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					HUCH, J H  • S A 01/2005




                                     Surgical Hospital,
                            Helsinki University Central Hospital
                                             and
                           Department of Surgery, Jorvi Hospital
                            Helsinki University Central Hospital
                                   University of Helsinki
                                             and
                                Central Hospital of Jyväskylä




      HOW TO IMPROVE RESULTS IN RECTAL
              CANCER SURGERY
                                    A CLINICAL STUDY




                                      J V


                                  A D




    To be presented, with the assent of the Faculty of Medicine, University of Helsinki,
  for public examination in the Auditorium of Jorvi Hospital, Helsinki University Central
              Hospital, Turuntie 150, Espoo, on October 28th, 2005, at 12 noon
Supervised by        Docent I K, MD
                     Central Hospital of Jyväskylä
                     Jyväskylä, Finland

Reviewed by          Professor H J, MD
                     Helsinki University Central Hospital
                     Helsinki, Finland

                     Professor J M, MD
                     Oulu University Central Hospital
                     Oulu, Finland

Opponent             L P, MD, PhD, FRCS, FRCS (Glasg)
                     Professor of Surgery
                     Department of Surgery, University Hospital
                     Uppsala, Sweden




Publisher            Hospital District of Helsinki and Uusimaa
                     HUCH, Jorvi Hospital
                     Turuntie  • FIN– Espoo • Finland
                     tel +   • telefax +   
                     http://www.hus.fi/jorvi • firstname.surname@hus.fi

Editorial Board      H A, Editor in chief
                     T B
                     K J
                     T H
                     J K
                     L T


                                      ISSN -
                              ISBN --- (paperback)
                                 ISBN --- (PDF)

                http://www.hus.fi/jorvi/julkaisut • http://ethesis.helsinki.fi

                             Helsinki University Printing House
                                       Helsinki 
CONTENTS




LIST OF ORIGINAL ARTICLES..................................................................................................4
LIST OF ABBREVIATIONS .........................................................................................................5
ABSTRACT...................................................................................................................................6
INTRODUCTION ........................................................................................................................8
REVIEW OF THE LITERATURE ...............................................................................................10
           Colorectal cancer screening .........................................................................................10
                    Faecal occult blood tests ...............................................................................10
                    Endoscopic screening ...................................................................................10
                    Biomarkers of neoplastic transformation....................................................11
           Surgical treatment .........................................................................................................11
                     Anatomical aspects .......................................................................................11
                     Spread patterns..............................................................................................12
                     Surgical techniques .......................................................................................12
           Complications connected to surgery...........................................................................13
                   Mortality and morbidity................................................................................13
                   Anorectal dysfunction...................................................................................14
                   Sexual and urinary dysfunction ..................................................................15
           Local recurrence and survival ......................................................................................16
           Elderly patients – special considerations ....................................................................17
           e role of adjuvant therapies ......................................................................................17
                    Preoperative radiotherapy and chemoradiotherapy ..................................17
                    Tumour response ..........................................................................................18
           Quality of life after rectal cancer surgery.....................................................................19
AIMS OF THE STUDY...............................................................................................................20
PATIENTS AND METHODS.....................................................................................................21
RESULTS ....................................................................................................................................25
DISCUSSION .............................................................................................................................32
CONCLUSIONS.........................................................................................................................37
ACKNOWLEDGEMENTS.........................................................................................................38
REFERENCES ............................................................................................................................40
ORIGINAL PUBLICATIONS.....................................................................................................50
LIST OF ORIGINAL ARTICLES




    is thesis is based on the following original articles, which are referred to in
    the text by their Roman numerals:

    I   V J, K S, A L, K I. A comparison
        of peanut agglutinin (PNA) -test and immunochemical faecal occult blood
        test in detecting colorectal neoplasia in symptomatic patients. Scand J Clin
        Lab Invest ; : –.

    II V J, H L, S P, K L, S T, H A,
       K I. New approaches in the management of rectal carcinoma
       result in reduced local recurrence rate and improved survival. Eur J Surg
       ; : –.

    III V J, S P, H A, K I. Complications and Survival
        after surgery for rectal cancer in patients younger than and aged  or
        older. Dis Colon Rectum ; : –.

    IV V J, J M, K M, J I, K I.
       Tumor regression grading in the evaluation of tumor response after
       different preoperative radiotherapy treatments for rectal carcinoma. Int J
       Colorectal Dis ; : –.

    V V J, K M, K I. Impact of functional
      results on quality of life after rectal cancer surgery. Dis Colon Rectum
      (submitted).




4                                                    HUCH, Jorvi Hospital Publications • Series A 01/2005
LIST OF ABBREVIATIONS




                         APR              Abdominoperineal resection
                         AR               Anterior resection
                         ASA              American Society of Anaesthesiologists score
                         CRM              Circumferential resection margin
                         ERUS             Endorectal ultrasound examination
                         FOBT             Faecal occult blood test
                         Gy               Gray (radiation dose)
                         HAR              High anterior resection
                         HRQoL            Health related quality of life
                         LAR              Low anterior resection
                         PNA              Peanut agglutinin
                         PRT              Preoperative radiotherapy
                         QoL              Quality of life
                         RAND  -item Quality of Life questionnaire
                                 distributed by RAND corporation
                         RT               Radiotherapy
                         SF             Short Form  (Quality of Life questionnaire)
                         TME              Total mesorectal excision
                         TRG              Tumour regression grading




HUCH, Jorvi Hospital Publications • Series A 01/2005                                      5
ABSTRACT




e aim of the present study was to examine       periods (Study II). A significantly lower
possibilities for improvement of the results     -year crude survival was seen in the older
in rectal cancer surgery from detection of       age group compared to younger patients
the cancer to outcome in terms of survival       (  vs.  , P = .). However, -year
and patient satisfaction.                        cancer-specific survival (  vs.  ,
    In Study I the sensitivity and specificity   P = .) and disease-free -year survival
for detecting colorectal neoplasia of PNA-       (  vs.  , P = .) were similar in both
rectal mucus test was compared with those        groups. e number of complications ( 
of an immunological test for faecal occult       vs.  ) and -day mortality (  vs. )
blood (Hemolex) in  patients examined         were similar in both groups. More elderly
for colorectal symptoms in the Surgical          patients were not operated on at all ( 
Hospital of Helsinki University Central          vs.  , P = .) compared to patients
Hospital. e sensitivity of the PNA-test         younger than  (Study III). ese studies
and Hemolex for colorectal neoplasia was         show that adopting TME-technique and
  vs.   and specificity   vs.        selective use of preoperative radiotherapy
(P = .) showing that a single PNA-test       leads to improved survival. Furthermore,
is as sensitive indicator of colorectal neo-     in selected elderly patients major curative
plasia as Hemolex completed over three           rectal cancer surgery can be done with
days, but lacks specificity. Some commonly       similar indications, perioperative morbid-
expressed PNA-binding proteins were iden-        ity and mortality as well as -year cancer-
tified both in normal mucosa and colorectal      specific and disease-free survival as in
cancer, but expression of  kD PNA-bind-       younger patients.
ing protein was seen almost exclusively in          Patients treated for rectal cancer in the
colorectal cancer. Characterization of that      Central Hospital of Jyväskylä during –
cancer-associated antigen may help in de-         (N = ) were included in Studies IV
veloping a more specific PNA-test.               and V. e usefulness of histologic tumour
    e patients treated in the Surgical          regression grading (TRG) in quantifying the
Hospital for rectal cancer during –        effect of preoperative radiotherapy (PRT)
(conventional surgery, N = ) and dur-         or chemoradiation was examined and
ing – (total mesorectal excision,          compared with the downstaging defined as
TME, N = ), were included in Studies           a change in preoperative T stage obtained
II and III. e effect of refinement of the       with endorectal ultrasound examination
surgical technique in complication rate,         (uT) and pathologic stage (pT) (Study
local recurrence rate and survival was           IV). e histologic tumour regression was
studied, as well as whether elderly patients     more marked after long-term chemora-
(≥  years, N = ) can be treated using        diation than after short-course radiotherapy
similar indications as younger patients          (P = .). Complete response (no residual
(N = ) with acceptable perioperative          tumour, TRG ) was seen in   of the pa-
morbidity, mortality and survival. e            tients and total or major regression (TRG
actuarial local recurrence rate for poten-       –) in   of the patients treated with
tially curative rectal cancer improved from       Gy chemoradiation (N = ). Of those
  to   and the crude -year survival        treated with  Gy PRT (N = ),  
from   to   between the two study          showed major tumour regression. When


6                                                        HUCH, Jorvi Hospital Publications • Series A 01/2005
comparing uT with pT,   of the tumours              QoL of rectal cancer patients was not worse
were downstaged, but less than half of                 than that of general population. Between
the dowstaged tumours showed marked                    the treatment groups (sphincter-preserv-
response by TRG. In comparison,   of                ing surgery vs. abdominoperineal resec-
the tumours with no downstaging showed                 tion) there was no significant difference in
marked response by TRG (P = .). In as-              QoL. Major bowel dysfunction impaired
sessing tumour response to preoperative                social functioning significantly compared
adjuvant therapy TRG seems to offer a more             to patients without such symptoms. e
reliable means than uT-downstaging, which              QoL of symptomatic patients was similar
did not correlate with TRG results.                    to that of patients having undergone APR.
   e impact of surgery-related adverse                Urinary dysfunction impaired social func-
effects on the quality of life (QoL) was ex-           tioning and impotence physical and social
amined using generic RAND- question-                 functioning. In an attempt to improve QoL
naire and questionnaires assessing urinary,            after rectal cancer surgery, minimizing the
sexual and bowel dysfunction. Results                  incidence of organ dysfunction seems to be
were compared with age and sex-matched                 at least as important as aiming to sphincter-
Finnish general population (Study V). e               sparing surgery.




