. The
        combination of a serum PSA test and digital rectal exam remains the most sensitive
        combination for diagnosing a prostatic malignancy (245, 247).
        Because of these limitations, adaptations to enhance the diagnostic utility of PSA for
        diagnosing prostate cancer have been advocated. It is important to recognise that
        these serve only as a guide in helping to decide whether or not to proceed to biopsies,
        with limited utility for extrapolation to individual patients.

        1. Free/total PSA
        This test measures the percentage of free (or unbound) PSA in the blood, and
        compares it with the percentage bound to proteins (α1 antichymotrypsin and α2
        macroglobulin) with its application most useful in younger men, as alluded to, above. In
        prostate cancer, most of the PSA in blood is bound so the lower the ratio of free to total PSA or
        the percentage of free PSA, the higher the likelihood that the patient has prostate cancer. The

32
                                                           Chapter 10. PROSTATE CANCER


proportion of free PSA in seminal fluid is much higher than in serum, consistent with its
physiological role in liquefaction (276). Levels of free-PSA but not complex-PSA in blood
significantly correlate with PSA in semen in young men, with blood levels of complex-PSA,
but not free-PSA, increasing with age (277). The free/total PSA test can help to discriminate
between patients with indeterminate PSA levels (4-10.0 ng/ml) who are at the greatest risk of
having prostate cancer, in particular aggressive disease (257, 278).

2. PSA velocity
PSA velocity measures the speed at which a series of PSA values increases in value over a
period of time (279). Any change in PSA >0.75 ng/ml in a year, is concerning for cancer
although bacterial prostatic infection may be responsible for this degree of change.

3. PSA density
PSA density is a measure of the concentration of PSA in a man's prostate. It compares the
value of his PSA and the size of his prostate (280). Most neoplastic prostate glands produce
higher serum PSA levels than do non-malignant glands. Consequently, a serum PSA of 5.0
ng/ml in a patient with a 20 gram prostate is more worrisome for cancer than that a PSA of 5.0
ng/ml in a man with a 60 gram prostate, especially if there is a predominance of transitional
zone tissue (BPH) in the latter.
To determine the PSA density, a PSA level is obtained and is divided by the volume of the
prostate, as estimated by TRUS. A value >0.15 ng/ml per gram of prostate tissue is considered
worrisome for prostate cancer. PSA density has been extended to include transition zone
measurements in relation to the overall size of the prostate as the transition zone is the site in
which BPH develops with ~25% of prostate cancers also arising in this zone. The larger the
transition zone in relation to the overall size of the gland, the lower the likelihood of prostate
cancer, other things being equal.

E. Prostatic Fluid
Deficiencies in the use of PSA in the diagnosis of prostate cancer have led to research into
examining the cellular contents of the prostate more directly. Bostwick Laboratories provide a
test that assays for PCA3/DD3 RNA ( http://www.bostwicklaboratories.com/) from prostatic
cells in urine immediately following DRE (168, 169). Tinzl et al (2004) (169) reported that
detection of the non-coding PCA/DD3 RNA, which is highly overexpressed in most prostate
cancers (167), provided sensitivities of 73%, 84% and 84% with specificities of 61%, 80%
and 70% for serum PSA values of <4 ng/ml, 4-10 ng/ml and >10 ng/ml, respectively, in the
detection of prostate cancer (169).
Fradet et al (2004) (170) reported on a multi-centre evaluation of this marker in a paper titled
„uPM3, a new molecular urine test for the detection of prostate cancer‟. 443 of 517 (86%)
samples provided by patients undergoing prostatic biopsies at 5 centres were assessable by
this molecular assay. The overall uPM3 sensitivity and specificity were 66% and 89%,
respectively. In men with a PSA level <4 ng/ml, the sensitivity was 74% and specificity 91%;
for PSA levels 4-10 ng/ml, the sensitivity was 58% and specificity 91%; for PSA levels >10
ng/ml, the sensitivity and specificity was 79% and 80%, respectively. The overall accuracy
was 81% compared with 43% and 47% for total PSA at a cutoff of 2.5 and 4.0 ng/ml,
respectively.

F. Prostate Needle Biopsies
Once the possibility of a prostatic cancer is raised, whether by rectal examination, PSA
parameters, or a combination of both, the second part of the contemporary two-step
early-diagnostic approach, TRUS-guided prostate biopsies, is usually performed. TRUS
imaging permits spatial positioning of spring-loaded biopsy needles to provide a methodical
approach for obtaining tissue cores for standard histopathology. With few exceptions, TRUS
imaging by itself is non-diagnostic as only gross changes register as an abnormal appearance
on the monitor. The number of biopsy cores taken is important with the chance of missing a

                                                                                               33
Chapter 10. PROSTATE CANCER


        cancer by standard sextant biopsy estimated to be approximately 25% (281) so that, more
        recently, the numbers of cores recommended are at least 8 and preferably a minimum of 10. In
        addition, it is advocated that biopsies should be directed laterally and that they should include
        the anterior horns of the peripheral zone (263, 282-287). Many urologists routinely take 12
        biopsy cores now to minimise the likelihood of missing cancer.
        Guidelines established by the American Urologic Association recommend prostate needle
        biopsies for any man with a PSA value greater than 4.0 ng/ml, or an abnormal prostate on
        digital rectal examination (247).
        The issue of repeat biopsies was addressed by Djavan et al (2001) particularly in relation to
        when it is reasonable to stop repeating the biopsies. Cancer-detection rates in 1051 men
        biopsied were 22%, 10%, 5% and 4% with 1-4 TRUS biopsy sessions with 58%, 60.9%,
        86.3% and 100%, respectively, having organ-confined disease. Recently, Yanke et al (2005)
        extended experience with the Kattan Nomogram to predict the likelihood of a positive finding
        at a subsequent biopsy session. Predictor variables studied in the nomogram were patient age,
        family history of prostate cancer, prostate specific antigen slope, months from initial negative
        biopsy session, months from previous negative biopsy session, cumulative number of
        negative cores previously taken and previously detected high grade PIN or atypical small
        acinar proliferation. The authors evaluated a total of 356 repeat biopsy procedures for 230
        patients. The mean number of total cores per patient was 17.9 with 78 men having biopsies
        positive for cancer. The area under the ROC curve was 0.71, which was greater than any
        single risk factor (288).
        Routine practice involves peri-operative antibiotic prophylaxis with a pre-procedural enema
        and not proceeding if any faeces at all is present in the rectum, as determined by DRE. Since
        TRUS biopsies are unpleasant and uncomfortable, many urologists use anaesthesia (local or
        general) as a routine. Minor morbidity is common with this procedure with well over 50% of
        patients experiencing at least one complication. Fortunately the dreaded complication of
        life-threatening sepsis is uncommon, generally <1%, even though rates of bacteraemia vary
        greatly; blood in the urine, ejaculate and faeces are not infrequent sequelae with some men
        having difficulty voiding immediately following the procedure. (289-291).

        G. Histologic Analysis
        The Gleason Grading System
        The biopsy result provides important information for the patient and clinician on which to
        base management decisions (292, 293). In addition to the pre-biopsy PSA level, important
        prognostic factors include tumour volume (percentage of the core involved and the number of
        positive cores) and the histological grade of the tumour. Increasing tumour burden and poor
        histologic differentiation are associated with a higher risk of metastatic disease, an increased
        chance of post-treatment failure, and a worse overall prognosis (275, 294, 295).
        Histological analysis is based on the Gleason grading system that is regarded as the „gold
        standard‟ for classifying prostatic adenocarcinoma (296). Based on architectural patterns,
        tumour is assigned a rating between 1 and 5, with higher numbers representing less
        differentiated, more aggressive tumours (see Table 1 and Figure 1). A single prostate can
        harbour multiple foci of different histologic patterns of adenocarcinoma, and it is possible to
        have Gleason grade 3, 4 and 5 patterns in the same specimen: 85% of prostate tumours are
        multifocal. The Gleason score (or Gleason sum) is generated by combining the values of the
        first and second most common (dominant and subdominant). grades (i.e.: in a tumour with
        mostly Gleason grade 3 and some Gleason grade 4 disease, the Gleason score will be 3+4 = 7),
        assessed by the uropathologist using low-power light microscopy. The Gleason score
        provides important prognostic information.




34
                                                    Chapter 10. PROSTATE CANCER


Table 5. Gleason grading system


 Grade                      Histology                      Biologic Behaviour




 1&2                        closely-packed   glands        Indolent disease, rarely
                            forming a nodule               progressive




 3                          small         infiltrating     most common pattern;
                            glands, completelumen          less   aggressive than
                            formation                      pattern 4




 4                          fused glands, incomplete       indicates         tumour
                            lumen formation                progression




 5                          solid sheet or single cells,   Very    aggressive,   late
                            no lumen formation             stage




                                                                                   35
Chapter 10. PROSTATE CANCER




36
                                                   Chapter 10. PROSTATE CANCER


Figure 2a.

The presence of Gleason grade 4 or greater histology carries a significantly poorer
prognosis (297, 298). Stamey demonstrated that Gleason score 7 tumours can be
stratified, based on the amount of grade 4 disease (299). Those with <50% grade 4
behave similarly to Gleason score 6 (more favourable), while those with >50% grade
4 act like Gleason score 8 (unfavourable) cancers. The transition from Gleason 3 to
Gleason 4 appears to be a common event and represents a critical juncture in which
the tumor acquires a significantly more aggressive phenotype.

Prostatic Intra-epithelial Neoplasia




Figure 2b. Prostatic Intra-epithelial Neoplasia

Prostatic intraepithelial neoplasia [PIN] is believed to be a precursor of prostate
cancer, given the strong association between high grade PIN and prostatic
adenocarcinoma (300-303). The presence of high grade PIN is often indicative of the
presence of prostate cancer. It has been shown that more than 80 percent of prostates
with adenocarcinoma also contain high-grade PIN (PIN-11 & III). High-grade PIN
has cytologic features resembling cancer and carries many of the genetic alterations
of prostate cancer. The finding of high-grade PIN alone in a biopsy has been cited as
an indication to proceed with repeat biopsies given the high co-frequency between
high-grade PIN and carcinoma. However, in current practice, the predictive value of
PIN in finding cancer on subsequent biopsies has declined, probably due to the
extended biopsy techniques yielding higher rates of initial cancer detection (304). A
diagnosis of PIN by itself is certainly insufficient for a patient to undergo either
radical prostatectomy or radiotherapy.




                                                                                  37
Chapter 10. PROSTATE CANCER


        Atypical prostatic glandular proliferations
        Foci of atypical glands, also labeled atypical small acinar proliferation of uncertain
        significance, have features suspicious for but not diagnostic of cancer. These
        encompass a variety of lesions including benign mimickers of cancer, high-grade
        prostatic intraepithelial neoplasia (PIN), and small foci of carcinoma which, for a
        variety of reasons, cannot be accurately diagnosed. The reported incidence of these
        lesions on prostate needle biopsies is 1.5% to 5.3% (304). Patients with atypical
        glands on needle biopsy have a high risk of harbouring cancer. The reported
        incidence of prostate cancer from repeat biopsies has ranged from 34 to 60%.
        (304-306). Following an atypical diagnosis, biopsies need to be repeated (307).

        H Staging system
        Once a diagnosis of prostate cancer is made, it must be determined whether the
        patient is a candidate for potentially curative treatment (surgery or radiation). This
        depends upon several factors, including general health and projected longevity in
        conjunction with the likelihood that the cancer is still localized within the prostate
        and has not yet metastasized. The most important factor, however, is the patient‟s
        decision after he has considered the „pros and cons‟ of the various choices as they
        relate to him (see below).
        Currently, the TNM system is used for staging, and prostate cancers can be assigned
        both a clinical stage and, should the prostate be removed surgically, a pathologic
        stage. This differentiation is important with the clinical and pathological stage
        designated by the letters „c‟ and „p‟, respectively, preceding the stage denotation (e.g.
        cT2a = clinically, tumour is palpably involving one lobe of the prostate or less).

        Table 6. TNM staging classifications


         Primary Tumour




         Tx                                          Primary tumour cannot be assessed




         T0                                          No evidence of primary tumour




         T1                                          Clinically inapparent tumour           not
                                                     palpable not visible by imaging




         T1a                                         Incidental tumour in < 5% of TUR
                                                     tissue




38
                         Chapter 10. PROSTATE CANCER




Primary Tumour


T1b              Incidental tumour in > 5% of TUR
                 tissue




T1c              Needle biopsy prompted by elevated
                 PSA




T2               Organ confined




T2a              Tumour involves one half of one lobe
                 or less




T2b              Tumour involves more than half of one
                 lobe but not both lobes




T2c              Tumour involves both lobes




T3               Tumour extends beyond the prostatic
                 capsule




T3a              Extracapsular, unilateral and bilateral




T3b              Tumour invades seminal vesicles (s)




T4               Tumour      invades    bladder      neck,
                 sphincter, rectum, pelvic side wall



                                                           39
Chapter 10. PROSTATE CANCER




         Primary Tumour




         Lymph Nodes




         Nx                   Regional nodes were not assessed




         N0                   No regional nodes




         N1                   Regional node metastases




         Distant Metastases




         Mx                   Regional nodes not assessed




         M0                   No Metastases




         M1                   No distant




         M1a                  Non-regional lymph nodes




         M1b                  Bone(s)




         M1c                  Other site(s) with or without bone
                              disease


40
                                                         Chapter 10. PROSTATE CANCER




       Primary Tumour




VII. PROSTATE CANCER TREATMENT OPTIONS
      A. Introduction
      Traditionally, for a man with clinically-localized prostate cancer, there have been
      three treatment options: watchful waiting, radical RRP, and radiotherapy. For
      patients with advanced prostate cancer or for those men with sufficiently serious
      comorbidities such that surgery and radiotherapy are contraindicated, treatment
      options have generally been limited to hormonal ablation or watchful waiting (308,
      309). Over the past few years, chemotherapy and other experimental approaches
      also have been championed for those with advanced disease (310).
      A recent paper by Bill-Axelson et al (2005) (311) is timely in relation to whether
      treatment with curative intent, in particular by RRP, makes a difference to survival.
      From October 1989 to February 1999, these authors recruited 695 men who were
      randomised to RRP or watchful waiting. The updated data from this Scandinavian
      study demonstrates a significant difference in the overall (and not just cancer
      deemed) death rates in favour of RRP with a median of 8.2 years of follow-up;
      83/347 men in the surgery group and 106/348 men assigned to watchful-waiting
      died (P=0.04). (For 30/347 men randomised to surgery (8.6%) and 50/348 men
      assigned to watchful waiting (14.4%), death was attributed to prostate cancer).
      In their interim report, Holmberg et al (2002) (312) revealed the difference between
      their patients and those presenting contemporarily. For those men randomised to
      watchful waiting and RRP, respectively
          1. only 10.9% (38/348) and 12.4% (43/347) had their prostate cancers diagnosed
             through investigations of an abnormal PSA level
          2. 45.4% (158/348) and 50.7% (176/347) of men had serum PSA levels >10.1
             ng/ml at baseline
          3. 29.6% (103/348) and 26.2% (91/347) had Gleason scores of >7
          4. for 9.5% (33/348) and 13.3% (46/347) the diagnosis was made cytologically or
             the biopsy specimen could not be retrieved.
      Nevertheless, the updated 2005 results of this randomised, controlled trial are
      notable in that RRP reduced disease-specific mortality, overall mortality, and the
      risks of metastases and local progression. Although the absolute reduction in the
      risk of death after 10 years was small, the reductions in the risks of metastasis and
      local tumour progression were substantial (311).
      Both RRP and radiotherapy (including brachytherapy) have undergone substantial
      modifications during the past 1-2 decades. Unfortunately, however, both these
      forms of potentially curative treatment continue to have risks of significant
      unwanted effects in subgroups of men (see below). As a result, patients have to
      choose and, in so doing, „trade off‟ the risks of side-effect risks from one form of
      treatment with those from others. Other options, such as cryotherapy and
      High-Intensity Focused Ultrasound (HIFU) do not have sufficiently-established
      track records at this time to be recommended as routine options for localised

                                                                                        41
Chapter 10. PROSTATE CANCER


        prostate cancer, except in research settings. Unwanted consequences of HIFU vary
        considerably with impotence rates 44%-61%, grade 2-3 incontinence 0%-14%, and
        rectal fistulae 0.7%-3.2% (313). Although there have been a significant advancements
        in understanding the mechanisms of cancer cryotherapy for tumour destruction
        with improved delivery methods resulting in more effective local prostate cancer
        control, its most appropriate application is for patients with bulky local disease and
        local recurrence after radiation therapy. These topics have been reviewed recently in
        an excellent supplement of Urology (314, 315).
        http://www.nhmrc.gov.au/publications/_files/cp88.pdf
        http://www.nelh.nhs.uk/guidelinesdb/html/Prostate-ft.htm
        http://www.uroweb.nl/files/uploaded_files/2005ProstateCancer.pdf
        http://www.cancer.gov/cancertopics/understanding-prostate-cancer-treatment/p
        age5

        B. Pre-treatment decision-making
        Making decisions about prostate cancer treatments
        Men who are diagnosed with prostate cancer often find themselves in a situation of
        choosing between unfamiliar and often complex treatment choices, while facing the
        psychological distress of a cancer diagnosis. In this context decision-related distress
        is common and persistent . Population-based studies suggest that the medical
        treatments received by men with localised prostate cancer are influenced by age and
        by socio-economic factors that affect access to medical services. For example,
        assessed 3,073 North American men six months after treatment for localised prostate
        cancer. Conservative management was predicted by later stage disease, physical
        co-morbidity, older age, and being unmarried. As well, radical prostatectomy was
        received more frequently by Hispanics compared with non-Hispanic Caucasians
        and less frequently by men with lower education and income levels.
        utilised cancer registry data about 2,941 patients diagnosed with prostate cancer in
        the Netherlands and found that the presence of co-morbidities such as
        cardiovascular disease or diabetes had little effect on what medical treatments men
        received. Rather, men were more likely to receive radical prostatectomy if they were
        younger, had a small clinically localised tumour that was moderately differentiated
        and when they had been diagnosed in a hospital with a high clinical case load. These
        researchers concluded that treatment was mostly determined by the patient‟s age
        and the extent of the urologist‟s surgical experience. assessed clinical and
        socio-demographic factors to identify predictors of treatment choices amongst 1,809
        North American men, predominantly white middle class and affluent, who were
        diagnosed with prostate cancer as a result of a screening program. Younger age, a
        higher cancer stage and PSA level and being of non African-American race predicted
        receiving curative treatments. Men with normal sexual function were more likely to
        receive watchful waiting whereas men with normal urinary function were more
        likely to receive radical prostatectomy.
        Several studies have found that the clinician‟s recommendation strongly influences
        men‟s treatment choice . As well, lay health beliefs, such as the view that surgery is
        the best way to cure a cancer are a strong influence, with the use of such beliefs
        acting as a short cut to more effortful systematic processing . As one example, found
        only 13% of men made their decision about treatment for localised prostate cancer
        by weighing up the risks and benefits of each different medical treatment. Thus,


42
                                                      Chapter 10. PROSTATE CANCER


there is a need for care to be taken in supporting informed and patient oriented
choice.
In order to support men‟s decision making, as a minimum men should be provided
with evidence-based patient decision support materials to provide them with an
opportunity to become well informed about their treatment options. A recent
Cochrane review provides guidance on acceptable attributes of evidence based
decision aids and some of these can be web accessed ( www.prostatehealth.org.au 10;
www.ohri.ca/decisionaid11). As well, a generic decision aid, the Ottawa Personal
Decision Guide is available that can be adapted for use for most patient populations
(www.ohri.ca/decisionaid). Two of the present authors (SKS and RAG) are
currently validating a revised version of the Ottawa Personal Decision Guide within
a randomised control trial of a multi-component intervention targeted to the specific
challenges men experience in the early diagnostic and treatment phase of prostate
cancer. This approach integrates psychoeducation and decision support in a novel
approach . The psycho-educational component is informed by the stress and coping
model and problem solving therapy . Structured counselling protocols and patient
education materials underpin a telephone based nurse delivered support
intervention that commences at diagnosis and extends 6 to 8 weeks after treatment.
Peer support may also be helpful to men at the time of deciding about treatments.
Peers can provide support from the perspective of shared personal experience . In
this regard, men who have been previously diagnosed with prostate cancer can
provide first hand advice about what it is like to live with the effects of treatments,
practical advice about ways to cope, and ongoing social support. A range of peer
support programs are available world wide, with research suggesting they are
positively received by men . Peer support programs work well when they are
integrated into a broader support framework and are linked to clinicians, and many
are available that do this (table 7).

Table 7. Examples of prostate cancer Specific Peer support programmes


 Group Example                              Website




 Group Example                              Website




 Canadian prostate cancer Network           http://www.cpcn.org/
 (CAN)




 Us Too (US)                                http://www.ustoo.com/




 PSA:     Prostate    cancer     Support    http://www.prostatecancersupport.inf
                                                                                    43
Chapter 10. PROSTATE CANCER




         Group Example                               Website


         Association (UK)                            o/




         Prostate cancer Foundation of Australia     http://www.prostate.org.au/support.
         (AUST)                                      htm




         Prostate Awareness        and    Support    http://www.prostate.org.nz/index.ht
         Society (NZ)                                ml




         The Scottish Association of prostate        http://www.prostatescot.co.uk/
         cancer Support Groups




         Irish Cancer Society: Men against           http://www.cancer.ie/support/mac.p
         cancer                                      hp



        C. Clinical staging
        (i) Clinically insignificant tumours
        Because there was a pronounced increase in the number of men diagnosed with
        prostate cancer following the introduction and widespread use of the PSA blood test,
        concern arose that a proportion of these patients had insignificant disease which did
        not warrant treatment. As a result, Epstein et al (1994) (334) developed criteria to
        identify insignificant prostate cancer. These included a PSA density <0.15, a biopsy
        Gleason score <6, the presence of disease in fewer than 3/6 biopsy cores and <50%
        prostate cancer involvement in each of these cores.
        Bastian et al (2004) (335) reported on the analysis of these criteria in relation to 237
        patients who had RRPs between December 2002 and August 2003. The large
        majority (67%) had only one TRUS biopsy core positive and most (89.9% had
        Gleason 6 in the RRP specimen. However, 9.7% had Gleason 7 or 8 tumours and
        8.4% had non-organ confined disease, illustrating the problem of „undercalling‟
        when relying on biopsy information for stratifying patients into a good prognostic
        group.




44
                                                     Chapter 10. PROSTATE CANCER


(ii) Determining whether the tumour is localised
The presence of any cancer cells outside the prostate locally or at distant sites
following treatment with curative intent, is regarded as a portent for ultimate
treatment failure. The likelihood of cancer becoming evident after prostatectomy
and radiotherapy increases with pathologic stage (336, 337), both these therapies
being potentially curative for men with localized (T1 and T2; N0; M0) prostate
cancer (336-338). Because these treatments are considerable undertakings and may
cause problems in terms of their unwanted effects, it is imperative that, as far as
possible, pre-treatment staging excludes any evidence of locally-advanced or
metastatic disease.
However, the clinical staging of prostate cancer is inexact and this imprecision
continues to be a serious limitation in the overall management of patients with this
malignancy. PSA serology is a poor predictor of pathologic stage and needle
biopsies can misrepresent - usually understate - the volume, histology, and thus the
expected behaviour of a patient‟s tumour (339, 340). In addition, the presence of
extraprostatic extension is easily underappreciated by digital palpation, and
conventional imaging studies can fail to detect metastatic spread (341).
Approximately 25% of men with clinically localised disease experience an early
relapse despite successful treatment of the primary lesion, and up to 50 percent of
men with clinically organ-confined lesions are discovered to be understaged at time
of surgery (15, 342-346).
Cancer cells, particularly in the case of higher grade tumours, are apt to change
phenotype and be motile. Facilitated by enzymic breakdown of the extracellular
matrix, infiltration of motile cancer cells proceeds into extracellular tissues with
intravasation into vascular and lymphatic channels, occurring much earlier than was
appreciated previously. However, the rate-limiting steps in terms of metastasising
are extravasation from the circulation into tissues remote from the primary lesion
and the ability to grow and thrive in these new environments which, for prostate
cancer, are particularly the bone of the axial skeleton and pelvic and retroperitoneal
lymp nodes. A very recent report indicates that bone marrow-derived haemopoietic
progenitor cells expressing vascular endothelial growth factor 1 (VEGFR1) home to
tumour-specific pre-metastatic sites and form clusters, preceding the arrival of
tumour cells. These VEGFR1+ cells also express VLA-4 which binds to fibronectin,
upregulated in resident fibroblasts by tumour-specific growth factors, to provide a
permissive niche for incoming tumour cells. Thus a favourable environment for
secondary tumour cells to become established is pre-arranged even before arrival or
the tumour cells themselves (347).
One important though easily neglected role of clinicians is to inform patients of the
potential that RRP or radiotherapy, including brachytherapy, may not result in cure.
To help with this task, the Partin Tables may be used (248, 260). Initially published in
1993, these were subsequently updated to accommodate an earlier stage of
presentation at diagnosis for the majority of patients (348). The Partin Tables have
been validated by others in multicentre studies ( 349 ) although not all reports have
confirmed an improvement from earlier versions ( 350 ). In addition, Steuber at al
( 2005 ) found that the Partin Tables were less predictive for predominantly
transition zone tumours. They attributed this variance to the different biological
tumour characteristics of transitional zone lesions ( 351 ).
First published in 1993, subsequently modified (352) and validated in a number of
centres (353), nomograms have been created to summarize a multivariate logistic
regression analysis for the prediction of pathologic stage using the combination of
DRE, serum PSA and Gleason score. While these estimations do not predict whether
                                                                                     45
Chapter 10. PROSTATE CANCER


        or not a given patient will be cured with surgery, they do provide an indication of
        likelihood of disease-free recurrence at 5 years. Stratifying patients is often a helpful
        exercise in this regard. The use of nomograms based on age have been extended
        recently to include the use of percentage free PSA for determining the presence of
        prostate cancer ( 354 ).
        Problems with the application of tables and nomogram findings to individual
        patients are that PSA is a labile enzyme with serum levels affected by factors other
        than prostate cancer, TRUS biopsies tend to understate cancer both in terms of the
        extent of tumour and its Gleason score and clinical staging is subjective and
        relatively insensitive. Nevertheless, tables and nomograms based on pre-operative
        findings are useful to a degree. Post-operatively, however, incorporation of more
        definitive and comprehensive parameters obtained from pathology of the RRP
        specimen itself, enable formulation of more predictive nomograms (355).
        A number of studies have stratified patients with respect to likelihood of tumour
        progression with recurrent disease, if it does become evident, likely to do so for the
        first time within 5 years after RRP. Partin et al were the first to develop a simple
        biostatistical model equation which allowed categorisation of cases after RRP into 3
        risk groups reflecting a low, intermediate and high likelihood of PSA recurrence
        (356). After an extensive multifactorial regression analysis, they identified only 3
        variables viz. a sigmoidal transformation of PSA, Gleason sum of the RRP specimen
        and margin status or tumour confinement within the prostate. Other studies have
        confirmed the importance of these parameters and the prognostic value of the
        3-group categorisation approach (357, 358).

        Table. Box 2.


         Stratifying patients: Factors indicating a high likelihood of recurrence
         following treatment with curative intent




         PSA >10 ng/ml




         Gleason grade 4 or 5 pattern on biopsy




         Stage 2b (and higher stage) tumour



        (iii) Methods for Clinical Staging of Prostate cancer
        A combination of the following parameters is used routinely to estimate whether a
        prostate cancer is localized:
            1. clinical stage of the primary tumour (based on digital rectal examination)
            2. PSA serology


46
                                                      Chapter 10. PROSTATE CANCER


    3. the histologic grade of the prostate biopsy/ies (Uropathology expertise is
       essential in this interpretation)
    4. The number of positive cores and percentage involvement by tumour
    5. Imaging studies to identify the presence of metastases

1. Digital rectal examination (DRE)
Digital rectal examination understages organ-confined disease (245, 342-346). In a
published series of 601 men undergoing RRP, of the 565 men with cT2 disease, only
52% had organ-confined tumours (248). By comparison, of 36 men with cT3 disease,
19% had organ-confined lesions. Although there are reports of cure by RRP for cT3
disease, the presence of a bulky extra-prostatic tumour generally indicates a poor
outcome, given the high associated risk of metastatic disease (359, 360). Of particular
importance is palpable disease at the prostatic apex. The presence of a nodule on
digital rectal examination at the apex is often indicative of extraprostatic extension at
that location and tends to foreshadows a positive surgical margin or poorer result
post-radiotherapy (361-363).

2. PSA Serology
As PSA levels increase, the chance of non-localised disease increases accordingly
(247). Partin reported that, for men with PSA <10 ng/ml, 70-80% will have
organ-confined disease. This decreases to approximately 50% for men with PSA >10
ng/ml, and to approximately 25% for men with PSA >50 ng/ml (248). Sanwick et al
(1998) (295) showed that 37.5% of patients with PSA values between 10-15 ng/ml
and all patients with PSA values >15 ng/ml had evidence of extracapsular extension
(295).
Because PSA values vary widely within a given stage and overlap between different
stages, the predictive value of PSA in determining pathologic stage is weak (340).
Even with the combined use of DRE, serum PSA, and TRUS, it is not feasible to
reliably estimate the stage of an individual tumour prior to treatment. However,
after studying the PSA velocity of 1095 men with localized prostate cancer during
the year before diagnosis, D‟Amico et al (2004) (364) concluded that patients whose
PSA levels increase >2.0 ng per ml are particularly at risk of dying from prostate
cancer despite undergoing RRP. Despite initial enthusiasm for RT-PCR molecular
staging assays, at this time there is no indication for their routine use in preoperative
staging (365-367).

3. Histology
Oesterling et al. demonstrated the importance of Gleason grade on prostate needle
biopsies as a predictor of final pathology (368). Gleason score 6 tumours were
associated with a 24% risk of capsular penetration and a 29% probability of positive
surgical margins. This increased to a 62% risk of capsular penetration and a 48%
probability of positive surgical margins for Gleason score 7 cancers, and 85% and
59%, respectively, for Gleason score 8-10. Of 72 men with Gleason sore 8-10 tumors,
Partin et al. noted extraprostatic disease in 92% (248). Furthermore, some
circumspection should be exercised in using biopsy histology for prognosticating
since there is a tendency to under-represent the Gleason score and tumour volume
relative to pathology findings in the whole gland.

4. Tumour Volume from TRUS-guided biopsies
McNeal and associates have demonstrated that tumour volume on prostatectomy
specimens correlates with extracapsular extension (369). However, they found that
                                                                                      47
Chapter 10. PROSTATE CANCER


        an accurate measurement of tumour volume based on biopsy findings is very
        difficult technically. McNeal and Stamey have further proposed that the biological
        aggressiveness of prostate cancer is a direct function of the tumour volume (370).
        Hence, it can be implied that the larger the volume with biopsies, the greater the
        likelihood of extracapsular disease. This relationship has been confirmed in several
        studies which suggest that the tumour extent with prostate biopsies can predict T3
        disease. Using multivariate analysis models, Goto et al., determined that the length
        of cancer in needle biopsies could predict extraprostatic disease, and Sebo et al.
        demonstrated that the percent of needle biopsy cores and the surface area positive
        for cancer were strong predictors of pathologic stage and tumour volume of the
        pathologic specimen (294, 371).

        5. Imaging
        Clinical staging is performed routinely with technetium labelled phosphate
        radio-isotope bone scanning. Sites of increased radio-tracer uptake are those with
        greater metabolic activity, so called „hot-spots‟, and a malignant cause has to be
        differentiated from non-malignant diagnoses such as arthritis and Pagets Disease.
        The predilection for prostate cancer metastases to strongly favour the axial skeleton
        with limb involvement (apart from upper femora) much less common, helps in
        differentiating malignant prostatic from other causes of increased radio-isotope
        activity. Routine bone scanning is usual prior to treatment, irrespective of the
        likelihood or lack of likelihood of metastases being demonstrable, as a bone scan at
        this time serves as a baseline reference for subsequent monitoring.
        CT scanning is not always performed at baseline in men with a prostate cancer
        diagnosis. For detecting soft-tissue metastases, CT is the usual first-line investigation.
        However lymph node deposits need to be >1cm before they are usually regarded as
        pathological with the enlargement presumed to be due to prostate cancer until
        proven otherwise, especially if sited in pelvic and para-aortic regions.
        Magnetic Resonance Imaging (MRI) involving the use of an endorectal coil has been
        promoted to provide an improvement in detection of extracapsular disease but, in
        the overall context of patient assessment, this investigation adds little to clinical
        staging; however, MRI can be helpful in evaluating spinal secondaries, especially in
        relation to possible neural compression. The roles of positron emission tomography
        (PET) and ProstaScint scanning are not well established. A 70-80% sensitivity has
        been cited for ProstaScint in detecting lymph node metastases (372).

        D. Management Options
        Although routine PSA-based detection has increased the percentage of
        newly-diagnosed cases potentially curable by surgery or radiotherapy, a
        considerable proportion of patients are not candidates for such intervention (1).
        Common exclusionary factors include unresectable (locally-advanced) disease, „poor
        tumour pathology‟, the presence of demonstrable metastases and advancing age in
        association with a limited life-expectancy, this last factor begging the question why a
        diagnosis of prostate cancer was sought in the first place. In addition, there are some
        men who refuse therapy altogether for fear of anaesthesia or concerns over risks of
        incontinence and impotence. Because prostate cancer is relatively slowly growing,
        only those men with at least a 10-year life expectancy are usually considered for
        aggressive, potentially-curative treatment.
        Although RRP is not offered to men with cT3 or cT4 disease, radiotherapy, in
        combination with androgen ablation therapy, does have a more recognised role in
        locally advanced disease, especially with neo-adjunctive or adjunctive androgen
48
                                                     Chapter 10. PROSTATE CANCER


suppressive treatment (373-377). Justification may be based on a need to achieve
local control of the cancer, however, a proportion of patients with cT1 or cT2 tumors
that are upstaged to pT3 at time of surgery have been reported to have durable
cancer remissions (336, 378).
For clinically localised disease, there are 3 management options viz. RRP,
radiotherapy in the form of either external beam radiotherapy or brachytherapy and
watchful waiting. The last of these is not synonymous with patient disregard as,
apart from a need for ongoing support and counselling, these men need to be
monitored for disease progression and for potential future therapeutic intervention,
which may include treatment with curative intent.

E. Sexuality and prostate cancer
While most men appear to adjust well psychologically to the experience of prostate
cancer, sexual difficulties are frequently described as a bothersome problem
experienced by men following both surgery and radiation therapy for prostate
cancer . The nature of these difficulties goes beyond the symptom of erectile
dysfunction, although this is the effect most often described in the research
literature.
Physical effects men may experience include:
    1. Erectile dysfunction
    2. penile shortening
    3. loss of sexual desire
    4. less satisfying orgasms, and for a small percentage of men,
    5. painful orgasms .
The inability to achieve a spontaneous erection sufficient for penetrative sex has an
obvious direct impact upon intimate relations. However, this is more than just a
physical consequence, with the domains of quality of life that may be affected by
erectile dysfunction including impaired sexual performance; and changes in
relationships with women, sexual imaginings and masculinity . For example, men
who experience erectile dysfunction after treatment for prostate cancer describe
fears about intimate contact with partners, embarrassment about the failure or
potential failure to obtain an erection, and awkwardness about needing to use
mechanical devices or penile injections within an intimate encounter .
As well, men describe changes in the way they relate to women generally, with
regards to losing the enjoyment of sexual feelings in response to women they find
attractive. This loss of desire and arousal is broader than changes in the men‟s actual
relationships and extends to sexual fantasies and imaginings. Men may experience a
loss of feelings of masculinity and of self worth, as well as embarrassment and loss
of self esteem about other related physical changes such as penile shortening.
Studies suggest that an early return to sexual activity using intracavernous injections,
specifically by three months after surgery, may increase the recovery rate of
spontaneous erections after prostatectomy and improve men‟s responses to erectile
dysfunction treatments . However, problematically, after prostate cancer men may
be reluctant to seek help for sexual difficulties, with studies finding that up to five
years after treatment only about half of men seek medical treatment for erectile
dysfunction . Further, for those men who do seek treatment, improvements in
erectile function are modest. Thus, sexual dysfunction is an ongoing quality of life
problem for many men after being treated for prostate cancer.