HUCH, Jorvi Hospital Publications • Series A 01/2005                                              7
INTRODUCTION




Colorectal cancer is the second lead-           surgical technique has an important role
ing cause of cancer mortality in Western        in the outcome (Holm ; Porter ).
countries and its incidence and prevalence      Increasing evidence shows that refining
are increasing. In , a total of  new    and standardizing of surgical techniques
cases were detected in Finland (Finnish         decreases local recurrence rates as well as
Cancer Registry ). Of them  ( )       variability of results between individual sur-
were rectal tumours defined as having the       geons (Dahlberg ; e Norwegian Rectal
lower edge within  cm of the anus. Rectal     Cancer Group ; Kapiteijn ; Martling
cancer is the fifth most common cancer in       ). e technique of total mesorectal ex-
men and tenth most common cancer in             cision (TME), first introduced by Heald et al.
women with the incidence of ./         in  (Heald ), has been reported to
in men and ./  in women. With the       decrease the local recurrence rates to – 
population ageing the incidence is rising       and to improve the overall -year survival
even if the age-adjusted incidence seems to     from –  with conventional surgery
be stabilizing.                                 to   (Enker ; MacFarlane ).
   Prognosis depends on the extent of the       However, TME surgery seems to be associ-
disease at the time of diagnosis. e ben-       ated more often with potentially dangerous
eficial effect of early detection on mortal-    anastomotic leakages than the conventional
ity for colorectal cancer has been proved       surgery (Karanjia ).
in randomised screening programs (Towler           e number of elderly rectal cancer
). Based on an expected reduction           patients is increasing but few studies have
of   in mortality for colorectal cancer,     addressed the ability of elderly patients,
screening strategies are being evaluated for    who may have compromised physical ca-
implementation in several European coun-        pacity, to recover from adverse events that
tries, including Finland. Currently available   may occur in connection of major rectal
methods rely on faecal occult blood (FOB)       surgery. Uncertainty persists, as to whether
tests and subsequent endoscopic evalua-         elderly patients benefit from the same surgi-
tion in the case of positive test. Bleeding,    cal treatment as younger patients (Shankar
however, is not specific for colorectal neo-    ).
plasia and may be intermittent in the case         Additional benefits of local control can be
of asymptomatic tumours (Ahlquist ).        obtained with neoadjuvant treatment. It has
us faecal occult blood tests are hampered      been shown that preoperative radiotherapy
by high false positive and false negative       (PRT) or chemoradiotherapy increases the
rates. erefore, new non-invasive methods       resectability of low and locally advanced
to detect colorectal neoplasia at an early,     tumours (Minsky ) and improves local
asymptomatic phase are needed.                  tumour control and survival (Delaney ;
   Today, –  of patients can be oper-      Kapiteijn ; Swedish Rectal Cancer Trial
ated on with curative intent. However, a        ). However, dosage, timing and optimal
major problem after rectal cancer surgery       combination of radiotherapy and chemo-
is local recurrence after which outcome is      therapy are controversial as well as which
poor. Local recurrence rates vary consider-     patients should receive adjuvant treatment
ably between surgeons and institutions          (Simunovic ).
ranging from   to  , suggesting that          Both surgery and adjuvant treatments


8                                                        HUCH, Jorvi Hospital Publications • Series A 01/2005
are connected to adverse effects that may                  Improvements in treatment and early
significantly affect a person’s quality of life.       detection indicate that more patients will
Anal sphincter preservation is regarded                live with the consequences of the disease.
one of the main goals in rectal cancer                 Survival and local recurrence rate are im-
surgery to avoid disruption in a patient’s             portant but not the only factors contributing
quality of life (QoL) caused by colostomy              to good outcome results. Long-term func-
(Sprangers ). However, anal function               tional results have a major impact on quality
may be suboptimal after sphincter-saving               of life, which has emerged as an important
surgery, especially after coloanal anasto-             endpoint. With individualized treatment
moses (Lewis ). Also disturbances in               options available, emphasis can be placed
sexual and urinary functions are common                also to patient satisfaction and quality of life.
sequelae (Keating ). e effect of these            It is of major importance to pay attention to
physical disabilities in quality of life is not        details to ensure the best possible outcome
well known.                                            after treatment in all perspectives.




HUCH, Jorvi Hospital Publications • Series A 01/2005                                                  9
REVIEW OF THE LITERATURE




Colorectal cancer screening                      Rehydration by a drop of deionized water
                                                 increases the rate of positive tests from
ere is evidence that benign adenomatous         –  to –  (Mandel ). Rehydration
polyps develop into cancers in the colon.        thus increases the sensitivity of a guaiac
Accumulation of multiple genetic altera-         test, but is generally not recommended as
tions such as mutational activation of onco-     it decreases the specificity leading to high
genes and inactivation of tumour suppres-        number of false positive results.
sor genes leads to stepwise progression from        e sensitivity of guaiac based faecal
normal to hyperproliferative epithelium          occult blood test for detecting colorectal
and adenoma to carcinoma (Bronner ;          neoplasia in asymptomatic patients with an
Fearon ; Leslie ). Removing adeno-       average risk has been reported to be – 
matous polyps have been shown to reduce          (Hardcastle ; Kronborg ; Robinson
the incidence of colorectal cancer (Mandel       ; omas ) i.e. nearly half of the
; Winawer ). Also, early detection       cancers remain undetected with this test. A
of colorectal cancer by mass screening has       detection rate of –  has been reported
been shown to reduce mortality by   (RR       for symptomatic cancers (omas ).
.,   CI . to .) and, when ad-           Evidence     from     four    randomised
justed for screening attendance, by   (RR     controlled trials with Hemoccult II test
., CI .–.) (Towler ). However,      (Hardcastle ; Jorgensen ; Kewenter
the best screening method remains contro-        ; Kronborg ; Mandel ;
versial. e ideal screening requires high        Scholefield ) shows that detecting early
sensitivity and specificity in detecting early   stage cancers reduces mortality from the
stage disease and should be acceptable and       disease –  in the screened population
safe to patients, inexpensive and feasible in    (Table ).
general clinical practise (Winawer ).           Immunological tests, specific for human
                                                 haemoglobin, have been shown to be more
                                                 sensitive for symptomatic colorectal cancer
Faecal occult blood tests
                                                 than guaiac-based tests (Robinson ;
Guaiac tests based on the pseudoperoxidase       omas ). However, the specificity is
activity of haemin are the most commonly         lower;   vs.   in the asymptomatic
used tests both in the preliminary assess-       population and   vs.   in symptom-
ment of subjects with symptoms of colorec-       atic patients, respectively (Robinson ;
tal disease and in screening programs.           omas ). Randomised population
ese tests involve collection and testing of     based studies have not been performed
six samples from three consecutive stools        with immunological tests.
of a patient. A specific diet to minimize the
number of false positive results (avoidance
of red and white meat, fish, fresh fruit and
                                                 Endoscopic screening
uncooked vegetables i.e. substances with         Case-control and uncontrolled cohort
peroxidase or pseudoperoxidase activ-            studies suggest that endoscopic screening
ity) is recommended before the testing is        with polypectomy reduces the incidence of
performed. Stool samples can be tested in        colorectal cancer by –  (iis-Evensen
either a dehydrated or rehydrated state.         ; Winawer ) and may be even more


10                                                       HUCH, Jorvi Hospital Publications • Series A 01/2005
effective in detecting colorectal neoplasia                      antigens) (Shamsuddin ) or complex
than FOBT (Segnan ). Furthermore, an                         macromolecules (Roseth ). ese an-
increase in the proportion of early cancers                      tigens can be detected using lectin and an-
(Atkin ) and decrease of –  in can-                     tibody immunohistochemistry. Increased
cer mortality compared to non-screened                           binding of the lectin peanut agglutinin
patients have been reported (Muller ;                        (PNA) is a common feature in colorectal
Newcomb ; Selby ). However, no                           carcinoma and hyperplasia (Rhodes ).
results from randomized studies are avail-                       PNA binds to the disaccharide omsen-
able so far.                                                     Friedenreich blood group antigen (galac-
                                                                 tose-b--N-acetyl-galactosamine), which
                                                                 is an oncofetal antigen commonly ex-
Biomarkers of neoplastic transformation
                                                                 pressed in colorectal cancer but concealed
Specific biomarkers of neoplastic trans-                         by further glycolysation (sialylation and/or
formation in colorectal mucosa, including                        fucosylation) in the normal colorectal
mutations in APC (adenomatous polyposis                          mucosa (Campbell ). Previous studies
coli tumour suppressor gene), K-ras, p                         have shown that PNA-reactive carbohydrate
and BAT  (a marker of microsatellite in-                       alterations in rectal mucus have a sensi-
stability), have potential to be used as new,                    tivity of –  in detecting colorectal
non-invasive methods to detect colorec-                          cancer (Kellokumpu ; Sakamoto ;
tal neoplasia (Ahlquist ; Mak ;                          Shamsuddin ).
Sidranski ). Neoplasm-specific altered
DNA from tumour cells is released into the
bowel lumen more continuously than blood
                                                                 Surgical treatment
and is stable in stool having thus potential
to be used as a screening method. However,
                                                                 Anatomical aspects
colorectal neoplasms are genetically het-
erogeneous and multiple DNA alterations                          Rectum comprises the terminal  cm of
should be targeted to achieve high sensitiv-                     large bowel. Fatty tissue called mesorectum,
ity (Ahlquist ).                                             containing the terminal branches of the
   Besides tumour-derived mutations in                           superior rectal vessels and the lymphatic
genes the new biomarkers isolated from                           drainage of the rectum, surrounds the
faecal samples or bowel lumen include                            rectum and is covered by visceral fascia
secretion of abnormally glycosylated carbo-                      (fascia propria). Posteriorly rectum is
hydrate structures (e.g. tumour-associated                       wholly extraperitoneal whereas anteriorly