                                                                                     49
Chapter 10. PROSTATE CANCER


        Negative attitudes to help seeking for sexual problems are a barrier to men's
        psychosexual adjustment, suggesting a potential role for a counselling intervention .
        In particular, normalising help seeking for sexual problems; setting realistic goals
        and expectations about sexual function after treatment; reinforcing the need for
        flexibility, patience and persistence in managing erectile dysfunction; and
        encouraging and teaching a problem solving approach may be helpful. With regards
        to sources of help for sexual problems, men report a preference for help from their
        urologist or cancer specialist; written information about erectile dysfunction before
        and after treatment and one to one support . Including the man‟s partner in medical
        consultations about sexual problems is also likely to be helpful. Table 8 lists internet
        sites and self help books that may be helpful to patients and clinicians. As well,
        prostate cancer support groups may also be helpful for some men.
        A further approach is the integration of elements of sex therapy, such as sexual
        communication and stimulation, with medical treatments for erectile dysfunction. In
        this regard, a recent pilot of a four session counselling program to enhance sexual
        rehabilitation after treatment for localised prostate cancer produced improved
        sexual satisfaction in both men and their partners at three month follow up, and
        increased utilisation of medical treatments for erectile dysfunction at three and six
        months . Improvements in sexual satisfaction were not maintained at six months.
        Contrary to expectations, the presence of the man‟s partner during the intervention
        did not affect study outcomes. These authors are currently trialling an internet based
        version of this program in order to improve the acceptability of the program to men
        and study generalisability.

        Table 8. Examples of Internet Sites Relating to Prostate cancer and Sexuality


         Internet Sites




         Oncolink has links to chatlines for sexuality and cancer or fertility and cancer, and
         links               to                other               useful                sites.
         http://www.oncolink.upenn.edu/psychosocial/sexuality




         Cancer Source offers interactive            tools   and     community      resources.
         http://www.cancersource.com




         Association of Cancer Online Resources is a cancer online information system that
         offers access to electronic mailing lists and links to other sites.
         http://www.acor.org




         Andrology   Australia   has     resources           about    sexual     dysfunction.
         http://www.andrologyaustralia.org


50
                                                          Chapter 10. PROSTATE CANCER




       The Lions Prostate cancer Website has information on prostate cancertreatment
       and support groups, links t other sites, as well as an email advisory service.
       http://www.prostatehealth.org.au




       Books




       Sexuality and Fertility after Cancer by Leslie R. Schover, Ph.D., John Wiley &
       Sons, 1997. A how-to and educational book for all types of cancer.


       Sexuality & Cancer: For the Man Who Has Cancer and His Partner, prepared for
       the American Cancer Society by Leslie R. Schover, Ph.D. Large booklet available
       free of charge from ACS website and offices.


       His Prostate and Me: A Couple Deals with Prostate cancer by Desiree Lyon Howe,
       Winedale Publishing Company, 2002. A woman‟s perspective of coping as a
       couple with prostate cancer.


       Making Love Again:Hope for Couples Facing Loss of Sexual Intimacy, by Virginia
       and Keith Laken, Ant Hill Press, 2002. An unusually open, emotional account of
       one couple‟s struggle to get their sex life back to normal after radical
       prostatectomy.


       The Lovin‟ Ain‟t Over, The Couples guide to Better Sex after Prostate Disease by
       Ralph and Barbara Alterowitz, Health Education Literary Publisher, Westbury,
       NY.




       Acknowledgment: We are grateful to Professor Lesley Schover for assistance in
       compiling this table



VIII. RADICAL RETROPUBIC PROSTATECTOMY (RRP)
      There are two traditional approaches to the prostate for its total removal, retropubic
      and perineal. Throughout the world, the large majority of total (or so-called radical)
      prostatectomies are undertaken by the retropubic route with perineal prostatectomy
      performed by only a small number of urologists. The procedure of perineal
      prostatectomy is suited particularly to the removal of smaller prostates.



                                                                                         51
Chapter 10. PROSTATE CANCER


        Contemporary surgical management of prostate cancer has been shaped by two
        seminal events, development of the anatomic RRP by Walsh (393) and application of
        serum PSA as a means for early detection, resulting in many more young men being
        diagnosed with this condition than ever before. Consequently, there has been a
        concerted effort to improve long-term cancer control together with preservation of
        urinary and sexual function. Description of the anatomic RRP has improved
        understanding of prostatic and pelvic anatomy and of the structures involved in
        maintaining urinary continence and erectile function. As a result, more patients are
        cured of their cancers today and are satisfied with their quality of life
        post-prostatectomy, than ever before (394, 395).
        The modern RRP evolved from a succession of anatomic dissections and
        modifications to historical techniques (396, 397). The legacy of the anatomic RRP
        which permits preservation of the neurovascular bundle with maintenance of
        erections for many, better sphincter preservation with improved continence rates
        and more effective management of the dorsal vein complex resulting in less blood
        loss, has paved the way for not only faster and less morbid recovery (338) but also
        the newer adaptions of laparoscopic and robotic forms of RRP.

        A. Preoperative Consultation and Care
        In addition to having pathology and staging details reviewed together with their
        overall medical status, it is usual to provide candidates for RRP with detailed
        printed information and, as a routine, have concerns and questions addressed
        pre-operatively. Blood may be taken in advance to be used as needed
        peri-operatively as an autologous transfusion. It is standard procedure for
        compression stockings to be fitted immediately before surgery with intermittent calf
        compression applied throughout and after the operation, as part of the prophylaxis
        against deep venous thrombosis. Since the small risk of peri-operative mortality
        (usually <0.5%) is mostly due to cardiovascular/respiratory complications, some
        surgeons insist on having all candidates for RRP evaluated with stress testing by
        cardiovascular physicians.

        Delayed commencement of treatment
        In terms of timing, it is not uncommon for surgery to be delayed 6 weeks after TRUS
        biopsies to permit resolution of biopsy-induced inflammation. Patients often are
        concerned that a delay in treatment is deleterious to the likelihood of the surgery
        being curative.
        Graefen et al (2005) (398) analysed data from 795 patients with clinically localized
        prostate cancer who underwent RRP between January 1992 and June 2000 in relation
        to the time from biopsy to the date of RRP as a potential prognostic factor. For a
        mean follow-up of 33 months (1-116 months), 25% of the patients failed on the basis
        of a postoperative PSA level >0.1 ng/ml. They concluded that a treatment delay in
        the investigated time span of a few months did not adversely affect recurrence free
        survival rates and recommended that patients can be reassured that they can
        evaluate their management options without compromising efficacy due to a delay in
        initiation of treatment (398). Boorjian et al (2005 (399) reviewed 3,969 consecutive
        patients who underwent RRP for clinically localised cancer within one year of
        diagnosis. They reported that the time from biopsies to surgery did not influence the
        probability of biochemical recurrence, even for those considered to be at high risk of
        biochemical recurrence. The clinical and pathological features and not the delay
        were the important factors for estimating risk of biochemical recurrence (399).


52
                                                      Chapter 10. PROSTATE CANCER


B. Operative Technique
Most RRPs are performed under regional (epidural) or general anesthesia.
Advantages of the epidural approach include diminished blood loss, decreased
incidence of pulmonary embolus and improved post-operative analgesia. (400-402).
If general anaesthesia is used, post-operative analgesia is usually delivered
parenterally for at least 24 hours, often via patient controlled analgesia.
Subsequently, oral analgesics such as NSAIDs are used as indicated.
Commonly, a Pfannenstiel or a midline incision is made from the umbilicus to the
pubis and continued through to the space of Retzius. The peritoneum is mobilized
superiorly, enabling the surgery to be undertaken extraperitoneally. A
lymphadenectomy is performed, if indicated (see below). The principles and
techniques of the anatomic RRP (393) constitute the basis for the operative
procedure with various modifications such as bladder neck preservation having
been incorporated and used by some urologists. The entire operation is performed
under complete visualization with meticulous dissection in a relatively bloodless
field, to facilitate optimal cancer control, maximize post-operative continence and, if
nerve-sparing is attempted, retain potency. When the specimen is removed, it is
examined intraoperatively to ensure completeness of the resection and exclude any
evidence of grossly positive margins or violation of the prostatic capsule. An
indwelling urethral catheter is left for 1-2 weeks to maximize optimal healing of the
vesicourethral anastomosis. A drain is placed near the anastomosis site: it is usually
left in position for several days.

C Nerve-sparing prostatectomy
Sexual function is important in middle aged and older men (403,404) as well as their
partners. Helgason et al (1996) (403) reported physiological potency for 435
randomly selected Swedish men aged 50-59, 60-69 and 70-80 years to be 97%, 76%
and 51%, respectively. Blanker et al (2001) (404) confirmed this finding in data
collected from 1688 men with the prevalence of significant dysfunction ranging from
3% in 50-54 year olds to 26% in males between 70-78 years. Consequently, it is not
surprising that potency problems rate highly as an important consideration not only
in deciding whether or not to proceed to active treatment but in determining which
treatment to pursue. The importance of sexual function as a consideration is
illustrated by Singer et al (2001)(405) who reported that men undergoing treatment
for prostate cancer were willing to exchange an approximate 20% chance of being
cured of their cancers for an increased prospect of remaining potent after treatment
(405).
Consequently for many patients, the emphasis of RRP is no longer focused solely on
cancer control, but extends to include lifestyle issues (394, 395, 406,407). This is not a
dissimilar paradigm shift to that which has occurred with breast cancer treatment, as
sexuality issues have taken a prominent role influencing treatment decisions with
radical and partial mastectomies replaced by combination lumpectomy and
adjuvant therapy.
Potency and continence rates associated with nerve-sparing surgery vary among
surgeons and academic centres (see Table 9). It is fair to say that a degree of
scepticism is expressed regarding some of the claims made in respect to
post-operative potency, in particular. However, explanations for inconsistencies in
cited results include differences in surgical skill, patient selection and outcome
measurement methodology. Among these, patient selection ranks particularly
highly. Nonetheless, it is undisputed that increasing numbers of patients are

                                                                                       53
Chapter 10. PROSTATE CANCER


        sexually potent after surgery, albeit with the use of the phosphodiesterase inhibiting
        drugs (Viagra™, Cialis™ and Levitra™), as a result of the modifications
        incorporated into the technique of anatomic nerve-sparing RRP.

        Table 9. Potency rates after nerve-sparing radical prostatectomy


         Study                                      Potency Rate




         Jonler, et al (1994) (408)                 9%




         Fowler, et al (1993) (409)                 11%




         Heathcote, et al (1998) (410)              12%




         Ojdeby, et al (1996) (411)                 14%




         Gaylis, et al (1998) (412)                 18%




         Talcott, et al (1997) (413)                21%




         Sole-Balcells, et al (1992) (414)          39%




         Davidson, et al (1996) (415)               43%




         Ritchie, et al (1989) (416)                45%




         Catalona, et al (1999) (417)               67%


54
                                                      Chapter 10. PROSTATE CANCER




 Study                                        Potency Rate




 Quinlan, et al (1991) (418)                  68%




 Leandri, et al (1992) (419)                  71%




 Noh, et al (2005) (420)                      72%




 Walsh, (2000) (421)                          86%



Although definitions for above parameters vary, quality of life studies indicate that
the majority of patients are satisfied with the outcomes of their surgery (394, 395, 406,
407). Link et al (2005) (422) reported their experience with laparoscopic RRP using
the validated EPIC and a 5-item International Index of Erectile Function
questionnaires; 78.9% of men who were previously potent were having sexual
intercourse, albeit with the use of phosphodiesterase inhibitors in most instances, 12
months following surgery. Sexual bother decreased to 64% of baseline at 3 months
and did not show any significant improvement subsequently. By contrast, the sexual
function sub-domain, which refects erectile performance better, decreased to a mean
of 36% at 3 months but showed improvement subsequently to 51% of baseline at 6
months and 64% of baseline at 12 months. Recovery of sexual function was not
significantly affected by age or pre-operative potency status, although the extent of
nerve sparing was a significant predictor of outcome (422).

(i) Anatomical Considerations of Nerve-sparing Surgery
Normal post-prostatectomy erectile function depends upon preservation of the
autonomic cavernous nerves, located within the neurovascular bundles of the penis.
These nerves are located immediately posterolateral to the prostatic capsule, within
the periprostatic fascia at the junction of the lateral and posterior portions of the
endopelvic fascia. At this position, the lateral pelvic fascia is comprised of two layers,
the levator and the prostatic fascia. The neurovascular bundles pass between these
layers bilaterally and can be preserved by entering the periprostatic fascia laterally
and gently and meticulously dissecting them off the prostatic fascia.
If both neurovascular bundles are preserved, potency (defined as the ability to
sustain sufficient erections for sexual intercourse without any aids other than
phosphodiesterase inhibitors) can be as high as 68- 86% (338, 417). When only one
bundle is saved, potency rates diminish substantially (423). Given the importance of
sexual function to many men with prostate cancer and the differences when only
one bundle is spared instead of two, it is common practice for every effort to be

                                                                                      55
Chapter 10. PROSTATE CANCER


        made to preserve both neurovascular bundles whenever possible, as long as the
        potential of cure is not considered to be jeopardized – consistent with the wishes of
        the patient.

        (ii) Effect of Nerve-Sparing Surgery on Cancer Control
        The neurovascular bundles are mostly located outside of the prostatic capsule so,
        unless dissection violates the capsule, nerve-sparing radical prostatectomy should
        not compromise surgical cancer control if the tumour is organ-confined. Epstein et al
        followed patients with positive surgical margins present only in the posterolateral
        region and determined that post-prostatectomy relapse was uncommon (424). In this
        study, of 507 men with cT1 and cT2 tumours, the most common sites of positive
        margins were distal (22%), posterior (17%), and posterolateral (14%). Rosen
        confirmed these findings in 144 men undergoing radical prostatectomy (425). They
        demonstrated that, when positive margins were present, <10% had involvement in
        the region of the neurovascular bundles. Hence, in cases of extraprostatic extension,
        involvement of the posterolateral margin is less common than for other locations.
        Epstein also examined paired specimens from men with prostate tumors highly
        suspicious for posterolateral involvement who underwent nerve-sparing
        prostatectomy followed by excision of the neurovascular bundles on the suspect side
        (423). Cancer was found in the bundles in only 17.5% of the men. In men with
        clinically-suspicious but pathologically negative posterolateral margins, no tumour
        was found in the resected bundles.

        (iii) Sural nerve grafting
        In order to attempt to maximise preservation of the neurovascular bundles, technical
        modifications to RRP have been reported; many of these involve methods which
        improve visualisaton of the neurovascular bundles (420, 426, 427, 428). The potential
        problem of impotence, when preservation of the neurovascular bundle is not
        considered appropriate, has been addressed by sural nerve grafting, employing
        techniques established in the management of facial and peripheral nerve injuries
        (429, 430). Although this approach has met with a mixed reception by urologists,
        claimed success rates vary with one study having reported return of erectile activity
        in 75% of men with maximum return of function 14-18 months post-RRP (431).
        However, most Urologists cite much lower success rates.

        (iv) Laparoscopic and Robotic prostatectomy
        As expected, the recently introduced techniques of laparoscopic and robotic
        prostatectomy differ from open radical prostatectomy in that they have incorporated
        some adaptations for practical reasons. However, the principles of the prostatic
        cancer surgery remain the same and results to date are comparable (426, 432).
        Keyhole approaches are attractive to patients because of perceptions of reduced
        surgical trauma and morbidity with, by extrapolation, less post-operative pain -
        even though this is uncommonly problematic with the open approach. A recently
        reported prospective study of robot assisted laparoscopic prostatectomy (n = 159) is
        illustrative in that it did not provide a clinically meaningful decrease in
        post-operative pain compared with RRP (n = 154), which the authors ascribed
        primarily to the low pain scores reported in both groups. They concluded that
        outcomes other than pain will ultimately determine the role of laparoscopic radical
        prostatectomy and Robot assisted laparoscopic prostatectomy (433).
        Conceptually, better vision is afforded the surgeon with forms of endoscopic
        surgery to permit easier identification of structures, particularly apically (434, 435),
56
                                                      Chapter 10. PROSTATE CANCER


but there is the potential problem of delay if (the infrequent) conversion to an open
procedure is required in the event of bleeding. Unlike laparoscopic surgery,
robotically-performed procedures involve hand-eye coordination and hand
positions which are more akin to those used in open surgery; in addition, the
learning period appears to be shorter (436). Although the capital costs associated
with robotic surgery are, at present, very large, these are likely to decrease with time.

D. Pelvic Lymphadenectomy
Following bone, the pelvic lymph nodes are the second most common site of
prostate cancer metastases (437). While radionuclide bone scans provide a sensitive
method for evaluating skeletal lesions, the sensitivity of CT scans to delineate lymph
node metastases is poor (48, 49, 438). Pelvic lymphadenectomy prior to RRP to detect
metastatic lymphatic involvement is limited to patients at high risk for tumour cell
dissemination, then only proceeding to RRP if the lymph nodes are free of tumour.
In the PSA-era of the past 15 years, the rate of positive lymph nodes in patients
undergoing RRP has plummeted from approximately 25-30% to under 5% (439-442).
Consequently, there has been considerable debate regarding which patients should
have lymph node dissections. It is generally accepted that men with Gleason scores
< 7 and PSA values <10 ng/ml do not require pelvic lymphadenectomy (424). Some
investigators have increased these limits to include PSA values from 10-20 ng/ml
and Gleason 7 tumours (443).
The presence of a positive lymph node is a predictor of post-operative recurrence.
Most studies demonstrate that such foci of cancer herald subsequent curative
treatment failure: 10-year biochemical disease-free survival rates are low (361, 444).
In a study designed to determine if early versus delayed hormonal ablation therapy
in men with lymph node positive disease was advantageous, Messing et al (1999)
(445) reported on 51 men with lymph node positive disease who were randomized
to delayed therapy. At an average follow-up of 7 years, 16 percent had no
biochemical or clinical evidence of disease and were never started on androgen
ablation (445).
Pelvic lymphadenopathy can be performed as a separate procedure through a
"mini-laparotomy" or by laparoscopy, or can be combined with RRP (446). All nodal
tissue medial to the external iliac artery, from the junction of the external iliac and
hypogastric arteries to the obturator foramen is removed with this procedure. It is
then sent for frozen section histologic analysis. If lymphadenectomy is performed
prior to a planned RRP and the frozen section report indicates that there is no cancer
evident, it is usual to proceed with the prostatectomy. If there are tumour cells
present in the specimen, the planned RRP is almost always aborted.
Complications of pelvic lymphadenectomy are infrequent (415, 447-450). Injury to
the obturator nerve can occur in 1% of patients causing an inability to adduct the
thigh. If complete transection occurs, primary anastomosis can be performed.
Bleeding from obturator and iliac vessels is uncommon as are ureteric injuries. A
lymphocele may form in the pelvis which can become symptomatic and require
sclerosis or formal drainage into the peritoneal cavity. (451).