Table 1. Results of randomised controlled trials of colorectal cancer screening using
Hemoccult II test.


                                 Minnesota             Nottingham          Funen              Goteborg
 Study
                                 (Mandel 2000)         (Hardcastle 1996)   (Kronborg 1996)    (Kewenter 1994)
 Population size                 46 500                150 000             62 000             68 000
 Age group (years)               50–80                 45–74               45–75              60–64
 Study period (years)            18                    12                  13                 8
 Reduction of
                                  33* (21**)           15**                18**               12**
 mortality (%)
 RR (CI)                         0.80 (0.70–0.90)      0.85 (0.74–0.99)    0.82 (0.69–0.97)   0.88 (0.69–1.12)

* Annual screen
** Biennial testing


HUCH, Jorvi Hospital Publications • Series A 01/2005                                                             11
only the distal third is extraperitoneal and    Lateral lymphatic spread to internal iliac
separated from bladder and genital organs       nodes on the pelvic sidewalls may occur
by Denonvilliers´ fascia. Posteriorly there     especially in case of low rectal cancers in
is an avascular retrorectal space between       approximately   of patients and in up to
parietal and visceral fascia. Parietal fascia   one third of those with positive mesorectal
thickens over sacrum and coccyx forming a       nodes (Moriya ; Sugihara ; Ueno
dense Waldeyer´s fascia (Havenga a).        ).
   e pelvic autonomic nervous system
is located between peritoneum and vis-
                                                Surgical techniques
ceral fascia and is intimately related to the
rectum. Hypogastric nerves exit bilaterally     Radical surgery aims at removing the tu-
from the superior hypogastric plexus at the     mour with its all extensions, including the
level of the sacral promontory. Caudally        area of vascular and lymphatic drainage
they run parallel to ureter and iliac ves-      as well as direct spread to adjacent organs,
sels on each side of the pelvis uniting with    with adequate margins of clearance.
the pelvic splanchnic nerves to form the           Proximally, the mesorectum is removed
inferior hypogastric (pelvic) plexus, which     to the level of aortic bifurcation including
also has connections with sacral roots          all lymph nodes distal to the origin of the
(S–). e superior hypogastric plexus and      left colic artery. Caudally, the technique of
hypogastric nerves are mainly sympathetic       total mesorectal excision (TME) stresses the
whereas pelvic splanchnic nerves are para-      importance of removing an intact mesorec-
sympathetic. Pelvic plexus is a dense plaque    tal envelope from the promontorium down
of nerve tissue that sends fibers towards       to the anal hiatus in pelvic floor by sharp
bladder, urethra and genital organs. Lateral    dissection between the visceral and parietal
mesorectum fuses with this structure from       planes of the pelvic fascia, confirming that
where some fibers enter anterior rectal wall    none of the mesorectal tissue remains in
as well. All nerves and vessels are embed-      the pelvis. In case of high tumours, how-
ded in fat and fibrous tissue resembling a      ever, mesorectum is transected in -degree
ligament, hence the name lateral ligament       angle at least  cm below the tumour. Pelvic
(Church ; Havenga a; Maas ).        autonomic nerves are carefully visualized
                                                and preserved (Heald ).
                                                   Figure  shows the difference between
Spread patterns
                                                TME and conventional surgery. With con-
Tumour spread along the muscle tube             ventional technique there is a tendency to
beyond  cm of the palpable edge of the         cone the dissection plane towards the rectal
tumour seems to be uncommon, except             wall posteriorly and laterally endangering
in poorly differentiated lesions (Williams      the radicality. Tumour spread to the lateral
). Instead, tumour growth is more           resection margin occurs in approximately
rapid in the transverse than longitudinal         of patients treated with conventional
axis of the bowel. Subsequently, submucosa      techniques but in less than   of patients
and muscle layer of the bowel are invaded       treated by TME (Birbeck ; Cawthorn
allowing the tumour growth enter into           ; Haas-Kock de ; Quirke ;
the mesorectum. According to modern             Wibe ).
understanding, distal and proximal tumour          It has been shown that as long as meso-
spread as microscopic foci within the me-       rectum is completely removed, the distal
sorectum occur frequently (Heald ;          mucosal margin can usually be safely
Reynolds ).                                 reduced to less than  cm (Karanjia ;
   e main route of lymphatic spread is to      Rullier ). Total mobilization of rectum
the chain of glands along the superior hem-     to the anal hiatus and utilizing modern
orrhoidal and inferior mesenteric vessels.      stapling devices and surgical techniques in


12                                                      HUCH, Jorvi Hospital Publications • Series A 01/2005
creating colorectal or coloanal anastomoses            Complications connected to surgery
ensures that sphincter-sparing surgery can
now be performed in –  of patients                Mortality and morbidity
(Enker ; Tytherleigh ). e tech-               Overall morbidity after rectal cancer sur-
nique of intersphincteric resection enables            gery varies between –  (Arbman ;
sphincter preservation even in patients                Carlsen ; Martling ). In addition to
with carcinomas located at the anorectal               anastomotic dehiscence and acute urinary
junction, if not invading the anal sphincter           retention the most common perioperative
(Rullier ).                                        complications are the same as after any
   Abdominoperineal resection is still nec-            major abdominal surgery (haemorrhage,
essary for a subset of patients with very low          respiratory-, urinary and wound infections,
or advanced tumours.                                   paralytic ileus and cardiovascular events).
   After high anterior resection, the bowel               Postoperative mortality after elective
continuity is usually re-established by                operations is generally less than   after
straight end-to-end anastomosis whereas                both conventional and TME-surgery (Enker
after low or ultralow anterior resection               ; Graf ; Heald ; Marijnen
colorectal or coloanal anastomosis can be              ; Martling ). Cardiac complica-
performed using J-pouch (Lazorthes ;               tions and anastomotic dehiscence are the
Parc ), side-to-end anastomosis (Huber             most common reasons for postoperative
) or coloplasty (Z´graggen ) in-               death (Carlsen ; Enker ; Graf ;
stead to restore the reservoir capacity. e            Marijnen ).
use of colonic pouch may also enhance                     e risk for anastomotic dehiscence is
the healing of the anastomosis compared                greater after low than high anterior resec-
to straight anastomosis (Hallböök a;               tion (Karanjia ; Pakkastie ; Rullier
Hallböök b).                                       ). TME surgery, resulting in more low



Figure 1. Conventional (a) vs. total mesorectal excision (TME) (b) technique in rectal cancer
surgery.

 a.                                                    b.