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IX. RESULTS OF RADICAL RETROPUBIC PROSTATECTOMY
        A. Disease-free Recurrence and Survival
        (i) Pre-operative PSA
        The results of published series vary but, depending very much on the cases selected,
        survival rates at 10 years have been reported to exceed 90% (338, 452, 453) with a
        comparable percentage of continent and many men potent post-operatively (338).
        Lower preoperative PSA, pathologic stage, and Gleason grade are associated with
        high rates of cure after RRP. For patients with preoperative PSA values <10 ng/ml,
        Catalona demonstrated that 7-year disease-free survival was 76-93% (417). If PSA
        was >10 ng/ml, disease-free survival decreased to 51%. Similar results have been
        shown by others (247, 454, 455).

        (ii) Stage & Grade
        Not unexpectedly, the probability of cure is considerably greater for patients with
        localized, non-palpable, and well to moderately differentiated tumors. The risk of
        treatment failure rises in relation to increases in clinical and pathological stage and
        correlates with increasingly aggressive histologic patterns. Survival rates has been
        reported to decrease with increasing pathologic stage, from 81% for pT2 lesions, 76%
        for pT3 tumors and 19% for N(+) disease. As indicated above, survival rates also
        vary with grade. In a multi-institutional study, Gerber et al (1996) (456)
        demonstrated that 10 year progression-free rates correlated with grade with 87% of
        low-grade tumors, 68% of moderate and 52% of high-grade cancers progressing,
        with other authors reporting comparable results (339, 340, 455-457).

        (iii) Positive margins
        A positive surgical margins is present if the tumour extends to the edge of the
        specimen. Patients with positive surgical margins, whether surgically induced or not,
        have approximately a 2 fold higher recurrence rate compared with patients with
        negative margins. The progression-free probability at 5 years for men with negative
        margins at RRP has been reported to be ~80% compared with 42-64% for men with
        positive margins (297, 458)

        (iv) Molecular markers
        A number of molecular markers have been evaluated for their prognostic value but
        none has been adopted for routine use in practice. Amongst others, the potential of
        CD151, c-myc and calveolin-1 overexpression in predicting outcome has been
        discussed earlier in this chapter. Overexpression of p21 protein has been reported to
        be a predictor of response to salvage radiotherapy after RRP (459) and Fizazi et al
        (2002) (460) correlated p21 expression with progression to androgen independence.
        In addition, expression of p53 and the combined loss of PTEN and p27 have been
        shown to be predictive in the identification of the likelihood of disease recurrence
        (461, 462). Fradet et al (2004) (463) demonstrated that expression of NF-κB in prostate
        cancer cells at the sites of positive margins was highly indicative of biochemical recurrence
        (463).

        (v) Lymph node & seminal vesicle involvement
        Although clearly in the minority, some men with microscopic N(+) disease have undetectable
        PSA levels at 5-10 years. Progression in N(+) disease appears to be related to the volume of
        tumour in the lymph nodes. As well, not all men with seminal vesicle involvement have poor
        outcomes (464).
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Despite the observation that seminal vesicle and lymph node involvement are associated with
poor results post-prostatectomy, in the Catalona series, at seven years the disease-free survival
rates were 26% for men with seminal vesicle involvement and 9% for men with N(+) disease
(337). There also appears to be a difference if seminal vesicle involvement is a direct
extension from the primary tumour, in which case it behaves more like an extracapsular
extension rather than a separate metastatic focus which implies systemic involvement.

(vi) PSA monitoring
PSA serology is very useful in monitoring for disease recurrence post-RRP. If all cancer tissue
is removed, PSA values should drop to the undetectable range (between 0-0.02 ng/ml).
Understandably, patients become strongly focussed on their post-operative PSA values with
raised levels following RRP indicating persisting prostatic tissue at a distant and/or local site
(444, 452, 465). Most PSA recurrences occur in the first few years after surgery and precede
clinical evidence of disease by as much as 5 years. It is rare for the PSA to become detectable
after levels have been undetectable for 5 years. The rate of PSA doubling time is an important
predictor of poor prognosis (452, 466, 467).

Biochemical Recurrence (BCR)/Biochemical(PSA) Failure (BF)
Using the definition of PSA failure of the American Society of Therapeutic Radiation and
Oncology‟s (ASTRO‟s) 1996 consensus statement (ie 3 consecutively rising PSA values,
each obtained at least 3 months apart), D‟Amico et al analysed 888 patients followed for a
median time of 38 months (8-100) after RRP. Based on the medical literature, they established
3 groups using known prognostic factors (viz. PSA level, biopsy Gleason score and the
American Joint Commission on Cancer [AJCC] staging system). Over 95% of the PSA
failures were evident for the intermediate and high-risk groups by 4 years. Questioning the
ASTRO guidelines, Amling et al reviewed 2,782 RPP patients followed for a median of 6.3
years. After examining four points of “PSA cut-off”, these authors concluded that a
PSA >0.4ng/ml was most appropriate since a significant number of patients with a lower PSA
do not continue to increase or proceed to demonstrable metastases (468).
Freedland et al (2003) (469) undertook a retrospective review of 358 men who underwent
RRP between 1991 and 2001 to determine the most relevant cutpoint for determining
biochemical recurrence. For patients with a detectable postoperative PSA value from 0.11 to
0.2 ng/ml, the 1 and 3-year risk of PSA progression was 64% and 93%, respectively. For men
with a PSA value from 0.21-0.3 ng/ml, the 1 and 3-year risk of PSA progression was 86% and
100%, respectively. The 5-year risk of PSA recurrence using a greater than 0.1 ng/ml cutpoint
resulted in a 43% risk of recurrence compared with only 23% for a greater than 0.5 ng/mL
cutpoint (469). Contemporarily, it has become common practice to regard a PSA of >0.2ng/ml
as the cutpoint to indicate BCR.
Reporting on 213 men who had biochemical failure on the basis of a PSA of >0.2 ng/ml
following RRP for a mean follow-up of 56 months (range 1 to 125), 99 of whom were treated
with androgen ablation and/or radiation therapy at the time of detection of BF, Jhaveri et al
(1999) (470) cited 10-year overall survival rates of 88% compared with 93% for those who
did not have BF. They found no difference in survival rates in relation to age (>65 years),
preoperative PSA >10 ng/ml, biopsy or specimen Gleason score >7, clinical Stage including
the presence of extracapsular extension, positive surgical margins, and seminal vesicle
invasion. (470).

(vii) Prognosis
Pound et al (1999) (452) reported in a retrospective study on the fate of 304 men with
biochemical escape (PSA >0.2 ng/ml) following RRP, 103 of whom progressed to metastatic
disease, not having had androgen suppressive therapy. The median actuarial time to
metastases was 8 years from the time of PSA elevation and once patients developed
metastases, the median actuarial time to death was 5 years. The time interval from surgery to
the appearance of metastatic disease was predictive of the time until death (452).


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        However, it is clear that BCR in itself is not a predictor of imminent demise from prostate
        cancer and, as alluded to above, PSA doubling time (PSADT) is becoming accepted
        increasingly as a preferred prognostic indicator (471). Albertsen et al (2004) reported that men
        who had a PSADT of <1 year had a high risk of dying of prostate cancer within 10 years of
        diagnosis, and conversely (472). D‟Amico et al (2003) (473) examined the results of men who
        experienced BCR subsequent to RRP and radiation therapy. From their analyses of 5,918 men
        following RRP and 2,751 patients after radiation therapy, they concluded that a PSADT of
        <3months met the criteria of surrogacy in predicting death from prostate cancer at a median
        survival time of 6 years (473).

X. COMPLICATIONS OF RADICAL RETROPUBIC PROSTATECTOMY
        A. Incontinence
        Table 10. Continence rates after radical retropubic prostatectomy


         Study                           Percent Continent               Average Post-operative
                                                                         Length of Time to
                                                                         Regain Continence




         Shelfo et al (474)              88%                             6 months




         Lowe (475)                      85 to 100%                      12 months




         Goluboff et al (476)            92%                             6 months




         Catalona et al (417)            92%                             18 months




         Kaye et al (477)                93%                             2 months




         Walsh et al (421)               93%                             18 months




         Seaman et al (478)              97%                             6 months




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 Study                       Percent Continent            Average Post-operative
                                                          Length of Time to
                                                          Regain Continence


 Poore et al (479)           100%                         12 months



Continence rates from several institutions are represented in the table (above). In
general, >90% of patients are continent by their reckoning at 12 months. Most men
report little bother from urinary symptoms after RRP with socially acceptable
continence achieved usually within 3-6 months of surgery, although, for some
patients, regaining control can take up to 18 to 24 months. Factors influencing
continence include maintaining the integrity of periurethral support, the precision of
the vesicourethral anastomosis, patient age and co-morbidities, including
pre-prostatectomy detrusor dysfunction which may persist post-operatively. Return
of urinary control is considered to take longer in men over 65 years. Patients with
atherosclerotic and diabetic vasculopathy are more prone to prolonged incontinence,
probably the result of poor vascularization and healing of the periurethral and
sphincteric tissues. Biofeedback and Kegel exercises have been reported to hasten
the return of urinary control (480). If urinary control does not return, and the
incontinence is demonstrated to be sphincter failure by urodynamics investigations,
an artificial urinary sphincter may resolve the problem (481).
Bladder neck contractures occur in less than 10% of patients and can cause
symptoms ranging from poor urinary flow to complete incontinence (482, 483).
Bladder neck contractures can result from non-mucosa-to-mucosal anastomosis,
following heavy intraoperative bleeding and after prolonged urinary extravasation,
with a previous transurethral resection of the prostate possibly predisposing to this
problem. Treatment can consist of simple dilatation, although surgical incision of the
scarred tissue is usually performed. Urethral stricturing can also require dilatation
and/or incision with formal urethroplasty rarely warranted.

B. Impotence (& sexual dysfunction – see section VII. E)
Spontaneous post-prostatectomy erectile function depends upon preservation of at
least one neurovascular bundle. While surgical skill is an important factor in the
successful outcome of nerve-sparing prostatectomy, patient selection is paramount.
Younger men (<60-65 years old) with small, non-palpable, and low-grade tumours
have the best outcomes (421). Phosphodiesterase inhibitors (e.g.sildenafil/Viagra™,
tadalafil/Cialis™, vardenafil/Levitra™), intracorporeal injection of vasoactive
drugs such as prostaglandin E1 or Alprostadil, transurethral vasodilators
(medicated urethral system for erection [MUSE]) and vacuum constriction devices
(VCD) all have a role in erectile rehabilitation (484, 485). Although patients clearly
prefer oral medications (391), these may be less effective in the short term,
particularly if temporary neurovascular damage (neuropraxia) is present following
RRP (485) as well as following external beam radiotherapy, (389).
The results of the various treatment approaches were reviewed recently by Raina et
al (2005) (485). They reported that VCD efficacy rates range from 60-80% with
compliance at 12 months between 50% and 70%. Tightness or pain from the
constriction ring and decreased sensation of the penis, in particular the glans, were

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        common causes for noncomliance. Approximately 50% of men were afforded benefit
        from MUSE using Alprostadil with some non-nerve sparing RRP patients also able
        to achieve tumescence satisfactory for vaginal penetration. In addition to not
        achieving satisfactory penile tumescence, urethral pain and burning were cited
        causes for discontinuation. Intracorporeal penile injection therapy with PGE1 or
        Alprostadil is claimed to provide adequate rigidity in >75% of patients but ~50% of
        men do not continue with the treatment long-term. In addition to a lack of success
        with the technique, physical and emotional problems in addition to pain with with
        the injection were promoted as reasons for discontinuation. Penile fibrosis is
        reported to occur in up to 15% of men (485).
        Avoidance of penile hypoxia through regular tissue oxygenation via erections is
        considered to lessen the likelihood of lacunar fibrosis and, ultimately, erectile
        incapacity. Thus, there is a vogue currently to advocate a return to penile tumesence
        with the early commencement of one or a combination of the above treatments
        following RRP. Not unexpectedly, the use of oral phospodiesterase inhibiting drugs
        is most popular in this regard but, especially in the early post-operative period,
        other methods may be more effective. Despite high (>75%) efficacy and satisfaction
        rates, penile implant surgery is restricted to only those men with persisting erectile
        failure after having exhausted all less invasive options and all hope of spontaneous
        erectile recovery (485, 486).

        C. Bleeding
        The anatomic approach to RRP has improved awareness of, and abilities to control,
        the venous plexuses surrounding the prostate. Consequently, massive blood loss is
        rare. nevertheless, during nerve-sparing surgery it is not uncommon for 600-1200
        mL of blood to be lost. Many patients are encouraged to donate autologous blood
        preoperatively in case a transfusion is required intraoperatively or in the immediate
        post-operative period. The need for transfusion may be lessened by the use of a
        „cell-saver‟ during the operative procedure.

        D. Infection
        Despite using an iodine or alcohol-based skin preparation preoperatively, any time a
        skin incision is made there is the risk of both local and systemic infection. For this
        reason, it is usual to administer antibacterial drugs prophylactically. During RRP,
        the bladder is opened and, inevitably, urine spills into the surgical field. Several
        strategies can be used to diminish the risk of infection. Preoperative urinalysis and
        urine cultures identify patients with potential urinary tract infections which can be
        treated. After the vesicourethral anastomosis is completed, lavaging the pelvis with
        saline may help and post-operative drainage as a routine decreases the likelihood of
        localised sepsis occurring.

        E. Visceral Injuries
        Rectal injuries occur in under 1% of RRPs and may be more likely subsequent to
        previous rectal surgery or pelvic irradiation (415, 448, 482). If a rectal injury does
        occur, it can be repaired easily in most instances by oversewing the rectal wall. It is
        for this reason that some surgeons suggest that all patients are given a bowel
        preparation prior to surgery, to minimise wound contamination and lessen the need
        for a covering colostomy should an injury occur. Although extremely rare, ureteric
        injuries can happen during transection of the bladder neck and dissection of the
        seminal vesicles. Correction usually consists of a ureteroneocystotomy with
        insertion of a ureteric stent.

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     F. Deep vein thrombosis, pulmonary embolus & other problems
     Deep vein thrombosis and pulmonary embolus are diagnosed in approximately 1%
     of men having a RRP (415, 448, 482, 487). Their probability can be reduced by
     ensuring adequate hydration peri-operatively, using elastic compression stockings
     with sequential compression applied during and after surrgery and encouraging
     early ambulation. Subcutaneous heparin or clexane is also commonly used.
     All peri-operative complications are increased in patients with conditions
     characterised by impaired healing or reduced pelvic tissue vascularity (482). Thus,
     prior pelvic radiation, previous rectal surgery, inflammatory bowel disease, past
     procedures on the prostate, urethra, or bladder, diabetes mellitus, and
     vasculopathies can contribute to prolonged incontinence, impotence, hemorrhage,
     infection, and visceral injuries. In addition, co-morbid cardiac and respiratory
     conditions can contribute to perioperative morbidity and mortality.

XI. TREATMENT OF POST-PROSTATECTOMY RECURRENCES
     Overall, approximately 35% of men undergoing RRP will have a recurrence of their
     prostate cancer within 5 to 10 years (342-346). The following preoperative findings
     are associated with a high risk of surgical failure: cT3 lesions, cT1 or cT2 tumors
     with >Gleason grade 4 number on prostate biopsy, and serum PSA >10 ng/ml.
     Additional risk factors for recurrence after attempted definitive therapy include
     such additional pathologic determinants as tumor volume, vascular invasion,
     seminal vesicle or lymph node involvement, and positive surgical margins. The
     location of the positive margin can influence the likelihood of tumor recurrence and
     must be taken into consideration (292).
     The use of post-operative radiotherapy has been the focus of extensive investigation
     in recent years, including both retrospective and randomised prospective studies.
     The use of radiotherapy post-RRP can be with either adjuvant or salvage intent.
     Adjuvant radiotherapy is that used immediately post-operatively, in the aim of
     eliminating potential but as yet unidentifiable residual disease. Salvage therapy is
     conducted when recurrence is suspected - typically when a PSA rise is seen -
     although the immediate use of radiotherapy when an undetectable post-RRP PSA is
     not returned may also be regarded in this category.