HUCH, Jorvi Hospital Publications • Series A 01/2005                                            13
anastomoses, is associated with leakage          tients have some degree of incontinence
rates of up to over   compared with that      compared with –  after low anterior
of approximately   after conventional sur-     resection (Dennet ; Gamagami ;
gery (Nesbakken ). e mortality rate         Ortiz ; Rullier ). Ultralow anterior
associated with anastomotic leakage varies       resections, extending to the anorectal junc-
between   and   (Rullier ).             tion or more distally into the anal canal, and
   e use of a protective stoma after TME        coloanal anastomosis, have been associated
surgery and low anastomosis has been             with controversial functional results with
shown to lower the rate of clinically relevant   –  of patients having problems with
leakages from –  to –  (Carlsen          continence (Gamagami ). Functional
; Dehni ; Marijnen ; Marusch         results after intersphincteric resections, in-
), especially in men (Law ; Poon         cluding removal of internal sphincter, have
; Rullier ), and therefore its routine   been reported to be satisfactory with about
use has been recommended (Karanjia ).          to   of patients having occasional
A defunctioning stoma does not necessarily       soiling and –  suffering from urgency
prevent leakage, but reduces the need for        (Rullier ; Saito ; Schiessel ;
reoperations and the risk for permanent          Tiret ). Erratic defecation patterns have
stomas. Some favour selective use of stoma       been reported in  , urgency in   and
only, as complications related directly to       obstructed defecation in   of patients
stoma have been reported in –  of           after rectal cancer surgery (Ortiz ).
patients (Heald ; Poon ).                   Randomised trials that compared
   Preoperative radiotherapy utilizing mod-      J-pouch anastomosis with straight end-to-
ern techniques does not seem to increase         end anastomosis have shown functional
mortality or the risk of anastomotic leakage     superiority of the J-pouch, especially in the
(Enker ; Marijnen ; Swedish Rectal       early months after surgery (Hallböök b;
Cancer Trial ; Valero ).                 Lazorthes ; Ortiz ; Rullier ;
                                                 Seow-Choen ). Even after one year
                                                 urgency is more common and the median
Anorectal dysfunction
                                                 stool frequency per day higher with straight
Anterior resection is associated with a          anastomosis than with a J-pouch (Harris
variety of specific symptoms like increased      ; Lazorthes ), but may level by two
bowel function, erratic defecation pat-          years (Ho ). e majority of patients
terns, urgency, obstructed defecation and        with a pouch have a daily frequency of less
impairment of continence (Ortiz ).           than three bowel movements. In contrast,
Diminished rectal capacity and compli-           evacuation difficulties are more common
ance, impaired internal anal sphincter tone      with a pouch occurring in   to   of
and loss of rectoanal inhibitory reflex are      patients. e size of the pouch is critical to
the main causing factors (Lee ).             outcome; a – cm pouch seems to be op-
   e incidence of early postoperative           timal whereas a larger pouch is associated
functional disorders has been reported           with incomplete evacuation more often
to be as high as –  (Dennet ).          (Dennet ). Functional results compa-
Functional deficiencies improve over  to       rable to J pouch have been obtained using
years (Gamagami ; Ho ; Lee ;         end-to-side anastomosis (Machado )
Sailer ), but some degree of permanent       or coloplasty (Ho ; Pimentel ;
impairment of sphincter function after           Remzi ).
anterior resection seems inevitable (Lee            e effect of radiotherapy on anorectal
).                                           function is not fully known. Irradiated
   Functional results are worse the closer       patients recover slower from defecation
the anastomosis is to the anal canal. After      problems than patients treated with sur-
high anterior resection some   of pa-          gery alone (Marijnen ). ere is some


14                                                        HUCH, Jorvi Hospital Publications • Series A 01/2005
evidence that sphincter-related symptoms               tion has lowered the risk for sexual dysfunc-
(incontinence and pouch-related specific               tion but has not completely eliminated it
symptoms such as clustering and incom-                 (Keating ; Kim ; Nesbakken ;
plete evacuation) may also be more com-                Pocard ).
mon in irradiated patients than after surgery             e dysfunctional outcomes of pel-
alone (Gervaz ; Marijnen ).                    vic nerve damage in women are poorly
                                                       understood. e likely consequences,
                                                       impairment of sexual arousal and libido,
Sexual and urinary dysfunction
                                                       have been reported to be rare after TME
Disturbances to bladder and sexual func-               surgery (Havenga b; Nesbakken ;
tion are well known sequelae of rectal                 Platell ). Problems related to scarring
cancer surgery.                                        and changed anatomy (shortness or lack of
   Damage to the hypogastric nerves or                 elasticity of vagina during intercourse, dys-
sacral nerves or both, during operation is             pareunia) seem to be more common. Faecal
the most likely cause of sexual dysfunction            soiling during or after intercourse may also
(Havenga ; Keating ). It has been              be a problem.
shown that unilateral sacrifice of inferior               Adjuvant radiotherapy may affect on
hypogastric plexus with its parasympathetic            sexual functioning of both male and female
component makes failure of erection highly             patients. In a randomised study comparing
probable. Bilateral sacrifice makes total               Gy preoperative radiotherapy with sur-
impotence certain and often endangers                  gery alone, decrease in erectile function for
urinary function. Ejaculatory disorders are            up to  years was noted after PRT (Marijnen
related to sacrifice of the superior hypo-             ). Ejaculation disorders occurred more
gastric plexus (Maas ; Pocard ;                frequently too. In female patients, sexual ac-
Sugihara ).                                        tivity and functioning deteriorated signifi-
   Permanent complete or partial erectile              cantly more after PRT than surgery alone.
dysfunction has been reported in –  of               e rate of reported urinary dysfunction
patients, while –  of potent patients are          after surgery for rectal cancer ranges from
not able to ejaculate (Enker ; Havenga               to   (Leveckis ) presenting as
; Maas ; Nesbakken ; Sugihara              various complaints. e most common
). After abdominoperineal resection                symptoms are stress incontinence, urgency,
the risk for permanent impotence seems                 elevated frequency of voiding, difficulty
to be –  whereas low anterior resec-              emptying the bladder, loss of sensation of
tion carries about half the risk of impotence          fullness of the bladder and overflow incon-
compared to APR (Enker ; Havenga                   tinence.
; Keating ). Inadvertent damage to                Since most studies have been retrospec-
the pelvic nerves during the perineal phase            tive without urodynamic evaluation pre-
of operation particularly at the level of pros-        operatively, the incidence of dysfunction
tate may be one of the explanations for that,          attributable to surgery is not known. Many
but the altered anatomy of the pelvic floor            of these symptoms and latent dysfunction
caused by division of the perineal muscles             are very common in the population of
may also play a role. Patient age seems to be          same age as rectal cancer patients (Nuotio
the single most important factor affecting             ; Pocard ; Schatzl ), whereas
the risk of sexual dysfunction (Keating ).         urodynamic studies have shown that the
e risk has been reported to be more than              incidence of bladder dysfunction as a result
-fold in the patients over  years of age            of pelvic nerve injury seems to be fairly
compared with patients younger than that               low, –  (Del Rio ; Leveckis ).
(Havenga ). In patients, whose disease             With TME surgery and nerve preservation,
is confined to the mesorectum, adopting                neurogenic bladder requiring catheterisa-
TME-technique with pelvic nerve preserva-              tion is rare (Havenga ; Kneist ;


HUCH, Jorvi Hospital Publications • Series A 01/2005                                              15
Maas ), but occurs in –  if pelvic               Cancer of the low rectum treatable by ab-
autonomic nerves are completely sacrificed             dominoperineal resection is associated with
(Havenga ; Hojo ). ere does not               more local recurrences and poorer survival
seem to be any significant correlation be-             than anterior resection. After TME surgery,
tween the extent of nerve preservation and             -year survival rates of   after APR com-
minor urinary symptoms reported by the                 pared with that of   after sphincter pre-
patients (Maas ).                                  serving surgery have been reported (Enker
    Postoperative bladder dysfunction is of-           ). Similarly, local recurrence rates are
ten temporary (Del Rio ), whereas erec-            higher (–  vs. –  in midrectal can-
tile dysfunction does not seem to improve              cers), possibly because cancers of the low
after – months after surgery (Maas ).            rectum often present with more adverse risk
                                                       factors (positive nodal disease, vascular and
                                                       perineural invasion) (Enker ).
Local recurrence and survival
                                                          Circumferential resection margin (CRM)
With conventional blunt surgical resection             involvement has been shown to be a potent
of rectal cancer, local recurrence rates after         predictor of outcome with exponential
potentially curative operation are –              increase in the rate of local recurrence,
in reports from special interest centres and           metastasis and death with decreasing cir-
up to –  in general surgical practice.            cumferential margin. As many as   of the
With TME technique local recurrence rates              patients with margin involvement develop a
of below   have been reported consis-               local recurrence (Birbeck ; Nagtegaal
tently (Table ). Consequently, five-year              ; Quirke ). A disease-free margin
survival rates have improved from   to              of less than – mm carries a –  risk
  (Enker ; MacFarlane ; Wibe                of local recurrence compared to –  af-
a).                                                ter greater margins (Nagtegaal ; Wibe


Table 2. Local recurrence rate (LR) after surgery before and after adopting TME-surgery.
Figures are percents.


 Study                             Conventional surgery                   TME-surgery*
 (Period)                          Alone             With PRT             Alone                  With PRT
 1. Arbman et al
                                   22                                     6
 (1984–86 vs. 1990–92)
 2. Stockholm Study
                                   30                15                   9                      1.5
 (1980–87 vs. 1994–1997)
 3. Swedish Trial
                                   27                11
 (1987–90)
 4. Dutch Study
                                   22                                     9 (11)                 2.4 (5.8)
 (1987–90 vs. 1996–99)
 5. Danish Study
                                   30                                     11
 (1991–93 vs. 1996–98)
 6. Norwegian study
                                   28                                     8
 (1986–88 vs. 1993–99)

* Follow-up time since TME-surgery:
1. 4 years (Arbman 1996)
2. 2 years (Martling 2000)
3. (Swedish Rectal Cancer Trial 1997)
4. 2 years (Kapiteijn 2001; Kapiteijn 2002) (5 years(Marr 2005))
5. 3 years (Bulow 2003)
6. 3 years (Wibe 2003a)


16                                                                 HUCH, Jorvi Hospital Publications • Series A 01/2005
). About   of patients with positive            the other hand emergency presentation is
CRM develop metastasis compared with                   less common in rectal cancer than colon
  of patients with negative margins                 cancer (–  vs.  ) (Anderson ;
(Nagtegaal ; Wibe ). After a cura-             Shankar ). However, studies concern-
tive operation -year survival rate has been           ing the outcome of elderly patients with rec-
reported to be   vs.   in patients with          tal cancer are rare. In a retrospective study
and without CRM involvement, respectively              including  patients aged  or older and
(Birbeck ).                                         patients younger than that, the compli-
                                                       cation rate was similar in older and younger
                                                       age group (  vs.   respectively) and
Elderly patients – special
                                                       mortality rate .  vs. .  after elective
considerations                                         curative rectal cancer surgery (Puig-La Calle
Elderly patients with colorectal cancer                ). e selection criteria and number of
have a higher incidence of emergency                   patients deemed to be unfit for major sur-
presentation compared to younger patients              gery, however, was not reported.
(Anderson ; Hessman ; Mulcahy
). Perioperative mortality rates of the
elderly in different studies show a large
                                                       e role of adjuvant therapies
variability from  to   (Anderson ;
Chiappa ; Damhuis ; Fielding
                                                       Preoperative radiotherapy and
; Hessman ; Kingston ;
Mulcahy ); probably partly depending
                                                       chemoradiotherapy
on the proportion of emergency operations              Two European trials of conventional surgery
in each study. Emergency surgery is more               have shown that short-course preoperative
often than elective surgery associated with            radiotherapy ( Gy in five days) reduces
high perioperative morbidity and mortality             local recurrences from –  to – 
(Anderson ; Fielding ; Hessman                 (Holm ; Swedish Rectal Cancer Trial
; Mäkelä ).                                    ) and improves overall -year survival
    After elective surgery for colorectal can-         rate from –  to –  (Martling ;
cer, the cancer-specific survival seems to be          Swedish Rectal Cancer Trial ). In a ran-
similar to that of younger patients (Shankar           domised trial of standardized TME surgery,
). e number of patients deemed                    a decrease in local recurrence rate from
unfit for curative surgery, however, rises             .  in non-irradiated patients to .  in
with age (Damhuis ; Violi ). e                irradiated patients was seen at two years
concomitant diseases and fitness rather                after surgery (Kapiteijn ). A Swedish
than the chronological age seem to be the              study reported similar results; local recur-
factors affecting the outcome. In some stud-           rence rate was   vs. .  in non-irradi-
ies American Society of Anaesthesiologists             ated and irradiated patients, respectively
(ASA) score rather than the age was seen to            (Martling ) (Table ).
predict morbidity and mortality (Hessman                  Population-based studies have shown
), whereas others did not find that clas-          that –  of rectal cancer patients have
sification useful.                                     primarily nonresectable tumours and only
    Rectal cancer has many special features            half of them have distant metastases at the
with regard to anatomical boundaries and               time of diagnosis (Påhlman ). Locally
surgical strategies compared to cancer in              advanced tumours requiring downstaging
other parts of the large bowel. Rectal cancer          to be converted into mobile and resect-
surgery is associated with more frequent               able, cannot be effectively treated with  ×
complications (e.g. anastomotic leaks) than             Gy short course preoperative radiother-
cancer surgery for other parts of the large            apy (Marijnen ; Påhlman ). Long
bowel (Chiappa ; Hessman ). On                 course preoperative radiotherapy (– Gy


HUCH, Jorvi Hospital Publications • Series A 01/2005                                             17
over  to  weeks) or chemoradiotherapy               on treatment modality, also on interval
have been shown to increase the resect-               between preoperative adjuvant therapy
ability of low and locally advanced tumours           and operative treatment (Elsaleh ;
(Elsaleh ; Frykholm-Jansson ;                 Moore ), but the optimal interval is yet
Minsky ). In some cases preoperative              to be defined. Complete response has been
radiotherapy enables sphincter-saving sur-            reported to occur in –  of patients and
gery to be performed in patients, who would           seems to be associated with improved local
have previously required an abdominoperi-             control and survival (Garcia-Aguilar ;
neal resection (Crane ; Francois ;            Janjan a; Luna-Perez ; Minsky
Janjan b; Rullier ; Wagman ).             ; Ruo ; eodoropoulos )
Also, overall survival rates in patients with         but follow-up times are still fairly short.
T low rectal cancers have been reported              ree recent studies have reported, after a
to improve from   to   after PRT com-           mean follow-up time of  to  months, a
pared to those who underwent surgery only             disease-free survival of –  in patients
(Delaney ).                                       with complete or near-complete response
                                                      (Garcia-Aguilar ; Ruo ; Wheeler
                                                      ). In comparison, the disease-free sur-
Tumour response
                                                      vival was   in those with partial or no re-
Quantification of tumour response is es-              sponse (Garcia-Aguilar ). Another study
sential in comparing the effectiveness                reported the advantages of early survival in
of different multimodality treatments. A              complete responders to disappear by –
commonly used measure is a change in                  months after treatment (Onaitis ).
a T stage defined as a difference between                Besides complete response, also partial
endorectal ultrasound (ERUS) finding (uT)             radiation-induced histological changes
and pathologic T stage (pT). After high-dose          in malignant tumours (necrosis, stromal
long-term chemoradiotherapy tumour                    fibrosis, irradiation vasculopathy, peritu-
downstaging has been reported to occur in             morous inflammatory reactions) have been
–  of patients when using this criteria          well documented and can be quantified
(Garcia-Aguilar ; Janjan a; Moore             accurately (Bozzetti ; Bozzetti ;
; Rullier ; eodoropoulos ).              Dworak ; Ruo ; Wheeler ). A
Some studies report improved local recur-             pathologic staging system, tumour regres-
rence rates and cancer-specific survival in           sion grading (TRG) (Table ) has been
responders compared with non-responders               suggested (Bozzetti ; Dworak ;
(eodoropoulos ) whereas some have                Wheeler ) to enable the comparison of
not observed significant difference between           partial response as well and thus improve
the groups (Janjan a).                            the reliability of outcome comparisons be-
   Complete pathologic response i.e. steril-          tween different combined-modality treat-
ization of the tumour is a clearly definable          ments. is new grading method has not
measure for tumour response. e complete              been widely adopted so far.
response rate seems to be dependent except


Table 3. Tumour regression grading (Bozzetti 1996)

TRG1 – Complete regression, absence of residual tumour cells
TRG2 – Presence of rare residual cancer cells and prominent fibrosis
TRG3 – Fibrosis outgrowing residual cancer cells
TRG4 – Residual cancer cells outgrowing fibrosis
TRG5 – Absence of regression




18                                                              HUCH, Jorvi Hospital Publications • Series A 01/2005
Quality of life after                                  (Camilleri-Brennan ) which may con-
rectal cancer surgery                                  tribute to better QoL reported after HAR
                                                       than LAR (Engel ; Grumann ).
It has been assumed that permanent co-                 After LAR, functional results are better with
lostomy after rectal cancer surgery impairs            colonic pouch than with straight end-to-end
health related quality of life (HRQoL) more            anastomosis and accordingly, the quality of
than sphincter-sparing surgery. A recent               life of patients having J-pouch or coloplasty
Cochrane-analysis did not find support                 has been shown to be better, especially dur-
for this assumption (Pachler ). Several            ing the early postoperative period (Hallböök
of the studies that used validated generic             b; Remzi ; Sailer ).
and/or disease-specific quality of life in-                Urogenital dysfunction after rectal can-
struments, found that people undergoing                cer surgery occurs frequently (Camilleri-
APR did not have a poorer QoL than pa-                 Brennan ). Urinary dysfunction for any
tients undergoing anterior resection (Allal            reason seems to worsen social functioning
; Camilleri-Brennan ; Grumann                  (Nuotio ; Rauch ). e effect of sex-
; Hamashima ) or that stoma only               ual dysfunction on quality of life is not very
slightly affected the QoL (Jess ). In              well known, as a high percentage of rectal
contrast, a few other studies found a signifi-         cancer patients are elderly and often either
cantly poorer QoL after APR than after AR              not sexually active or choose not to answer
(Engel ; Grundman ; Kuzu ;                 the questions concerning sexuality (Engel
Marquis ). Tumor stage and site, level             ; Kuzu ; Rauch ). One study
of the anastomosis, surgical technique and             showed no difference in sexual dimen-
adjuvant treatment as well as the follow-up            sion of QoL between the treatment groups
time after surgery varies between the stud-            (Rauch ), whereas another larger study
ies (Pachler ), which may partly explain           reported lower scores in sexual functioning
the contradictory results.                             after APR than HAR or LAR (Engel ).
   Longitudinal studies have shown that                However, patients in the APR group were
quality of life improves with time (Engel              older, which may affect the results. Based on
; Grumann ), especially after low              this scarce data it has been suggested that
anterior resection (Engel ). Functional            sexual functioning may not affect overall
results after HAR are better than after LAR            quality of life (Engel ).




HUCH, Jorvi Hospital Publications • Series A 01/2005                                              19
AIMS OF THE STUDY




      e purpose of this study was to evaluate factors, which can be af-
      fected in order to improve results of rectal cancer treatment. e
      specific aims were

      . to evaluate the usefulness of PNA-test in screening for rectal
         neoplasia compared with occult faecal blood test.