     Adjuvant radiotherapy
     A number of retrospective comparative series have examined the potential benefit to
     adjuvant radiotherapy. Unselected series have suggested biochemical control rates
     in the combined surgery plus adjuvant radiotherapy cases of 52-93% compared to
     surgery only rates of 25-74% (488-492). More concordant results were seen in two
     published matched pair analyses which showed surgery only freedom from
     biochemical failure (FFbF) of 55-59% which was increased to 88-89% with the
     addition of radiotherapy (493, 494).
     Three randomised studies of adjuvant therapy have now been announced in abstract
     or publication form. These trials have focused on a subset of men at high risk of
     having residual disease with inclusion requiring either pathologically involved
     surgical margins or pathological stage T3 disease. The EORTC 22911 trial (495)
     randomised 1005 such patients to observation or post-RRP radiotherapy (60Gy)
     from 1992-2001. 30% of these had a detectable post-operative PSA. At a median
     follow-up of 5 years, biochemical progression-free survival was significantly
     improved in the irradiated arm (74.0% versus 52.6%; hazard ratio 0.48 [95% CI
     0.37-0.62]). Clinical progression and loco-regional failure were also significantly
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Chapter 10. PROSTATE CANCER


        improved. Too few death events have been recorded as yet to show a difference,
        although approximately twice as many deaths from prostate cancer had occurred in
        the observation arm compared with the irradiated. Grade 3 toxicity was uncommon,
        and not significantly different between the treatment arms (4.2% and 2.6%
        cumulative incidence rate at 5 years for the radiotherapy and observed arms
        respectively). In a detailed companion study, urinary incontinence (as defined by
        patient reported questionnaires and pad weight measurements) was found to not be
        increased by the addition of radiotherapy (496).
        Two additional similar randomised studies have been presented in abstract form to
        date. The German Cancer Society trial (ARO 96-02 / AUO AP 0995) was designed to
        asses to impact of adjuvant radiotherapy in those with pT3 disease or positive
        margins who achieved an undetectable PSA post-RRP (497). With a median
        follow-up of over 3 years, the results from 261 patients showed a better than 20%
        absolute improvement in the biochemical failure rate in the radiotherapy arm
        (hazard ratio 0.40 for the addition of radiotherapy when analysed by treatment
        received, p<0.0001). Grade 3 rectal toxicity was not observed in either group.
        Similarly, the Southwest Oncology Group study (SWOG 8794) randomised 419 pT3
        and margin positive men to have either observation or radiotherapy (498). 55% had a
        detectable post-RRP PSA. The risk of biochemical recurrence was reduced by 56% by
        adding adjuvant radiotherapy, and prospective quality of life assessment suggested
        no significant differences in the gastrointestinal, urinary and sexual domains at 5
        years. The risk of needing future salvage androgen suppression therapy was
        reduced by 56% also and clinically apparent relapse by 38% (both statistically
        significant). Distant metastasis and survival events were too infrequent in both
        studies to make meaningful assessment.
        This combination of randomised trial data (amounting to level 1 evidence) suggest
        that there is an unequivocal capacity for post-RRP adjuvant radiotherapy to
        approximately halve the chance of having a future PSA-detectable tumour
        recurrence in pT3 / margin positive patients, while maintaining a low level of
        toxicity. More maturity to the data is awaited to determine the overall impact this
        has on distant metastases or survival.

        Salvage radiotherapy
        The role of salvage radiotherapy is far less clearly defined, with no prospective
        studies of efficacy or toxicity to guide decisions. Retrospective analyses suggest that
        the PSA level prior to initiating the salvage radiotherapy is strongly predictive of
        outcome (499-501), with some series suggesting that treatment at PSA levels below 1
        ng/mL do substantially better than those above this level (502). This PSA effect has
        been shown to be independent of the PSA doubling time (503), potentially indicating
        that these patients benefit from early referral for treatment regardless of PSA
        dynamics. Indeed, one series demonstrated an independent benefit to the use of
        immediate adjuvant therapy rather than waiting until requiring salvage (504). Other
        prognostic factors which have described, although not consistently, have included
        seminal vesicle invasion, margin positivity, post-operative PSA nadir level, high
        gleason grade, and radiation dose (501-503). Larger series typically show a 5 year
        biochemical control rate in the order of 50% typically (501, 505), and over 70% for
        those with a pre-treatment PSA of less than 1 ng/mL and an operative Gleason score
        of 7 or lower (502). Despite the apparent ability to provide a substantial chance for
        long-term control in relapsed men, there is concerning data that post-RRP
        radiotherapy may be under-utilised. Only 55% and the 38% of the biochemical
        failures in the observation arms of the EORTC and SWOG randomised trials

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      respectively underwent potentially curative salvage radiotherapy, with the
      remaining being treated palliatively with observation or androgen suppression
      therapy. Prospective efficacy and toxicity data will be required to fully appreciate
      the therapeutic ratio of radiotherapy in this group of men.

XII. RADIOTHERAPY
      A. Introduction
      Contemporary radiation therapy can result in cure of prostate cancer in a substantial
      proportion of cases. Deliberation continues regarding when it is best used rather
      than other radical treatments, in particular, RRP. Direct randomised evaluation of
      them would appear unlikely to ever happen, given that a highly anticipated and
      well funded international trial comparing radical surgery with seed brachytherapy
      recently closed due to poor accrual (ACOSOG Z0070 – the “SPIRIT” trial). Without
      such evidence, non-randomised data describing both tumour control and quality of
      life issues must be balanced against each patient‟s concerns and overall health status.
      Multidisciplinary clinics should be regarded as the standard forum for helping
      patients balance these issues.
      Irrespective of the perceived tumour biology, men under 60 years of age are offered
      surgical therapy in many centres based on, amongst other issues, the practical
      advantages of ascertainment of pathological tumour stage (discussed above), more
      accurate grading and a more dependable early PSA endpoint of success in most
      cases. Many patients, however, will be offered radiotherapy preferentially. This may
      be on the basis of advancing age, a high risk of not achieving surgical complete
      clearance or patient preference. Evidence to help determine appropriate therapy is
      now available for many clinical scenarios within this group of men.

      B. Stratification of risk of progression & metastases
      In many cases, radiotherapy treatment decisions are now driven by the patient‟s risk
      profile tumour containment. These profiles were typically developed using
      historical data, and either externally validated or confirmed as clinically relevant by
      stratification levels in prospective trials. The most simple of these is a three tiered
      system with (506):
          1. Low risk: PSA10 ng/mL and Gleason Score 2-6 and stage cT1-cT2a
          2. High risk: either cT3 or cT4 or PSA>20 ng/mL or Gleason Score 8-10
          3. Intermediate risk falls between these levels
      While nomogram models (507) have been shown to have more reliable
      discrimination of outcome, the three level model serves well in relation to known
      therapeutic option categories. These may involve combinations of external beam
      radiotherapy (EBRT), brachytherapy (BT) or androgen suppression (AS) therapy.

      C. External Beam Radiotherapy
      For those with low risk prostate cancer, modern EBRT techniques appear to be
      highly efficacious (508, 509). PSA control would be expected in over 85% of such
      cases presently. These treatments are typically delivered using conformal 3D
      techniques, or intensity modulated radiotherapy (IMRT) where these more complex
      treatments may aid in controlling toxicity, especially at higher doses. These excellent
      results are yet to have an additional demonstrated benefit when combined with
      therapies such as AS.

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Chapter 10. PROSTATE CANCER


        High risk prostate cancer traditionally has been a disease with a poor outcome when
        treated with radiotherapy alone (as with surgery). In the days before PSA detection
        of tumours, biochemical recurrence rates were typically over 80% using
        radiotherapy as primary therapy (510). With the risk of both local and metastatic
        progression being of concern, randomised trials investigated the role of adjuvant AS
        in what are now known to be typically high risk patients. Published trials of locally
        advanced disease showed AS to have a beneficial effect when given after
        radiotherapy for a duration of either 2 years (511), 3 years (375) or indefinitely (512).
        An overall survival benefit of 16% at 5 years was seen in the Bolla et al trial when
        compared with radiotherapy alone. Hence, most men today with advanced cancers
        will have this style of treatment offered as a minimum. Fit men in this group may
        also be offered therapy on a clinical trial, as the improved results in this group are
        continuing to be optimised.
        Intermediate risk prostate cancer, however, appears to have a lesser reliance on
        treatment of sub-clinical metastatic disease present at diagnosis, as borne out in
        trials evaluating the value of local therapy intensity. Responses to increasing
        radiation doses (“dose escalation”) have now been shown in a randomised trial. For
        the subset of PSA 10-20 ng/mL, the freedom from failure rate at 6 years increased
        from 43% to 62% when the radiation dose was increased from 70Gy to 78Gy (513).
        This supports the results of other dose escalation observational series (509, 511, 514).
        Additionally, short-term use of AS combined with EBRT has shown to be of benefit
        to some patients. The precise explanation for this improvement in results is less clear
        though. Observational studies suggested a benefit predominately to intermediate
        and possibly high risk men (515). A number of randomised trials also now exist
        which, to some extent, cover this group of men. The mature RTOG 86-10 trial
        examined the role of 2 months of complete AS before as well as during radiotherapy
        in patients with bulky primary tumours and was conducted prior to the wide
        availability of PSA. The subanalysis by grade showed significant gains in
        loco-regional control, cancer-specific and overall survival in the Gleason 2-6
        tumours, also further reinforcing that bulky high-grade cancers should be
        approached as high risk disease. Another trial has recently reported a freedom from
        failure together with a survival advantage to having 6 months of neoadjuvant AS
        (NAAS) prior to 70Gy of EBRT in intermediate and high risk men (516).
        Somewhat disparate though are the results from the Trans-Tasman Radiation
        Oncology Group (TROG) 96.01 trial which compared radiotherapy of 66Gy alone to
        the same dose in combination with either 3 or 6 months of neoadjuvant maximum
        androgen blockade. Looking at the risk subsets of men from this study shows that
        the benefit shown for the use of 6 months NAAS (particularly in terms of freedom
        from BF and cancer-specific mortality) was primarily limited to the high risk men.
        The power to detect a difference, however, was limited by the small proportion of
        intermediate risk patients (517).
        Also somewhat confounding matters is a large 2x2 phase III trial of men with a
        calculated risk of nodal positivity >15% showing that 4 months of AS was a
        significant benefit only when given prior to and during radiotherapy (rather than
        adjuvantly), and furthermore, only when combined with whole pelvic radiation
        fields (rather than prostate only) (518). As most of these trials showing a benefit to
        AS in combination with radiotherapy have employed lower doses of radiation than
        used presently, the precise indications for combination therapy in this group are
        unclear, it does appear that a subgroup of men, who usually fit within the typical
        intermediate risk profile, will benefit from short term neoadjuvant therapy.


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                                                   Chapter 10. PROSTATE CANCER


Toxicity: The major concerns with EBRT are damage to normal tissues at risk viz. the
rectum, bladder/urethra as well as the neurovascularity involved with erectile
function. Modern planning systems have capabilities to produce detailed
descriptions of the dose to structures of interest (dose-volume histograms).
Applying accurate constraints to these parameters is partly the explanation for the
observation that serious toxicity from modern 3D EBRT is uncommon, with
evidence suggesting that it is less common now than with previous EBRT planning
and treatment techniques, even those previously using much lower doses (519).
During a typical radical course of EBRT, symptomatic urinary toxicity occurs in
most men which can be a combination of so-called irritative or obstructive
symptoms. Grade I-II toxicity typically not requiring any or only minor medical
intervention happens in approximately 50%, while serious problems potentially
requiring invasive intervention happen in less than 1%. Urethral stricturing is a
major concern after radiotherapy in high doses, and occur in approximately <1%
presently.
Towards the end of a course of radiotherapy, most men will be aware of some rectal
urgency associated with frequency. Rectal bleeding during or soon after therapy
occurs in 0-2% of men in modern series (519) with the late bleeding rate being
approximately 1% also. A measurable, but not clinically problematic, change in
bowel habit will be observed in 10-20% (519).
Changes in erectile function related to increases in radiation dose are yet to be
adequately documented in long-term data from large scale randomised dose trials.
Observational series do suggest that in those with adequate erections prior to
radiotherapy, 50% will maintain erectile function for more than 2 years (520). The
control arm (radiation alone to 66Gy) of a large Australian randomised trial showed
that 1 year after radiotherapy, approximately half of the patients sexually active
prior to treatment remained active (376). This trial also showed that the addition of
AS to radiotherapy does not appear to increase the toxicity of radiotherapy beyond
that seen with radiation alone, in agreement with other published results (521).

D. Brachytherapy
Brachytherapy (BT) for prostate cancer can involve 2 forms of interstitial implant
therapy, either permanent low dose-rate (LDR) radioactive seed implant or a
temporary high dose-rate (HDR) implant.

(i) LDR seed implant
For men with early stage prostate cancer, the use of seed BT has increased
dramatically over the past decade with potentially a quarter of all early cancers now
being treated this way in the USA (522). The modern technique uses accurate
imaging and guidance systems to place metal seeds, containing either Iodine125 or
Palladium103 as the radioactive source, in a planned array within the prostate to
deliver a conformal dose of radiotherapy.
Typically a TRUS unit is used to image the prostate in real-time (with CT or MRI
used in some centres) and a template utilised to guide needles loaded with the seeds
into the prostate transperineally. The procedure is usually relatively simple and
brief from the patient‟s viewpoint, often administered in an outpatient setting,
making it attractive to many. A number of series have now reported both PSA and
toxicity outcomes for many thousands of men treated this way (523, 524). Although
the long-term results published for this procedure amount to beyond 10 years at


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        only a few centres (525, 526), the tumour control rates appear to be similar to those of
        surgery.
        Biochemical control rates for those in the low risk group are presently greater than
        85% (524, 525, 527), and shown to be equivalent or better than results of similar
        EBRT treated cohorts. Moving beyond the low risk category, the use of seed BT as
        the sole treatment modality almost universally shows an increase in the biochemical
        failure (BF) rates. In these cases, recommendations range from using seed BT in
        combination with EBRT, in combination with AS, or using EBRT only. No
        randomised evidence exists to help with this decision, however, there is
        considerable experience using seed BT in combination with EBRT indicating
        potential for good outcomes in this group (528). High risk men typically do poorly
        with seed BT alone and are rarely considered suitable for this therapy.

        Toxicity
        Following a seed implant, the dose of radiation is delivered over some months,
        depending on the half-life of the isotope. The predominant toxicity of the implant is
        that of urinary irritation, and typically the symptoms peak at 2-10 weeks
        (isotope-related) and the majority will have returned to normal at 12 months (529).
        These initial symptoms can be troublesome, with most series reporting rises in the
        International Prostate Symptom Score of 7-12 units at their worst, indicating
        moderate bother (373, 530, 531). Rectal toxicity is uncommon, with bleeding or
        fistula formation occurring in <1% (532).
        Erectile function maintenance has been reported in a number of prospective
        brachytherapy studies. The highly conformal dose distribution of seed BT
        theoretically may reduce the dose of radiation to the structures important for
        maintaining erectile function, and this seems to be demonstrated in the relatively
        early figures. The loss of adequate erectile function rates appears to occur in 30-50%
        of patients by 3 years (533, 534) and longer term results are awaited.

        (ii) HDR temporary implant
        HDR brachytherapy of the prostate has been utilised in a number of centres now for
        well over a decade (535-541). Proponents of the technique are in favour of the highly
        conformal nature of the radiation dosimetry able to be achieved with HDR, as well
        as a theoretical biological advantage in prostate cancer (542). It is performed by
        placing a series of fine BT catheters in the prostate transperineally, using a technique
        similar to the guidance of the needles for LDR seed BT. These are subsequently
        loaded with a radioactive source which sits at various positions in the catheters for
        various durations to build up a dose of radiation as predetermined by a computer
        planning system. It is typically used in combination with a truncated course of EBRT,
        although there are experimental protocols in place for using it as monotherapy.
        Results using this technique are encouraging, and would appear to justify the
        theoretical basis of its use. Series routinely report freedom from biochemical failure
        results of better than 90% and better than 80% for low and intermediate risk patients
        respectively (537, 539, 540). Late urinary complications (grade 3) appear to occur in
        about 5%, and are typically „obstructive‟ symptoms. Significant rectal toxicity is
        uncommon; the maintenance of erectile function is poorly reported to date.

        E. Defining biochemical failure (BF) after radiotherapy
        The definition of therapeutic failure based on the post-radiotherapy PSA profile
        (“biochemical failure”) is a more difficult prospect than following radical
        prostatectomy. After surgery, essentially all the PSA-secreting tissue is removed,
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and hence an undetectable level is considered desirable. Naturally, this situation
does not exist following radiotherapy; with the prostate remaining in situ with
variable residual function. Early after the inception of PSA testing, the publication of
BF results was based on a variety of interpretations which were felt by individuals to
describe a high likelihood of recurrent disease. In response to concerns regarding the
potential lack comparability of such published results, an ASTRO consensus panel
was convened in 1996 to discuss future BF publication criteria. The panel considered
data from a number of clinical databases, all treated with external beam therapy. The
subsequently published definition of BF, known as the ASTRO consensus definition
(ACD), stipulated BF to have occurred when three consecutive PSA rises are seen
and the date of failure to be retrospectively backdated to the midpoint of the PSA
nadir and first rise. This was largely based on the finding that three consecutive PSA
rises was followed by a further rise in 89% of cases, plus the clinically plausible
argument that the recurrence actually commenced well prior to the confirmatory
third rise. Relatively little was known at the time regarding the relationship between
the ACD BF status and clinical endpoints (543).
The ACD has been widely embraced for the analysis of post-radiotherapy results. A
large number of concerns about its performance have been raised however.
Although BF would appear to occur rarely after 5 years using the ACD, the
reliability of the results are known to be highly dependent on the duration of
follow-up. Practically this has shown to potentially worsen the derived freedom
from BF (FFBF) rate by approximately 25% when the same data is analysed at a
median follow-up of 6 years against that obtained at 2 years (544). This creates
difficulty when examining the results of more recent series (for example, a new
treatment technique) with historical data; the contemporary data will be favourably
biased. This phenomenon is known to be an artefact of the backdating in the ACD.
Furthermore, the known independent prognostic value of ACD BF and overall
survival (relative risk 1.27) is substantially weakened by backdating (545).
The ACD has also been criticised for having unpredictable results when applied to
treatment modalities other than EBRT, for which it was not planned to be utilised.
False positive results can be problematic with seed brachytherapy, where benign
PSA fluctuations (“bounces”) are seen in approximately one-third of cases (546).
Similarly, when the testosterone recovers after combined AS and radiotherapy there
may be a concurrent PSA rise of a level sufficient to trigger ACD BF in up to
approximately 20% of cases (547, 548). There is poor applicability to surgical data,
with backdating particularly creating differences in the late risk of failure (468). A
further surgical analysis suggested that the ACD may underestimate the risk of BF
by as much as 30%, however this study illustrates the propensity for the ACD to be
misinterpreted (549). By stipulating the nadir date to be the date of surgery, rather
than the defined last non-rising PSA date, the backdating effect was exaggerated to
the theoretical extreme, further reinforcing the finding that the there are multiple
areas of potential misinterpretation in the ACD (550), and that original publication
guidelines are poorly adhered to (551).
A number of analyses of very large and mature patient cohorts have been published
which suggest alternative BF definitions may be superior to the ACD. These have
focused on the correlation of PSA dynamics and subsequent clinical events in the
aim of finding a BF definition which is both sensitive in detecting recurrence early,
yet specific to those factors which are likely to be clinically relevant in the future –
data which was unknown at the time of the original consensus meeting.
The most ambitious undertaking was that of Thames et al (2003) (552). This study
assimilated PSA and clinical outcomes of 4839 T1-T2 prostate cancer patients from

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        nine USA institutions treated with EBRT without planned AS. A total of 102
        different definitions of BF were assessed using a variety of quantitative measures of
        prediction of clinical failure. A number of definitions were found to have
        substantially better performance than the ACD. In particular, nadir (the lowest level
        to date) plus either 2 or 3 ng/mL showed good sensitivity, specificity and predictive
        indices in relation to clinical failure without resorting to backdating and prospective
        in nature (that is, it used only the PSA data available prior to failure, as would
        happen in the clinic). The nadir + 2 ng/mL definition, for example, showed a
        sensitivity, specificity and relative risk of clinical failure of 0.74, 0.84 and 58.4
        respectively, while the ACD had respective values of 0.61, 0.80 and 7.0. Similarly,
        Kestin et al (2004) (553) used the mature data of 727 men to show the nadir + 2
        ng/mL definition had a 73% versus 3% rate of clinical failure at 10 years for those
        who were deemed as BF or not respectively, while the ACD had 64% against 14%.
        Further analysis of the sensitivity and specificity characteristics using receiver
        operating characteristics show that the optimum balance appears with the nadir + 2
        ng/ml or an absolute level of 3 ng/ml definitions (554).
        Analysis of the interaction of various BF definitions and AS therapy have been
        performed by Pickles et al (2003) (548). The nadir + 2 ng/mL performed better in
        terms of predicting clinical failure in their cohort of 1490 patients, and especially so
        in those previously receiving AS, and this was also confirmed by Zietman et al (2005)
        (547). It would also appear that the definition of the nadir + 2 ng/mL style will be
        relatively unlikely to be influenced by PSA bounces related to seed brachytherapy,
        given the median bounce level is 0.4-0.7 ng/mL (546) and less than 3% are of
        sufficient level to trigger a false positive BF with this definition (555). In view of the
        considerable advances in the understanding of PSA biology following radiotherapy,
        another consensus meeting to discuss an update to the ACD was convened in
        January 2005. Results from this meeting are expected soon.