      . to find out whether total mesorectal excision (TME) technique
         alone or combined with preoperative radiotherapy reduces lo-
         cal recurrence rate and improves survival;

      . to evaluate if elderly patients ( years or older) can be treated
         using similar indications and treatment strategy as in younger
         patients without increasing complication risk;

      . to evaluate the usefulness of tumour regression grading in
         comparing histopathologic effects of different neoadjuvant
         treatments in rectal cancer patients; and

      . to assess the impact of treatment-related adverse effects in
         quality of life after rectal cancer surgery.




20                                                 HUCH, Jorvi Hospital Publications • Series A 01/2005
PATIENTS AND METHODS




Patients                                                        S II  III Between January 
                                                                and December , a total of  patients
is study was carried out at the Surgical                       with rectal cancer were admitted ( men,
Hospital, Helsinki University Central                            women, mean age  years) to the
Hospital, and at the Central Hospital of                        IV Clinic of Surgery, Helsinki University
Jyväskylä. e research material in the stud-                    Central Hospital.
ies I, II and III consists of patients who were                    Of the  patients,  were admitted
operated on for rectal cancer or examined                       during the period – and  during
for colorectal symptoms at the Surgical                         –. Major potentially curative opera-
Hospital, Helsinki University Central                           tions using a conventional technique were
Hospital between  and . Patients in                     done for  of the  during –.
the studies IV and V were treated for rectal                    Between  and , major potentially
cancer in Central Hospital of Jyväskylä be-                     curative resections using the principles of
tween  and  (Table ). e data of                       TME-technique were done for  of the
patients were gathered retrospectively until                     patients. e patients, who underwent
year  and prospectively thereafter.                         major potentially curative operations dur-
                                                                ing both periods, were included in Study II
S I From  to  samples of rec-                       comparing the outcome between treatment
tal mucus were obtained from  patients                       strategies.
undergoing colonoscopy for lower gastroin-                         All  patients, of whom  patients
testinal symptoms (e.g. altered bowel habits,                   ( ) were aged  or older and 
abdominal pain, anaemia, hemorrhagia ex                         younger than  years, were enrolled in
ano). From  to ,  patients also                      Study III comparing the treatment strate-
completed Hemolex test over three days pri-                     gies and outcome between elderly and
or to the outpatient appointment. ese                       young patients.
patients were selected for Study I. Informed
consent for obtaining mucus samples for                         S IV  V A total of  patients
PNA-test was received from all patients and                     ( men and  women, mean age , range
the study was approved by the ethical com-                      –) with rectal cancer were admitted to
mittee of the hospital.                                         Jyväskylä Central Hospital between January


Table 4. Number of patients included in the different papers


 Study                                                 Period               No of patients
 I PNA vs. Hemolex test                                1992–94                 199
                                                       1980–90                 144 (Conventional surgery)
 II The effect of treatment strategy
                                                       1991–97                  61 (TME surgery)
                                                                               199 (< 75 years)
 III Treatment strategy of the elderly                 1980–97
                                                                                95 (≥ 75 years)
 IV Quality of life                                    1999–2003                94
 V Tumour regression grading                           1999–2003               135



HUCH, Jorvi Hospital Publications • Series A 01/2005                                                        21
 and December . Of them,              PNA Samples of rectal mucus, obtained
patients underwent either curative or pal-       prior to colonoscopy with a cotton stick
liative major resection. Nine patients had an    through a proctoscope from macroscopi-
inoperable advanced disease.                     cally normal mucosa, were applied on
   Patients with high or midrectal tumours       nitrocellulose filters. e presence of PNA-
penetrating the bowel wall (uT) as judged       reactive glycoconjugates in rectal mucus
by endorectal ultrasound received a short-       was determined by a peroxidase-conju-
course preoperative  Gy radiotherapy           gated PNA-overlay procedure (Kellokumpu
whereas patients with uT-tumors in              ). Two observers unaware of the
proximity to the anal verge necessitating ab-    colonoscopy findings examined PNA-re-
dominoperineal resection, or with fixed or       activity.
locally advanced tumours, received a long           PNA-binding profiles of paired normal
course preoperative radiotherapy ( Gy          and malignant colorectal tissue samples
over five weeks) combined with weekly            taken from  cancer patients during surgery
infusion of -fluorouracil.                      were analysed by the PNA-overlay proce-
   Study IV comprises the  patients, who      dure. erefore, tissue samples were ground
underwent either curative or palliative ma-      in a mortar under liquid nitrogen, and de-
jor resection. e histological response of       tergent-solubilize using   TX-,  mM
the tumours after different preoperative ra-     Tris (pH .) supplemented with proteinase
diation treatments was evaluated. Of the      inhibitors tablets (Complete, mini, Roche
patients, who underwent curative resection,      Diagnostics Gmbh, Mannheim, Germany).
 were alive without any sign of recurrent       ml of detergent solution was used per 
disease after a minimum follow-up of one         mg of frozen tissue, and vortexed on ice for
year. For Study V they were sent a RAND-          min before clearing with centrifuga-
 (SF-) quality of life questionnaire and     tion (  × g, + °C). A × concentrated
a specific disease-related questionnaire         SDS sample buffer was added and boiled
assessing problems with urinary, sexual or       for  min. . microliters (about –
defecation-related functions.                    microgram of protein) from each sample
                                                 was subjected to SDS polyacrylamide gel
                                                 electrophoresis. e samples were then
                                                 transferred to a nitrocellulose filter. e filter
Methods
                                                 was quenched with   BSA (bovine serum
                                                 albumin, fraction V, Sigma Chemicals) in
Screening methods of symptomatic                 blotting buffer overnight, and probed with
patients (Study I)                               PNA in the same buffer (. microgram / 
H Hemolex (Orion Diagnostica,              ml of  mM Tris/ mM NaCl, .  BSA,
Espoo, Finland) is a test based on im-           .  Tween). e enhanced chemilumines-
munochemical detection of native human           ence-method (ECL) and exposure onto the
haemoglobin with a sensitivity of . mL of      Fuji RX film for – min was used for the
blood per  g of stool. e test kit includes   visualization of the proteins on the filter.
a latex reagent consisting of polystyrene
beads coated with antibodies produced in
                                                 Preoperative evaluation (studies II–V)
swine against human haemoglobin. ese
agglutinate when haemoglobin is present in       Tumours were classified as low (≤  cm),
the specimen in non-digested form giving         mid (– cm) or high (– cm) rectal
visually detectable granular agglutination       tumours. e distance of the tumour from
(Väänänen ). e patients completed           the anal verge was assessed with a rigid sig-
Hemolex test over three days prior to the        moidoscope (studies II–III) or colonoscope
outpatient appointment.                          (studies IV–V) and biopsies were taken.
                                                 Chest radiography, liver ultrasonography,


22                                                        HUCH, Jorvi Hospital Publications • Series A 01/2005
and computed tomography when necessary                    High dose preoperative radiotherapy
were used to rule out distant spread.                  ( Gy over five weeks) combined with
   In Study IV endorectal ultrasound                   radiosensitizing -fluorouracil (-FU 
(ERUS) staging was done according to                   mg/m/day once a week as an intravenous
Hildebrandt´s criteria (Hildebrandt )              bolus) was delivered using three or four-
using a ° rotating ∕ MHz endoprobe               field technique with the same target volume
(type , Bruell & Kjaell Ltg, Sandtoften,           as in short-course radiotherapy and includ-
Denmark). Magnetic resonance imaging                   ing pelvic organs infiltrated by the tumour.
(MRI) and/or computed tomography (CT)                  High dose preoperative chemoradiotherapy
were performed as complementary studies                was indicated in the case of large, fixed
in the case of fixed or locally advanced tu-           uT / tumours or with low (<  cm from
mours or if ERUS was not successful.                   the anal verge) uT tumours requiring
                                                       abdominoperineal resection. All patients
                                                       were planned to undergo surgical resection
Surgical techniques
                                                       within  to  weeks after completion of PRT.
Conventional surgery (Studies II and III) was             Adjuvant postoperative chemotherapy
defined as sharp dissection and excision of            consisting of -FU ( mg/m/day) as an
the mesorectum at least  cm distally from             intravenous bolus in six cycles and low dose
the lower margin of the tumour. In high and            leucovorin ( mg/m) (O´Connell ) for
midrectal tumours the mesorectum was di-               five consecutive days every  to  weeks was
vided perpendicularly to the rectum and the            prescribed routinely to all patients having
lateral ligaments were ligated and divided.            tumours with metastatic lymph nodes.
Blunt dissection was not used.
   Since  (studies II–V) surgery was per-
                                                       Pathologic evaluation
formed according to the principles of total
mesorectal excision technique (MacFarlane              e tumours were classified according to
) except in high (>  cm from the anal            the Turnbull modification of Dukes´ clas-
margin) rectal tumours in which a  cm                 sification during –, and according
distal margin was considered adequate.                 to the UICC TNM categories (Sobin )
Total mesorectal excision was defined as               during –. Assessment of the larg-
complete removal of the intact mesorec-                est tumour diameter as well as manual
tum down to the pelvic floor, preserving               lymph node harvesting was done in fresh
pelvic nerve plexuses. For rectal wall, i.e.           specimens.
the muscular tube, a margin of – cm was                  e operation was considered curative if
considered adequate.                                   no visible tumour was left behind and his-
                                                       topathological specimens showed tumour-
                                                       free distal margins. Lateral margins were
Adjuvant treatments
                                                       not assessed during the period –
Short-course preoperative radiotherapy                 (Studies II–III). In Study IV the circumfer-
( Gy,  Gy in five fractions) (Påhlman               ential, radial resection margins were mea-
) followed by resection within a week              sured in formalin ( ) fixed specimens
was chosen for patients with high (– cm            mounted on macroslides. Tumour response
from the anal verge) and midrectal (– cm            to radiotherapy was quantified using the
from the anal verge) uT tumours amenable              tumour regression grading (TRG, Table )
to anterior resection. External beam ra-               (Wheeler ).
diation therapy was delivered using three
or four-field technique. e clinical target
                                                       Quality of life assessment (study V)
volume included the mesorectum and the
pelvic sidewalls including the internal iliac          Quality of life assessment was done using
lymph nodes.                                           a validated Finnish version (Aalto ) of