        F. Management of local failure after radiotherapy
        A detectable and rising PSA above the nadir value following radiation therapy may
        represent local or distant failure, or both. Determining the site or sites of tumour,
        although highly desirable, is notoroiously difficult with currently available
        diagnostic techniques with BF often preceding clinically evidence of metastases by
        several years. Consequently, a diagnosis of localized disease without metastases, can
        be only inferred. However, selecting the most appropriate therapeutic approach
        may be aided by reference to initial clinical staging, PSA and Gleason score from
        TRUS biopsies.
        In addition to pre-treatment clinical and post-treatment pathological factors, PSA
        kinetics and, specifically, a pretreatment PSA velocity >2 ng/ml/year, an interval to
        PSA failure <3 years and a post-treatment PSA doubling time <3 months place a
        man at increased risk for metastases and subsequent prostate cancer-specific
        mortality, making these patients poor candidates for local-only salvage therapy.
        Men with any Gleason 8-10 tumour in their TRUS biopsy cores or those whose cores
        indicated seminal vesicle involvement are also very likely to have non-localised
        disease. As a result, Lee and D‟Amico (2005) (556) identified an optimal candidate
        for local-only salvage therapy as one whose pretreatment PSA velocity was <2
        ng/ml/year, interval to PSA failure exceeded 3 years, post-treatment PSA doubling
        time was at least 12 months and whose TRUS biopsy cores contained a Gleason score
        of less than 8 (556).
        Touma et al (2005) (557) reviewed the current status of local salvage therapies
        following radiation failure for prostate cancer, reporting that salvage RRP offered

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      5-year biochemical relapse-free rates of 55 to 69%. They identified a life expectancy
      of at least 10 years, pre-radiation and pre-operative PSA <10 ng/ml and localized
      preoperative stage as desirable factors for RRP after radiotherapy failure. However,
      patients need to be aware that higher complication rates are to be expected
      compared with primary RRP, which include rectal injuries, bladder neck contracture
      and urinary incontinence (557).
      As discussed above in Section VII, the most appropriate application of cryotherapy
      is for patients with bulky local disease and local recurrence after radiation therapy
      (315). Touma et al (2005) (557) noted that urinary incontinence, impotence, pelvic
      pain and urinary retention were the major side effects of salvage cryotherapy cited
      and considered salvage cryotherapy to be a valid option in hormonally naïve
      patients with preoperative PSA <10 ng/ml, Gleason score <8 and clinical stage <T3,
      being especially suitable for older men with some comorbidities but who are still
      considered to be reasonable anesthetic risks (557).
      HIFU (also addressed briefly in Section VII) may have a role in these types of
      patients but relevant data to make this assertion are not yet available (313). Apart
      from local treatments, androgen suppression treatments may be considered
      (detailed in Section XIII, below).

      G. Quality of life issues in prostate cancer radiotherapy
      Considerable interest exists regarding the treatment modality in early prostate
      cancer, and the impact it has on the patient‟s quality of life (QOL). Once more,
      randomised data are lacking, although at least three large prospective series have
      now been published comparing treatment modalities (413, 558, 559).
      EBRT was typically associated with the most bowel dysfunction, which settles over
      1-2 years, and then tends to be stable. Acute urinary bother is mild, but significant
      worsening of symptoms at later stages (beyond 5 years) has been reported and
      requires further investigation (559). Sexual function consistently deteriorated over
      time in all series after EBRT, although notably, at the same rate as the untreated
      controls of one series.
      Seed BT has initial elevation of urinary bother that settles to a large degree in the first
      2 years. There is however, the suggestion that there may be subsequent deterioration
      of continence over the next 4 years. This has not been corroborated in other studies
      to date (560). Rectal morbidity, although typically minor, is documented to steadily
      settle with time. Erectile function deteriorates in the initial 1-2 years typically, but
      the longer term results of one series suggest little change in the QOL impact of this
      beyond that time.
      Each of these series had a RRP control arm for comparison, which yielded consistent
      findings. RRP always led to a high QOL impact in terms of urinary continence and
      sexual dysfunction within the first 6 months post-therapy. These both improve over
      the first 2 years, but should be considered likely to remain stable beyond that time.
      Long-term follow-up comparisons in well designed trials will be required to
      ultimately decide the overall QOL trade-offs with each particular therapy.

XIII. SYSTEMIC THERAPIES
      Although much attention is focussed on early diagnosis and localised disease, a
      considerable proportion of patients continues to present with extra-prostatic disease
      (561). In addition, approximately 25% of men treated initially with curative intent
      experience prostate specific antigen (PSA) failure or develop clinically detectable
      metastases within 5 years following therapy (562). The cornerstone of treatment for
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        patients with prostate cancer metastases is hormonal manipulation: approximately
        80% of patients have a durable clinical regression with androgen suppression
        therapy.

        A. Hormonal Therapy
        It is now well over 60 years since Huggins and Hodges reported their observation
        (308, 309) that prostate cancer was an androgen dependent tumour which regressed
        following bilateral orchidectomy. In the interim, a number of alternative methods
        have become available for achieving castrate testosterone levels. These include
        bilateral orchidectomy/orchiectomy (regarded as the reference treatment),
        Luteinising Hormone Releasing Hormone (LHRH) agonists, antiandrogens and
        oestrogens, all of which have significant adverse or unwanted effects.

        (i) Bilateral orchidectomy/orchiectomy, LHRH agonists &
        antiandrogens:
        Historically, bilateral orchidectomy has been the reference treatment for advanced
        prostate cancer which, by targeting the major source of androgen production,
        dramatically diminishes the number of tumour epithelial cells and accompanying
        neovasculature. LHRH agonists, after initially stimulating LH and hence
        testosterone synthesis by the testicles, occupy LHRH receptors to prevent
        subsequent production of both these hormones. In addition, LHRH agonists can
        have a a further action by targeting LHRH receptors on prostate tumour cells (563,
        564).
        The unwanted effects of bilateral orchidectomy and LHRH agonists are generally
        considered to be comparable apart from the fact that the former requires an
        operation, with physical and possible psychological consequences, and the latter
        necessitates regular interval injections and commencement of therapy has an
        accompanying risk of an initial surge in testosterone (the so-called flare reaction)
        due the drug initially stimulating production of luteinising hormone before blocking
        production.
        Reduced libido and impotence are to be expected following surgical or medical
        castration together with a loss of bone substance and muscle mass. As a condition,
        osteoporosis is underdiagnosed in men and it is only relatively recently that its
        relationship with bilateral orchidectomy and LHRH agonists has been appreciated
        (565-567). The high prevalence of osteoporosis together with its debilitating
        consequence of bone fractures has prompted advocacy for the use of
        bisphosphonates in prostate cancer patients, especially those committed to
        longstanding castration (see below). Hot flushes can be problematic for many men
        and tiredness from anaemia can compound debility. A minority of men receiving
        LHRH analogues develop gynaecomastia.
        The American Society of Clinical Oncology recommends bilateral orchidectomy or
        LHRH agonists as initial androgen suppression treatments (568). Non-steroidal
        anti-androgens may be considered alternatives but the steroidal anti-androgen
        cyproterone acetate should not be offered as monotherapy (568). The UK Committee
        on the Safety of Medicines recommends that, because of the risk of hepatotoxicity,
        cyproterone use in prostate cancer should be restricted to short courses unless
        patients are unresponsive to or intolerant of other treatments. Unwanted effects with
        non-steroidal antiandrogens are common with gynaecomastia and breast pain
        troublesome for many: a cessation rate for these medications has been reported to be
        4-10%, in particular with flutamide (568, 569). Hepatotoxicity is a potential problem
        with all antiandrogens but especially cyproterone acetate.( 568).
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Green et al (2004) (570) reported the results of our study of 82 men randomised to
leuprorelin (Lucrin™), goserelin (Zoladex™), cyproterone acetate (Androcur™) or
watchful waiting, 62 of whom completed 12 months of follow-up. In addition to a
non-treatment (watchful waiting) control group, a non-cancer community reference
group was also evaluated. Findings were compared in relation to cognition and
quality of life. Most patients had serum PSA levels between 30 and 60 ng/ml at
baseline. Using well-validated and established instruments, they found that ~50% of
men in all treatment groups, but none of the controls, had significant cognitive
deterioration at 12 months, in particular in relation to complex information
processing. Although the cognitive defects were of a magnitude comparable with
sleep-deprivation or mild inebriation, there was no consistent association between
subjective cognitive changes and objective deficits. In addition, there were more
instances of a deterioration of quality of life for the men on hormonal treatments at
12 months, in particular in relation to sexual function (570).
Unlike other studies addressing cognition and quality of life, Green et al‟s paper is
important as all patients were randomised to management regimens which included
a non-drug (control) arm and this study was completely independent of any
industry-sponsorship. Consequently, these findings are much more compelling than
those reported from less robustly designed studies and those trials sponsored or
supported by industry (571-577)

(ii) Oestrogens
Oral oestrogen therapy, the most common form of androgen suppressive medication
for many years, is now rarely used as first line hormonal treatment because of
associated cardiovascular complications with oral administration, although this
route of delivery is employed not uncommonly in Japan for a short period to offset
the flare effect of LHRH agonists (578). An increased cardiovascular morbidity was
reported to be present with the oral form of oestrogens even in patients without
overt cardiovascular disease affecting one quarter of such patients during their first
year of treatment (579). However, a dose-response relationship is said to be present
in terms of cardiovascular morbidity and mortality with one mg daily of
diethylstilboestrol (DES) (with or without aspirin) stated to be comparable with
bilateral orchidectomy in the treatment of advanced disease but without increased
cardiovascular complications. Klotz et al (1999) (580) found that venous thrombosis
was not prevented when DES was prescribed together with low-dose warfarin (580).
The increased susceptibility to cardiovascular complications in patients taking
oestrogens appears to be critically related to the route of administration. This
predeliction is reported to be significantly reduced (581) or avoided by parenteral
delivery. An increased synthesis of coagulation factors, in particular Factor VII,
results from oral oestrogen therapy and this is thought to be responsible for the
increased rate of cardiovascular problems in these patients (582, 583). Consequently,
many investigators have advocated a re-evaluation of oestrogen treatment (584-587),
especially since all forms of oestrogen, including parenteral and transdermal patch
preparations, are cheap (588) and, unlike bilateral orchidectomy and LHRH agonists
in particular, this medication is not considered to induce osteoporosis ( 581).
Furthermore, oestrogens may have a role in ameliorating agitation in some men
receiving LHRH agonists.
Ockrim et al (2003) (589) reported their experience with 20 men with newly
diagnosed locally advanced or metastatic prostate cancer treated with transdermal
estradiol patches in particular in relation to bone mineral density. They found that at
1 year that the mean bone mineral density had increased by 3.6% and concluded that

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        transdermal estradiol protects against bone loss in men with prostate cancer and
        may improve bone density in those at risk for osteoporotic fracture. Local experience
        with this form of delivery has been that patch displacement can occur with sweating,
        especially in active men: serial serum testosterone levels may be used to optimise the
        frequency and duration of patch application.

        (iii) Commencement of hormone therapy
        Despite many attempts to demonstrate otherwise, there is no clear evidence that
        commencing androgen suppression therapy early improves survival (568, 590).
        Early commencement does, however, increase the likelihood and duration of
        unwanted effects. Since in terms of lifestyle effects, commencing androgen
        suppression is likely to adversely affect libido, potency, physical mobility and
        strength, body habitus, cognition and liver function (with anti-androgens), a body of
        clinicians advocates carefully delaying commencement by balancing the unwanted
        effects of treatment with those of the disease being treated. In conjunction with
        patients‟ wishes, PSA doubling times and development of lesions on bone scans can
        be helpful in deciding when to commence androgen suppression.
        By upsetting homeostasis at a molecular level, androgen suppressive therapies may
        in fact contribute to tumour progression in those remaining prostate cancer cells
        after commencement of treatment (38). Unlike androgen receptors which are sited in
        prostate epithelial cells, oestrogen receptors are present in both epithelial and
        stromal cells. Compartmentalisation of the two ERs is reported with ERα exclusively
        in stroma and ERβ predominantly in the epithelial compartment (38, 591). ERβ is considered
        to have a role against prostate cancer dedifferentiation in contrast to the proliferative effect of
        ERα and androgens (592). In prostatic epithelial cells, testosterone is reduced by 5α-reductase
        to dihydrotestosterone which, in turn, is converted into 3α-diol and 3β-Adiol. Unlike
        testosterone and dihydrotestosterone, these two metabolites do not bind to the androgen
        receptor but possess high affinity for oestrogen receptors. By binding to estrogen receptor β
        (ERβ), 3β-Adiol induces expression of the cell adhesion molecule E-cadherin, the presence of
        which in prostate cancer cell membranes is associated with a less aggressive phenotype.
        Decreased expression of many C-CAMs including E-cadherin, have been associated with the
        progression of prostate cancer (38,107).
        However, there are many clinicians and patients who become pre-occupied with lowering the
        serum PSA levels at all costs. A survey of American Urologists indicated that 68%
        recommended hormone suppression therapy for an elevated PSA after radical prostatectomy
        (562, 593). Thus, an increasing PSA often serves as the trigger for commencement of what
        translates into long-term androgen suppressive therapy for a large proportion of patients in
        spite of a lack of clear evidence of a survival benefit with early treatment (594, 595).

        (iv) Combined androgen Blockade (CAB)/Maximum Adrogen Blockade
        (MAD)
        Since bilateral orchidectomy and LHRH analogue treatment address testicular androgen
        production exclusively and a small contribution to overall androgen levels is made by adrenal
        androgens, CAB was initiated. However, despite extensive trialling, only a modest survival
        benefit has been demonstrated but at the cost of a higher side-effect profile for patients (596).
        The limited survival benefit appears to be associated with the use of non-steroidal
        antiandrogens and only becomes evident after 5 years of therapy. This topic has been
        reviewed recently by Loblaw et al (2004) (568).

        (v) Intermittent Androgen Blockade (IAB)
        Intermittent hormone therapy was instituted to lessen the duration of unwanted effects from
        androgen suppression therapy, usually being limited to those patients who demonstrate a
        pronounced PSA response and find the unwanted effects of androgen suppression

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problematical. However, this approach to androgen delivery begs the question, why was the
treatment started when it was since, most often, IAB seems to be used for men who
commenced their androgen suppression very early. Other issues with IAB are that not all the
adverse affects of androgen suppression are reversible and recovery of the
hypothalamic-pituitary-testicular axis is variable, especially after prolonged LHRH
administration. Indeed, castrate levels of testosterone and LH may persist for up to 1 year (or
even longer) after discontinuing LHRH agonist treatment (597).

(vi) Hormone escape
Once prostate cancer metastasizes following effective androgen suppression therapy, its toll,
with regard to pain, suffering, and disability, can be considerable due to incapacitating
sequelae of disseminated and hormone-refractory disease, for which no curative treatments
currently exist. PSA evidence of hormone escape usually precedes other barometers of
disease progression and metastasis. Newling et al (1993) (598) reported that, for men with
newly diagnosed metastatic prostate cancer who were randomised in the EORTC study 30853
to receive goserelin and flutamide or bilateral orchidectomy, the median time for survival
following PSA progression was 52 weeks compared with 41 weeks for bone metastases and
28 weeks and 33 weeks for progression of regional and distant lymph nodes, respectively
(598). However, as suggested by a reducing mortality rate for this condition in many countries,
these estimates may no longer be accurate for a variety of reasons addressed throughout this
chapter.
As outlined above, prostate cancer has a particular predilection for androgens that serve as this
malignancy‟s preferred ligand. When androgen suppression is invoked initially, the tumour
regression effect can be dramatic with both epithelial cells and tumour neovasculature being
affected significantly (599). However, tumour repression is not permanent with a median time
to relapse of 18 months (600). Nevertheless, maintaining suppression of circulating androgens
remains important as the androgen receptor pathway continues to be very active in „hormone
escape‟ patients. Amplification and overexpression of the androgen receptor gene, as well as
post-translational modifications to the AR occur, resulting in the cancer cells becoming
„super-sensitive‟ to androgens (601-603).
In conjunction with these changes is activation of other genes that, through signal transduction
pathways, facilitate receptivity to a variety of ligands including other hormones and drugs,
especially antiandrogens (604). Consequently stopping an antiandrogen may afford a
temporary respite to tumour regression manifested by a reduction of serum PSA in some
patients (605).
Paradoxically, for those patients receiving monotherapy in the form of LHRH agonists or a
previous bilateral orchidectomy, the addition of an antiandrogen may cause a clinical
regression for a short time and this is often recommended before proceeding to chemotherapy
or radiotherapy in the form of radio-isotopes or local external beam treatment to isolated
troublesome secondary deposits. Recent research has provided support for modulation of the
oestrogen receptor axis in disease no longer responding to androgen suppression by LHRH
agonists, bilateral orchidectomy or antiandrogens by targeting oestrogen receptors in
metastatic disease (606).
Hormone-refractory prostate cancer is said to be present when there is evidence of
progression despite the use of first and second line hormonal manipulation. Although the
administration of bisphosphonate and chemotherapeutic interventions may provide benefit in
the short term (see below) these palliating approaches merely serve to temporise the situation
in this subterminal/terminal phase of the disease. Clarke (2003) (607) divided the urological
issues to be considered into:
    1. Lower urinary tract dysfunction
    2. Ureteric obstruction
    3. Skeletal, dysfunction
    4. Bone mrrow insufficiency

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            5. Lymphoedema
            6. Rectal obstruction/infiltration
            7. Pain
            8. Psychological dysfunction/impaired quality of life.
        It is this last point in particular which needs to be considered paramount so that unreasonable
        attempts to prolong life are not undertaken, especially when these are not in concert with
        individual patient‟s wishes. For example, it may be preferable not to treat ureteric obstruction
        and allow the patient to die painlessly from uraemia than protract his demise for a short but
        miserable period by instigating various interventions. A number of other disciplines are often
        involved at this stage as indicated, which include medical and radiation oncology,
        interventional radiology, pain management specialists and palliative care clinicians amongst
        others. It is important that pastoral care support is available as appropriate.
        A further web-site is:
        http://www.cancer.gov/cancertopics/understanding-prostate-cancer-treatment/page6

        B. Chemotherapy
        In reports published to 1991, the rates of objective clinical response of prostate cancer to
        available cytotoxic agents were disappointingly poor. A summary overall response rate of just
        8.7% (with a 95% confidence interval of 6.4-9.0%) was responsible for Yagoda and Petrylak
        (608) concluding hormone-refractory prostate cancer to be unresponsive to conventional
        chemotherapy of the time.
        Initial randomised data for the use of mitoxantrone chemotherapy in prostate cancer (thought
        to be the most effective agent of the period) became available in 1996 with the publication by
        Tannock et al (609). By randomising 161 men with symptomatic hormone-refractory disease,
        they were able to show a significant reduction in the need for analgesia (the primary end-point)
        in those who received mitoxantrone plus prednisone compared with the control arm of
        prednisone only. Analgesic responses were also substantially longer in the chemotherapy arm.
        In a subsequent CALGB trial looking at survival end-points, no survival benefit was shown
        when mitoxantrone was added to hydrocortisone, although there was an overall improvement
        in the quality of life and duration of analgesic response (8 months on average) in those on the
        chemotherapy arm (610).
        Further preclinical activity had also been suggested when prostate cancer was exposed to
        taxanes, a class of microtubule stabilising agents. Predominately, these agents work by
        blocking the ability of cells to depolymerize the microtubule cytoskeleton during normal
        mitosis, thus inducing a lethal cell cycle arrest at the G2M phase. In particular, docetaxel
        appeared the most active form and was taken to clinical testing.
        A number of phase I/II trials were conducted using either single agent docetaxel or in
        combination with estramustine, an agent thought to possibly potentiate the taxane effect by
        acting on a different microtubule pathway. Used as single agent therapy, docetaxel showed
        significant PSA responses (a PSA level decline of greater than 50%) in 38-48%, and up to
        68% in the combination therapy trials (611). Responses in measurable soft tissue disease
        ranged from 20-55%. Neutropenia was a feature in over two-thirds of the patients treated on a
        three weekly single agent docetaxel schedule, and less common when given weekly. Similar
        toxicity was seen with the combination therapy trials, except for the addition of
        thrombo-embolic complications in up to 10% related to the estramustine.
        Large randomised trials to comprehensively test the efficacy of docetaxel in advanced
        hormone-refractory prostate cancer, in comparison with mitoxantrone, have now been
        published. The TAX 327 trial of Tannock et al (612) randomly allocated 1006 patients to one
        of three treatment arms, the „control reference‟ being three weekly mitoxantrone plus
        prednisone (M/P): the docetaxel arms were given either weekly for 5 of 6 weeks or three
        weekly with prednisone (D/P). The three weekly schedule of D/P showed a significantly
        improved overall survival compared with M/P, with the risk of death reduced by 24% (95% CI

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0.62-0.94, p=0.009) leading to a median survival prolongation of 2.5 months (18.9 against
16.5 months). Other significant benefits were seen in the decrease of PSA levels, analgesic
responses and the patient-reported quality of life assessment in the D/P group. Toxicity was
lowest in the M/P arm, while the highest in the weekly D/P group. As this group did not,
however, show a survival benefit, it was concluded that the three weekly schedule of D/P was
optimal.
The other phase III trial was conducted by the SouthWest Oncology Group (SWOG) and
accrued 674 eligible patients to either receive M/P or docetaxel and estramustine (D/E) three
weekly (613). Using the primary overall survival endpoint, a significant benefit was found for
the D/E arm, with the median survival increasing from 15.6 to 17.5 months associated with a
hazard ratio of 0.80. PSA declines of >50% were seen in 50% of D/E men, and 27% of those
on M/P (p<0.001). Pain relief was not significantly different between the arms and there was
substantially more toxicity in those having D/E, although the neutropenia rates were
comparable.
The consistency of the results between these large trials has demonstrated that alteration of the
natural history of hormone-refractory prostate cancer can be made using cytotoxic agents, and
survival advantages, albeit small, can be made. Therefore, in the context of a patient with a
rising PSA on hormonal therapy, the first line use of docetaxel-based chemotherapy is
considered standard of care by many. For those not medically suitable for this therapy,
mitoxantrone-based therapy should still be considered for its known palliative capacity in
those with symptomatic disease, along with lesser toxicity.

C Bisphosphonates
Bisphosphonates were initially examined for the prophylaxis and treatment of osteoporosis,
particularly in women (614) but, more recently, for osteoporosis in men following androgen
deprivation +/- external beam radiotherapy (614, 615). Bisphosphonates inhibit osteoclast
activity so, in addition to their potentially protective effect with respect to the development of
osteoporosis there is a possible role in metastatic bone disease. Osteoclast activity is an
integral part of the metastatic process for both osteolytic and, more commonly, osteoblastic
bone metastases in prostate cancer (616).
Most experience with bisphosphonates in cancer has been with multiple myeloma and breast
cancer patients but results from these studies cannot be extrapolated to men with prostate
cancer. In addition, not all bisphosphonates are equal with studies with the first generation
compound Clodronate failing to show a clear advantage compared with placebo (617).
However, the third generation bisphosphonate zoledronic acid did demonstrate increased
apoptosis in prostate cancer cell lines in vitro and inhibited growth of osteoblastic and
osteolytic metastases in vivo (618). Furthermore, Zoledronate has been shown recently to
expand γδT cells which exhibit cytolytic activity independent of MHC (see next section;
(619).
Saad et al (2002) (620) reported their experience with 4 mg and 8 mg of zoledronic acid given
intravenously 3-weekly over 5 minutes initially, but subsequently 15 minutes to increase renal
safety, in a double-blind randomised controlled trial for 15 months. A total of 643 patients
with documented bone metastases were randomised to one of the 3 groups. Only 98/214
(45.8%) and 77/221 (35.3%) of the patients who initially received 4 mg and 8 mg of
zoledronic acid, respectively, received at least 12 months of study drug compared with 77/208
(37%) randomised to placebo. The 8 mg dose was reduced to 4 mg during the study because of
renal toxicity.
The reasons for discontinuation were withdrawal of consent, adverse events and death, most
common in the 8/4mg zoledronic acid group, and unsatisfactory therapeutic effect, especially
in the placebo group. During the study, at least one skeletal-related event occurred in 71
(33.2%) compared with 92 (44.2%) of patients randomised to 4 mg zoledronic acid and
placebo, respectively. Pain and analgesic scores increased more in patients who received
placebo than zoledronic acid but there were no differences in disease progression,
performance status or quality-of-life scores among the groups (620).

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        Saad et al (2004) (621) subsequently reported the results from 122 men who completed a total
        of 24 months on study. Fewer patients in the 4-mg zoledronic acid group than in the placebo
        group had at least one SRE (38% versus 49%). The median time to the first skeletal related
        event was 488 days for the 4-mg zoledronic acid group versus 321 days for the placebo group
        (P =.009). Compared with placebo, 4 mg of zoledronic acid reduced the ongoing risk of SREs
        by 36%. These authors concluded that long-term treatment with 4 mg of zoledronic acid is
        safe and provides sustained clinical benefits for men with metastatic hormone-refractory
        prostate cancer. Since the optimal timing for commencing administration of zoledronate may
        be at an earlier phase in the disease, trials are underway with patients with hormone sensitive
        rather than refractory disease.

        D Bone-seeking radio-isotopes
        Widespread skeletal metastases may not be easily amenable to relatively localised external
        beam radiotherapy. The systemic use of bone-seeking radio-isotopes can be useful in this
        situation,  with    proven    efficacy   for    two   agents     –    Strontium89      and
        Samarium153-ethylenediaminetetramethylene (EDTMP).
        Strontium89 (Sr89) is an agent which behaves biologically in a manner analogous to calcium
        (with which it shares a relationship on the periodic table of elements), and hence is
        incorporated into sclerotic bone metastases avidly. It is a pure beta emitter, with a half-life of
        approximately 50 days, although half is typically excreted from the body in 2 weeks (mainly
        in the urine). Samarium153 is chelated to EDTMP to enable preferential binding to bone.
        Physically it has a much shorter half-life (46 hours) than strontium89 and has gamma as well
        as beta emissions, enabling imaging on gamma cameras. Producing radiation damage for only
        a short distance in tissues, these agents concentrate effect in bone metastases with little
        deposition of dose in soft tissues.
        Following intravenous administration, maximal effect on pain is usually seen in 2-4 weeks.
        Randomised trials comparing Sr89 against or in combination with EBRT showed no
        significant difference in analgesic efficacy, although the occurrence of new areas of pain and
        analgesic requirements was significantly reduced in two randomised series (622, 623),
        although one other suggested inferiority to EBRT (624). Similar efficacy is reported for
        Samarium153 (625, 626), with both typically reducing pain to some degree in 70% of patients,
        an effect which lasts for 3-4 months on average. A small percentage of patients will
        experience a flare (a temporary increase) in pain in the first week.
        The predominate toxicity of these agents is that of bone marrow suppression, and in particular,
        most patients will have a measurable decrease in the platelet count (on average a 30% drop) or
        white cell count. Repeat doses must therefore be given with caution (especially within 3
        months) and close monitoring of the blood count will be required. This will be a prime
        concern in patients being considered for chemotherapy.
        These agents are presently being further investigated for their efficacy in combination with
        chemotherapy (627, 628).

        E. Emerging Therapies: Vaccines in Prostate cancer
        (i) Introduction
        Of the various treatment approaches being examined for prostate cancer, nothing seems to
        have captured the public‟s imagination quite as vividly as have vaccines. Although
        considerable advances have been made in understanding the processes involved with different
        vaccine approaches, overall clinical results remain modest so, with changes being
        implemented continually this form of therapy must still be regarded as experimental.
        Historically, the prostate was considered to be an “immunologically privileged” site (629, 630)
        and was regarded as lacking a network of intraprostatic (631) and afferent lymphatics (632) .
        Although neither McCullough nor Gittes was able to demonstrate extraprostatic lymphatic
        drainage following intra-glandular injections of iodinated emulsified oils and India ink carbon
        particles, respectively (629), Gardiner et al in 1979 described lymphoscintigraphic evidence
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of lymphatic drainage following intra-glandular injections of technetium labelled antimony
sulphide colloid into clinically benign prostates of volunteer patients (633, 634) That
intraprostatic lymphatics do exist was elegantly demonstrated by Zeng et al (2004, 2005) (635,
636) who showed recently that, not only does the prostate contain lymphatics, but
peritumoural lymhangiogenesis is demonstrable within prostates harbouring cancer.
Furthermore, they found a relationship between peri-tumoural lymphatic vessel density and
the presence of lymph node metastases (635, 636).
Further endorsement of Zeng et al‟s findings (635, 636) in relation to finally destroying the
myth of the prostate being an „immunologically privileged‟ site, is Vesulainen et al‟s report
that lymphocytic infiltrates correlate with an improved 10-year survival for patients with
primary prostate cancer (637). This observation by Vesalainen et al (1994) (637) also serves
to encourage approaches to enhance lymphocytic infiltration with enhancement of its
cytotoxic activity through prostate cancer immunotherapy.

(ii) Effector arms available for recruitment for cell killing in tumour
vaccines
Active vaccination strategies can exploit a number of candidate immunological cells as
effectors or mediators for immunological therapies (638). These include:
    1. B cells with production of antibodies
    2. Monocytes/macrophages
    3. Natural killer (NK) cells
    4. NK T-cells
    5. γδ T-cells
    6. αβ Cytotoxic CD8+ T-cells
    7. αβ CD4+ Helper T-cells
A primitive level of tumour target recognition can be employed by monocytes, involving
interactions with overabundant or aberrant cell surface molecules on cancers. NK cells, which
provide the earliest effector mechanism against disseminated blood-borne metastases,
identify absence of self on the basis of aberrant or absent expression of major
histocompatibility (MHC) class I antigens. NKT and some γδ T-cells subsets recognize lipid
antigens presented on CD1c, which is related in evolution to the major histocompatibility
complex (MHC) molecules (see below). The balance between interactions with numerous
inhibitory and activating receptors for MHC and other MHC-related molecules governs the
outcome of NK-mediated recognition of tumour cells. However, the major roles of these more
broadly reactive (and therefore immediately responsive) cell types in tumour immunity may
be in directing the initial phase of activation of more specific effector arms of adaptive
immunity, namely αβ CD4+ and CD8+ T-cells.

(iii) Methods of cell killing
1. Antibody-directed cell killing
The interleukins (IL) 4, 5, 6 & 10 activate or influence B lymphocyte differentiation to
antibody-making plasma cells. However, cell killing via antibodies is dependent upon more
than just attachment of the binding Fab fragment of the immunoglobulin molecule to its
specific target epitope. Additional requirements include activation of complement to induce
phagocytosis, or interaction with NK-cells, polymorphonuclear leucocytes, or monocytes to
provide antibody dependent cell-mediated cytotoxicity (ADCC). These mechanisms may also
contribute to the success of clinically available immunotherapies based on the passive
administration of monoclonal antibodies to destroy targeted cancer cells, such as Herceptin®,
used in cancer of the breast. Unlike in breast cancer, Her-2neu does not appear to be
overexpressed frequently in prostate cancer (639) so that the drug has little role here. Specific
antibody-related mechanisms which trigger cell death in prostate cancer are under

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        development, but are not yet available clinically. Despite correlations between survival and
        levels of anti-tumour antibodies, there is little evidence that antibodies actively induced by
        immunization can induce tumour regression.

        2. Cell-directed killing
        Macrophages, which are the archetypical phagocyte, destroy cells by releasing reactive
        oxygen intermediates and tumour necrosis factor (TNF). By contrast, NK, NKT and cytotoxic
        (αβ and γδ) T-lymphocytes (CTL) effect cell killing chiefly through the release of perforin and
        granzymes, or by ligating Fas on the tumour cell surface to cause apoptosis of targets.
        As well as malignant epithelial cells, tumour stroma, including endothelial cells, fibroblasts
        and infiltrating cells, may also be an important target for cell-directed killing (640). Further,
        interferon γ (IFNγ) production by T and NK cells may be crucial in tumour immunity, either
        by inhibiting stromal functions (e.g., angiogenesis) or enhancing tumour cell recognition by
        CTL, for example by upregulating MHC antigens.

        (iv) αβ Cytotoxic T-cells, Helper T-cells and Dendritic Cells:
        Both αβ CD8+ Cytotoxic T-cells and CD4+ Helper T-cells are unable to recognise naked
        antigen, requiring it to be presented to them on a platter that, for the former is the MHC class
        I receptor and for CD4+ Helper T-cells is the MHC class II receptor. The antigen is recognised
        by CD8+ and CD4+ T cells in the form of short, 8-10 or 12-20 amino acid fragments of
        proteins, respectively. Critically, the antigen may not be cell-surface associated, but may be
        derived from any intracellular compartment. Indeed, defective ribosomal products (including
        mistranslated proteins) are preferential targets for CD8+ T cells (641), while
        membrane-associated proteins are frequent targets for CD4+ T cells.




        Figure 3. Production of peptides for presentation on MHC receptors for T-cell
        recogntion. The 9-11 amino-acid peptides displayed by MHC class I receptor molecules
        on the cell surface are generally, but not exclusively, derived from endogenous proteins

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made by the antigen-presenting cell. A process called cross priming may also allow
external proteins to be presented via the class I pathway.