HUCH, Jorvi Hospital Publications • Series A 01/2005                                            23
the RAND -item health survey quality of        sample (age – years) was derived from
life questionnaire (Hays ) and a specific    the Finnish population registry.
disease-related questionnaire assessing
problems with urinary, sexual or defeca-
                                                 Statistics
tion-related functions.
    e RAND- consists of  items as-          Chi-square tests or Fishers exact tests were
sessing eight dimensions of health from the      used to compare the association between
patient’s viewpoint. ese dimensions mea-        categorical variables. Actuarial survival
sure physical functioning, role limitations      and local recurrence rates were assessed
because of physical or emotional problems,       using Kaplan-Meier plots with log-rank
social functioning, mental health, energy        analysis (Study II and III). Mann-Whitney
and vitality, body pain and general health       U tests were used to compare continuous
perception. e scoring scale ranges from        data and to detect significant differences in
to , with high scores indicating high level   health-related quality of life scores between
of functioning and good quality of life.         subgroups. Differences in HRQoL between
    A sub sample of persons aged –           patient and population controls of same age
years from a Finnish population study            and sex were analysed by ANCOVA (analysis
(Aalto ) was used as a population con-       of covariance) adjusting the HRQoL means
trol group in examining the level of health      for sex and age (Study V). A P-value < .
related quality of life (HRQoL) in RAND-       was considered statistically significant.
subscales among patients. e population




24                                                       HUCH, Jorvi Hospital Publications • Series A 01/2005
RESULTS




Study I                                                       enomas and carcinomas vs. normal mucosa
                                                              and hyperplastic polyps) was   vs.  
Details of the clinical findings in the                    and specificity    vs.   (P = .).
symptomatic patients and the sensitiv-                        e positive predictive values  of the PNA
ity  for carcinoma of both tests are shown                   and Hemolex test were   vs.   and
in Table . e sensitivity of the PNA-test                    negative predictive value    vs.  . e
and Hemolex for colorectal neoplasia (ad-                     accuracy  of the PNA-test and Hemolex was
                                                                vs.  .
1
    Sensitivity = Proportion of diseased subjects, who have      SDS-PAGE and PNA-overlay showed
    a positive test
2
    Specificity = Proportion of non-diseased subjects, who
                                                              some commonly expressed PNA-bind-
    yield a negative test result                              ing proteins both in normal mucosa and
3
    Positive/negative predictive value = Proportion of all    colorectal cancer. Instead, expression of
    individuals with positive/negative tests who do/do not
    have the disease                                           kD PNA-binding protein was seen sig-
4
    Accuracy = Proportion of true positive and negative       nificantly more often (P < .) in colorectal
    tests of all those who were tested
                                                              cancer than normal mucosa (Figure ).


Table 5. Test positivity according to clinicopathological characteristics.


                                              Total            Positive PNA        Positive Hemolex
    Clinicopathological variable                                                                      P
                                              N                N ( %)              N ( %)
    Carcinoma                                 36               30 (83)            26 (72)             0.45
    Adenoma                                   38               21 (55)            18 (50)             0.8
    Inflammatory bowel disease                27               14 (52)            13 (48)             1.0
    Hyperplastic polyps                       21               10 (48)              5 (25)            0.3
    Normal/diverticulosis                     77               21 (27)              9 (12)            0.3



Figure 2. Peanut agglutinin (PNA)-binding proteins in 12 paired samples of normal colorec-
tal mucosa and colorectal cancer. Notice that both normal (n) and cancer tissues (c) express
PNA-reactive proteins. Only the 160 kD band (marked with arrow) appears to be quite
specific to colorectal cancer tissues. Numbers on the left denote the molecular size stan-
dards used.




HUCH, Jorvi Hospital Publications • Series A 01/2005                                                         25
Study II–III                                            Local recurrence rate and survival
Table  shows the patient and tumour                    e actuarial local recurrence rate was  
characteristics from the two study periods              in the first period utilizing conventional
included in studies II and III (– and             surgery and   after adopting TME surgery
–) as well as the data from the third             and selective use of preoperative radiother-
study period (–, N = ).                      apy (P = ., Fig. ). e actuarial crude


Table 6. Details of patients who underwent potentially curative operations during the three
study periods (1980–90, 1991–97, 1999–2003). Data are number (%) of patients except were
otherwise stated


                                     1980–90                 1991–97                    1999–2003
                                     (N = 144)               (N = 61)                   (N = 113)
 Sex (male: female)                  69 (48): 75 (52)        22 (36): 39 (64)           78 (69): 35 (31)
 Mean age (range)                    70 (41–91)              65 (36–82)                 68 (41–91)
 Dukes´ classification
   A                                 40 (28)                 18 (29)                    47 (42)
   B                                 79 (54)                 28 (46)                    40 (35)
   C                                 24 (17)                 14 (23)                    24 (21)
   D*                                1 (1)                   1 (2)                      2 (2)
 Site of tumour
     Upper rectum (12–15 cm)         33 (23)                 10 (16)                    28 (25)
     Middle rectum (8–11 cm)         51 (35)                 18 (30)                    31 (27)
     Lower rectum (≤ 7 cm)           60 (42)                 33 (54)                    54 (48)
 Operation
   Anterior resection                76 (53)                 43 (71)                    73 (65)
   Abdominoperineal resection        68 (47)                 18 (29)                    40 (35)
 Preoperative radiotherapy           0                       29 (48)                    80 (71)

* Liver metastasis resected later


Figure 3. Actuarial cancer-specific survival (upper curves) and local recurrence rates (lower
curves) after major curative surgery during the two study periods.




           1980–90 (conventional surgery)
           1991–97 (TME surgery)


26                                                              HUCH, Jorvi Hospital Publications • Series A 01/2005
-year survival improved from   to                       Figure 4. Actuarial cancer-specific survival
(P = .) and the cancer-specific survival                    after major curative surgery according to
from   to   (P = ., Fig. ) between                   patient age.
the two study periods.
   During –, the five-year crude
survival was significantly lower in the older
age group (  vs.  , P = .), but the -
year cancer-specific survival (  vs.  ,
P = .) (Fig. ) and the disease-free -year
survival (  vs.  , P = .) were similar
in both groups.
   More patients in the elderly group (/
,  ) than in the younger age group
(/,  ) had a poor physical condition
(compromised cardiac and/or respiratory
function, symptoms in mild exercise) and
underwent local excision (P = .). Ten                                 75 years or older
                                                                         Below 75 years
elderly patients ( ) were not operated on
at all in contrast to  patients ( ) younger
than  (P = .).                                          with / patients ( ) after TME surgery
                                                               (P = .). Twenty of the  elderly patients
                                                               ( ) and  of the  patients ( ) in
Complications
                                                               the younger age group after curative surgery
Overall,  of the  patients ( ) who                     had complications (P = .). e overall
underwent major curative surgery during                        incidence of postoperative complications
– had complications. After conven-                       after potentially curative major operations
tional surgery / patients ( ) had                      during the all three study periods is shown
postoperative complications compared                           in Table .



Table 7. Postoperative complications after potentially curative major operations during the
three study periods. Data are number ( %) of patients.


                                                 1980–1990           1991–1997               1999–2003
 Postoperative death                             1/144 (1)           0                       3/113 (3)
 Anastomotic
   Leak                                          4/76 (5)            8/43 (19)               4/73 (6)
   Stenosis                                      1/76 (1)            8/43 (19)               5/73 (7)
 Postoperative bleeding                          0                   2/61 (3)                1/113 (1)
 Infections
    Abdominal wound                              2/144 (1)           0                       7/113 (6)
    Perineal wound                               4/68 (5)            1/18 (6)                8/40 (20)
    Systemic sepsis                              3/144 (2)           1/61 (2)                1/113 (1)
    Pneumonia                                    4/144 (3)           1/61 (2)                2/113 (2)
 Cardiovascular                                  2/144 (1)           0                       3/113 (3)
 Urinary                                         8/144 (6)           4/61 (7)                6/113 (5)
 Other                                           3/144 (2)           1/61 (2)                6/113 (5)
 No pts with complications*                      32/144 (22)         21/61 (34)              39/113 (35)

* Some patients had more than one complication


HUCH, Jorvi Hospital Publications • Series A 01/2005                                                          27
   After curative anterior resection / of               patients developed anastomotic leaks. Table
the patients ( ) during the first period and              shows the incidence of anastomotic leak-
/ ( ) during the second period devel-                ages in respect to the type of anastomosis
oped anastomotic leaks (P = .). During                  and use of protective stoma.
–, when all low anastomoses were                      After elective operations during –,
constructed using J-pouch and usually pro-                 one elderly patient died due to anastomotic
tected with a temporary stoma, / ( )                  leakage. us operative -day mortality


Table 8. Incidence of anastomotic leakages after curative resection for rectal cancer during
the three study periods in respect to the type of operation (HAR = high anterior resection,
LAR = low anterior resection).