The 12-20 amino-acid peptides displayed by the MHC class II receptor molecules on the cell
surface are typically derived from extracellular proteins taken up by the antigen presenting
cell.
CD4 and CD8 T cells are referred to as the adaptive arm of the cellular immune response
because the relevant antigen-specific, and naïve yet-to-be-primed, T cells must expand
considerably in number before sufficient are present to be effective. This expansion
occurs in the specialised environment of lymph nodes, in response to antigen
presented by antigen presenting cells (APCs). One obvious possibility is that tumour
cells infiltrating lymph nodes might act as APC, and cause this expansion (642).
However, most reports support mature dendritic cells (DC) as the only APCs with
the ability to prime naïve T-cells, and from the perspective of therapeutic potential,
most recent attention has concentrated on directly or indirectly targeting antigen to
these. Nonetheless, a recent report indicates that γδ T-cells may also have this capacity
(643) being able to simulate mature DC function by processing and displaying antigens as
well as providing co-stimulatory signals sufficient for strong induction of naïve αβT-cell
proliferation and differentiation.
DCs constitute only ~0.2% of the circulating white blood cell population (644) but are
distributed throughout tissues where they act as sentinels. They function as biological
vacuum-cleaners by pinocytosing, endocytosing and phagocytosing extracellular antigens,
processing up to 4 times their own volume of extracellular fluid (ECF) in 1 hour, and
converting proteins into peptide (645). A more important source of antigens may be apoptotic
or necrotic cells; their display of aberrant surface molecules (such as phosphatidyl serine,
usually confined to the inner plasma membrane leaflet), marks them as targets for
phagocytosis by DC. DC have the unique property of efficiently cross-presenting antigens:
that is, they are capable of processing antigens derived from other cells, and presenting
derived peptide fragments on their MHC class I molecules, for presentation to CD8 T cells.
Like other “professional” APC such as monocytes, they can also present extracellular
antigens via MHC class II, for presentation to CD4 T cells.
Highly motile DCs with their captured antigens migrate via lymphatic channels to lymph
nodes where the antigen is presented to prime naïve T-cells or re-activate resting memory
T-cells. Signalling through pattern-recognition receptors on DC, such as Toll-Like
Receptors (TLR), facilitates their migration, and subsequent secretion of IL-2 & IL-12,
which appear to be crucial cytokines for the development of a successful cellular
response. Early interactions with activated NK cells and CD4 T cells in the lymph
node may further contribute to the effectiveness of the priming process (646-649).




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        Figure 4. Precise alignment of co-stimulatory & adhesion molecules required for
        T-cell recognition of presented antigen in MHC receptor

        (v) Ignorance, Tolerance to self, and autoimmunity
        Autoimmune disorders tell us that the immune system can effectively target self
        antigens. Some self-reactive T cells escape deletion in the thymus (i.e., central
        tolerance) and inactivation in the periphery (i.e., peripheral tolerance), for example
        via regulatory T cells. Insufficient presentation of antigen or access to target tissues
        could account for “ignorance”, in which potentially self-reactive T cells remain in a
        resting state. For immunological purposes, most tumour antigens (with the possible
        exception of mutated or aberrantly translated proteins) fall into these categories. The
        challenge for tumour vaccine strategies is to convince the immune system that these
        antigens are legitimate targets for attack.

        (vi) Some strategies employed by tumours to thwart cytotoxicity
        Successful prostate tumours „evolve‟ genetically, epigenetically, or environmentally
        to evade detection and destruction by immune defence mechanisms. Strategies
        include:


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    1. Reduced MHC class I expression
    1. Loss of co-stimulatory molecules
    1. Antigen negative variants
    1. Production of mucins to disguise antigens
    1. Tumour production of Fasl
    1. Significantly reduced DC numbers
    2. Expression of activation markers by only a small subset of DCs (650)
    3. Suppression of T-cell proliferation by PSA in a dose-dependent manner (651)

(vii) Immunotherapeutic strategies
The current status of vaccine studies in prostate cancer was recently reviewed by
McNeel and Malkovsky (2005) (652): a brief outline of the various approaches
available is provided below. A major limitation with immunotherapy studies is a
lack of known antigens recognized by T cells and expressed by prostate cancers. This
deficiency is related to the difficulty of generating cell lines from patients‟ tumours.
Antigens validated thus far (such as hTERT, survivin, PSMA, PSA) have been first
proposed on the basis of selective overexpression in tumours, rather than discovered
ab initio using T cells recognizing tumour cells. We thus have no knowledge of their
relative importance in T cell mediated immunity. Nonetheless, the prostate is a
highly specialized organ, and therefore (if tolerance can be overcome) potentially
expresses many putative specific targets for an immune response.

(a) Passive immunisation
Although passive immunization with in vitro-activated anti-tumour T cells is used
against other tumours, in particular for lymphomas as a result of Epstein-Barr viral
infections following organ transplantation, the relative difficulty of generating and
validating anti-tumour T cells has discouraged this approach in prostate cancer.

(b) Non-specific immune stimulants & adjuvants

1. Cytokines
The use of cytokines such as GM-CSF and IL-2 therapeutically was initially in the
form of unphysiological doses delivered intravenously and, as such, was associated
with significant systemic side-effects. More recently, cytokine activities have been
harnessed more discretely as part of other treatments rather than as therapies in
their own right.
GM-CSF, in particular, is an important component in many vaccines, regulating
growth and differentiation of haemopoietic cells and acting at several sites in the
generation of the immune response. These include activation of ADCC of
neutrophils, chemo-attraction of eosinophils and induction of differentiation of DCs
(652).

2. Non-specific Adjuvants
Flt3 ligand, is a growth and differentiation factor for DCs. In a transgenic murine
model, Flt3 ligand on its own was able to result in prostate cancer regression (653) In
support of this finding, McNeel et al (2003) (654) reported a marked increase in DCs
in the blood with vaccine preparations containing flt3 ligand (654).
An attenuated form of the tuberculosis bacilli, bacillus Calmete-Guérin (BCG), is a
non-specific immune stimulant which was initially developed to vaccinate patients
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        against tuberculosis. The major role for BCG oncologically is as an intravesical agent
        in superficial bladder cancer where it is administered to minimize tumour
        recurrences. However, it has potential utility in DC-based vaccines as a non-specific
        immune stimulant. Another mycobacterium, mycobacterium vaccae was
        administered in combination with irradiated cell lines by Eaton et al (2002) (655) in
        60 men with prostate cancer: although there was absence of a clinical response, some
        increases in specific antibodies were present in association with T cell proliferation
        (655).
        A further non-specific adjuvant we have used in one of our studies is keyhole limpet
        haemocyanin (KLH). However, one concern with the use of nonspecific adjuvants
        such as Flt3 ligand, BCG and KLH is that, although they may invoke proliferation
        and expansion of dendritic or T-cells, these may not induce/include those
        particularly relevant lymphocytes to produce the desired response for effective
        tumour cell killing.

        3. Specific Adjuvants
        Ligands for the Toll-Like Receptors (TLRs), pattern recognition receptors of the
        immune system, have received much attention recently, in particular
        deoxycytidyl-deoxyguanosin oligodeoxynucleorides (CpG). CpG which mediates its
        activities via TLR-9 induces DC activation and proliferation, increased
        co-stimulatory molecule expression and secretion of IFN, Il-1, 6 &12 and TNFα (656).
        In addition to adjuvants specifically included in vaccine preparations to enhance efficacy,
        other therapies may interact with patients‟ immunological responses. Certain
        nitrogen-containing bisphosphonates such as paidronate and zoledronic acid are potent
        stimulators of Vγ9Vδ2 cells which constitute the majority of the small population of γδT-cells
        in the peripheral circulation. Vγ9Vδ2 cells recognise non-peptide antigens and, as they are not
        reliant upon antigen presentation via the MHC receptor, are able to effect target cell killing
        rapidly (657).

        (c) Active immunization
        The recent expansion of interest in vaccines has been largely focused on DCs together with αβ
        Cytotoxic CD8+ T-cells and Helper CD4+ T-lymphocyte recruitment and activation.
        Potential sources of DC cells for vaccine production are umbilical cord blood, bone marrow
        and peripheral blood. The discovery that myeloid DCs can be generated readily from
        monocytes or very early (CD34+) precursors has served as a great boost with most studies
        using monocyte-derived DCs (MoDCs) which are loaded with antigen in-vitro. This topic has
        been reviewed recently in an excellent article by Figdor et al (2004) (644).
        To date, the large majority of prostate cancer vaccine studies have been phase I trials
        undertaken on patients with advanced disease. Large tumour burdens and the heterogeneity of
        these patients‟ cancers together with potential sub-optimal immunocompetence of the vaccine
        recipients may serve to understate the real potential of this therapeutic approach. In contrast to
        cytotoxic chemotherapy regimens, a striking feature has been just how well these vaccines
        have been tolerated with a virtual absence of serious adverse events.
        Heiser et al (2002) (658) examined escalating doses of PSA mRNA-transfected DCs in their
        vaccines without any evidence of dose-related toxicity or adverse effects and Ridgway et al
        (2003) (659) reported that, in 100 trials which involved >1000 patients, there was a complete
        absence of severe adverse events (659) Certainly, the concern of inducing serious
        auto-immune reactions has not been seen, at least in the short-term.

        1. Whole cell vaccines
        As clinical studies with re-injection of irradiated autologous tumour cells alone did not
        demonstrate a significant benefit, immune stimulants were introduced and used concomitantly.
        Simons reported injection of autologous cancer cells transfected with retroviral construct to
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express GM-CSF into patients with advanced prostate cancer (660) as a prelude to the use of
the androgen dependent and PSA producing LNCaP and androgen independent and non-PSA
secreting PC3 cell lines transfected to express GM-CSF (661).
Because of the limited number of prostate cancer cell lines available for use as a source of
antigens for presentation to T cells, one strategy to increase the number and variety of antigens
has involved culturing freshly obtained prostatic tumours which are then transfected after
several passages to confer immortality (Onyvax™). Although this approach promises to
provide a greater range of readily available and suitable antigens, that the cells are transfected
virally is likely to limit their utility to patients with advanced disease, at least initially.
In order to overcome the limitations imposed by cell lines, we have been harvesting soft tissue
metastases from men with progressing hormone-escape cancer. The tumour is then processed,
which includes a sub-lethal dose of radiation, prior to being made available to DCs derived
from cells of the monocyte lineage (MoDCs) in vitro. In this ongoing trial, we have had one
man who has demonstrated a complete response at 12 months with total resolution of large
lymph node metastases radiologically and a PSA which has decreased from 150 ng/ml at
baseline to 4.7 ng/ml. Other patients have demonstrated partial responses - approximately
20% overall – but most have not. Amongst other explanations for the variability in response,
this may indicate that harvested tumours did not reflect a sufficiently comprehensive
representation of antigenically relevant molecular changes common to all metastases which
could be processed by DCs and presented to αβ T cells to result in killing of all tumour cells.

2. Protein-based vaccines
A more defined approach than using whole cells containing a variety of proteins and other
factors, is to use flagged proteins, in particular those which are predominantly prostate
specific (lineage markers) as the source of antigens for priming DCs. Unlike whole cell
preparations, these have the potential advantage of being recombinant with the added
possibility of subtle modifications being incorporated to enhance their immunogenicity with
APC processing. Those examined have included prostate acid phosphatase (PAP) (662), and
prostate specific antigen (PSA) (663-665) in particular.

3. Peptide-based vaccines
As αβ cytotoxic CD8+ T-cells and αβhelper CD4+ T-cells recognize antigens as processed
8-10 or 12-20 amino acids, respectively, by APCs through their appropriate MHC receptors,
so vaccines have been produced with specific peptides. Among the many molecular targets to
which peptide sequences can be constructed, prostate specific membrane antigen (PSMA)
peptides were used most widely especially in early phase I-II trials, with reported response
rates of 20-30% (666, 667) Unlike PSA which, at a cellular level, is expressed more strongly
in non-cancerous cells, PSMA is overexpressed in most prostate cancers as well as in tumour
neovasculature (138).
Although peptides are very attractive in the sense that they can be synthesized and made
available as „off-the shelf‟ preparations, they have the huge disadvantage that patient
responses are MHC restricted. Consequently, people who do not have the appropriate HLA
phenotype, which for PSMA peptides is HLA-A2+ (constituting ~40% of populations in
many western countries), are unlikely to mount a TH1 response if they are administered
vaccines based on PSMA peptides.
In order to overcome this problem, Noguchi et al (2003) (668) tested 10 men with hormone
escape prostate cancer to determine whether or not cytotoxic T cell precursors were detectable
for 14 peptides. As these peptides were HLA-A24 restricted, all ten were shown to express the
HLA-A24+ phenotype before commencement of the study. Patients were then vaccinated
subcutaneously with up to 4 types of peptides to which their pre-vaccination peripheral blood
mononuclear cells reacted. Four of the 10 men developed increased cytotoxic T-cell responses
to peptides and cancer cells with anti-peptide IgG antibodies identified in 7 patients. One man
developed a partial response with an 89% decrease in PSA. Stable disease was demonstrated
in 5 of the 10 patients for a median duration of 2 months (668).

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        4. RNA
        Recently, use of RNA has attracted much attention for a number of reasons, not least of which
        is the need for only minute amounts of tumour tissue or recombinant material required.
        Tumour RNA potentially encodes multiple epitopes for many HLA alleles and, consequently,
        extends the scope of vaccination to cancers in which potent T cell epitopes have not been
        identified (669) In order to permit this approach, techniques have been developed recently for
        highly efficient RNA transfection of DCs by electroporation (670-672). RNA taken up by
        DCs is translated and the resulting polypeptides have the potential to bind to MHC molecules
        for presentation to T cells.
        Cytoplasmic antigens in somatic cells, as a result of intracellular degrading processes, are
        channelled preferentially via the Class-I presentation pathway, thereby activating primarily
        antigen-specific CD8+ T cells (673). By contrast, membrane-associated antigens are more
        likely to be shunted through the endosomal pathway and peptides presented on MHC-Class II
        receptor for CD4+ T-cell recognition (Figure 3).
        The importance of mounting both a CD4+ and a CD8+ response for effective tumour killing
        has been highlighted recently. Furthermore, the importance of activating specific CD4+ T
        cells concurrently to facilitate initiation, potentiation & maintenance of an effective
        anti-tumour immune response may be harnessed more precisely via RNA (674-676).
        Heiser et al (2001) (677) reported induction of a polyclonal CaP-specific cytotoxic T-cell
        lymphocyte (CTL) response with DCs transfected with amplified tumour RNA (677).
        Subsequently the same group published their experience with a vaccine consisting of DCs
        transfected with mRNA encoding PSA. They found a potent T-cell mediated anti-tumour
        response in-vitro prompting a phase I study in which this finding was replicated in all patients,
        6/7 of whom had a significant decrease in the log slope of PSA (644).
        More recently, a strategy to curtail immortality of tumour cells was reported by Su et al (2005)
        (669) who targeted telomerase, the enzyme that prevents telomeres on the ends of
        chromosomes from shortening (669). By priming DCs with the human teleomerase reverse
        transcriptase (hTERT), αβ CD8+ cytotoxic T-cells can be primed to target tumours. Although
        this strategy, which can be engineered to obtain both CD8 and CD4 responses, is likely to be
        comprehensive in targeting most tumour cells, a theoretical concern is that other immortal
        cells such as non-cancer stem cells also may be affected by vaccines targeting telomerase
        (669).

        5. Carbohydrates
        Tumours expressing high levels of certain carbohydrate antigens exhibit a greater propensity
        for progressing and metastasising, which is manifested in a reduced survival rate. In prostate
        cancer, globo-H, MUC1,GM2 and Thompson-Friedenreich antigen have been found to be
        preferentially expressed (678,679) in this regard and this has led to vaccine trials with
        combination carbohydrate-KLH conjugates (680, 681).

        6. Viruses
        Based on the observation that a number of viral pathogens are able to elicit potent cytotoxic
        T-cell responses, viral constructs which express specific epitopes have been used. These
        include recombinant vaccinia and fowlpox viruses expressing PSA and B7.1 co-stimulatory
        genes (682, 683) In addition, DNA plasmids which encode for selelcted genes, have been used
        to produce immune responses to the gene products (684).

        (viii) Summary
        Although considerable advances are being made in vaccine therapies, they remain
        experimental and, as such, need to be integrated into clinical management in the form of
        research trials. However, it is hoped that the promise they bring will be realised increasingly
        so that they become an established form of therapy in the foreseeable future.


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XVII. CONCLUSIONS
      The contemporary management of prostate cancer has been shaped the utilization of PSA
      serology for prostate cancer detection and monitoring. One result of PSA early detection
      programmes is that younger patients are being diagnosed with and treated for prostate cancer.
      Consequently, there has been a concerted effort to improve long-term cancer control while
      preserving urinary and sexual function. This has been facilitated by the anatomic radical
      prostatectomy with, more recently, endoscopic modifications, as well as by advances in
      radiotherapy and other treatments. Consequently, increasing numbers of men are being cured
      of their prostate cancers and, by tailoring therapy to accomodate patients‟ wishes, more and
      more are able to be satisfied with their quality of life throughout what is often a long period of
      management.
      The past 10 years has witnessed a surge in basic, clinical, and translational research in prostate
      cancer. Fortunately, we are in the midst of a period of unprecedented collaboration between
      scientists and clinicians placing patients in a most favourable position to benefit from
      advances in basic science and experimental therapeutics. Even if a cure is not imminent, the
      welfare and quality of life of those diagnosed with this condition promises to continue to
      improve at an exponential rate through the careful and critical application of research
      findings.

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Notes
        1. http://www.andrologyaustralia.org/
        2. http://www.prostatehealth.org.au/
        3. http://www.cdc.gov/cancer/prostate
        4. http://www.cancerbacup.org.uk/
        5. http://www.bostwicklaboratories.com/
        6. http://www.nhmrc.gov.au/publications/_files/cp88.pdf
        7. http://www.nelh.nhs.uk/guidelinesdb/html/Prostate-ft.htm
        8. http://www.uroweb.nl/files/uploaded_files/2005ProstateCancer.pdf
        9.
               http://www.cancer.gov/cancertopics/understanding-prostate-cancer-treatm
             ent/page5
        10. http://www.prostatehealth.org.au/
        11. http://www.ohri.ca/decisionaid




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