                                        Leakages / total number of patients
                                        1980–90                  1991–97                       1999–2003
    HAR                                 4 / 76*                  1 / 10*                       0 / 20**
    LAR
      Straight anastomosis              0                        5 / 23                        0
      Straight anastomosis + stoma      0                        0                             0
      J-pouch                           0                        2/4                           2/2
      J-pouch + stoma                   0                        0/7                           2 / 51
    Total***                            4 / 76 (5 %)             8 / 43 (19 %)                 4 / 73 (5 %)

* Straight anastomosis without protective stoma
** Straight anastomosis with (7 patients) or without (13 patients) a protective stoma
*** P = 0.02



Table 9. Tumour regression grading (TRG) in different treatment groups.


    Tumour regression grade a          5               4             3                2                   1
    Preoperative radiotherapy (number of patients (%))
    No radiotherapy (n = 40)           27 (68)         12 (30)       0                1 (2) b             0
    25 Gy (n = 42)                     12 (29)         21 (50)       8 (19)           1 (2)               0
    50 Gy (n = 44)                     4 (9)           8 (18)        15 (34)          14 (32)             3 (7)

a
    TRG 1, 2 and 3 correspond to a regression exceeding 50 % of the tumour mass
b
    This patient had a small polypoid lesion, which was originally removed endoscopically with snare and
    electrocoagulation. Only a 7 mm lesion was seen in the resected specimen.




Table 10. Comparison of histopathologic response (TRG) and dowstaging (pT lower than uT
stage) in 83 patients, who had a successful endorectal ultrasound (ERUS) examination and
received either 25 Gy radiotherapy or 50 Gy chemoradiation preoperatively. TRG classes 1 to
3 are considered `marked response´ regression exceeding 50 % of the tumour mass.


    TRG                                                    Marked response                No response
    Downstaged                  Yes                        12                             14
                                No                         28                             29
    P = 0.05                                               40                             43



28                                                                  HUCH, Jorvi Hospital Publications • Series A 01/2005
was   (N = ) and  after potentially cura-              ere was a marked discordance between
tive conventional and TME surgery, respec-                 the two methods in estimating tumour
tively. Consequently, the -day mortal-                   response after  Gy radiotherapy or  Gy
ity was   (N = ) and  in the elderly and               chemoradiation (P = .). Of the  tu-
younger age group. During – the                    mours,  showed marked regression by
mortality rate was   (/ patients); one               TRG without any change in T-stage and 
patient died due to anastomotic leakage.                   tumours that showed no response in TRG
                                                           were downstaged when comparing uT-stage
                                                           with pT-stage.
Study IV

Tumour regression grading                                  Study V
Results of TRG of the  patients according
                                                           Quality of life
to treatment group are shown in Table .
Complete regression (TRG ) was present in                 e patient group reported significantly
three patients ( ) and tumour regression                 better general health perception and poorer
more than   (TRG –; fibrous tissue                    social functioning than population controls
outgrowing the amount of residual tumour                   of same age and sex (Table ). Between the
cells) in  ( ) of the  patients treated             treatment groups there were no significant
with high dose ( Gy) chemoradiation. In                  differences (Figure ). However, after APR
those  patients treated with short course                physical functioning tended to be lower
( Gy) radiotherapy only  ( , P = .)               (P = .) compared with low anterior
had tumour regression of TRG –.                          resection.
   Endorectal ultrasound examination                          Major bowel dysfunction (frequency
(ERUS) was done in  patients. Of them,                  >  bowel movements/day, major inconti-
 patients underwent surgery alone. In                    nence (Jorge ), urgency or constipation
them, ERUS had an accuracy (uT-stage                       (Drossman )) impaired social function-
same as pT-stage) of  . e comparison                   ing significantly (P = .) in patients hav-
of TRG findings and uT vs. pT change after                 ing undergone anterior resection compared
different treatments is shown in Table .                 with the patients without such problems


Table 11. Health related quality of life according to RAND 36 (SF36) among general popula-
tion (N=1440) and patients who had curative resection for rectal cancer (N = 71, age < 80
years). The values are adjusted for age and gender.


                               General population         Rectal cancer patients
 QoL-dimensions*                                                                   P-value
                               Mean           (95 % CI)   Mean       (95 % CI)
 PF                            74.8           73.5–76.0   73.9       67.4–80.2     0.79
 RP                            62.5           60.4–64.6   54.9       44.2–65.5     0.17
 RE                            68.7           66.7–70.8   61.9       51.6–72.1     0.20
 SF                            79.9           78.6–81.2   68.9       62.4–75.4     0.002
 MH                            73.8           72.8–74.9   77.5       72.9–82.9     0.19
 EV                            62.7           61.5–64.0   64.0       57.7–70.3     0.70
 BP                            70.0           68.6–71.4   67.9       60.9–74.8     0.55
 HP                            55.9           54.8–57.6   63.3       57.7–68.9     0.01

* PF = physical functioning; RP = role limitations due to physical problems; RE = role limitations due to
  emotional problems; SF = social functioning; MH = mental health; EV = energy and vitality; BP = body
  pain; HP = general health perception.


HUCH, Jorvi Hospital Publications • Series A 01/2005                                                   29
(Figure ). Increased bowel frequency (> )            (P = .) and general health perception
or constipation after low anterior resection           (P = .). e patients without urgency or
did not significantly affect the QoL scores.           fecal incontinence had a significantly better
Incontinence worsened social functioning               physical functioning than the patients, who
significantly (P = .). Urgency impaired             underwent abdominoperineal resection
social functioning (P = .), mental health           (P = . and ., respectively), whereas


Figure 5. Quality of life after rectal cancer surgery in different treatment groups (HAR=
high anterior resection; LAR = low anterior resection; APR = anterior resection).




PF = physical functioning; RP = role limitations due to physical problems;
RE = role limitations due to emotional problems; SF = social functioning;
MH = mental health; EV = energy and vitality; P = body pain;
HP = general health perception.



Figure 6. Quality of life after anterior resection in patients with (N = 35) or without (N = 18)
major bowel dysfunction. In comparison, values of the patients who underwent APR (n=28)
are shown.




PF = physical functioning; RP = role limitations due to physical problems;
RE = role limitations due to emotional problems; SF = social functioning;
MH = mental health; EV = energy and vitality; P = body pain;
HP = general health perception.



30                                                               HUCH, Jorvi Hospital Publications • Series A 01/2005
the patients having such problems had no               urinary dysfunction. In patients reporting
statistically significant differences in RAND-         sexual dysfunction only a complete loss of
 QoL scores compared with APR patients.              erection was associated with significantly
   Patients with urinary dysfunction had               worse physical functioning (P = .) and
worse social functioning (P = .) and                social functioning (P = .).
more pain (P = .) than patients with no




HUCH, Jorvi Hospital Publications • Series A 01/2005                                          31
DISCUSSION




Despite the fact that –  of patients       for faecal occult blood (Towler ), there
presenting with colorectal cancer may un-       is a need for tests with higher sensitivity and
dergo surgical resection for possible cure      specificity.
and that recent advances in multimodality           In our study, we compared the sensitivity
therapy has improved survival of advanced       and specificity of single PNA-rectal mucus
disease, nearly   of patients with cancers   test with those of Hemolex, a test completed
of the colon and rectum die from their dis-     over three days and based on immuno-
ease. More effective preventive measures        chemical detection of native human hae-
together with further refinement of surgical    moglobin. Immunological tests have been
techniques and adjuvant treatments are          shown to be more sensitive for symptomatic
clearly warranted to improve the outcome        colorectal cancer than guaiac-based tests
results of this common disease.                 (Robinson ; omas ). In contrast,
                                                lower specificities (  vs.   in symp-
                                                tomatic patients and   vs.   in the as-
Screening
                                                ymptomatic population) has been reported
Advisory Committee on Cancer Prevention         using immunological tests than guaiac-tests
recommends screening for colorectal             (Robinson ; omas ).
cancer to be considered in the countries of         We have found that in symptomatic
European Union (Advisory Committee on           patients a single PNA-test is as sensitive for
Cancer Prevention ). Colorectal cancer      colorectal carcinoma as a serial Hemolex
is a major health problem, which usually        (  vs.  ). e PNA-test, however, had
develops from benign adenomatous polyp          a lower specificity for colorectal neoplasia
slowly over approximately  years provid-      than Hemolex (  vs.  ), making it
ing an opportunity for early detection and      less suitable for screening purposes in its
removal in pre-cancerous stage or as an         present form. e reduced specificity of
early stage cancer (Bronner ; Winawer       the PNA-test may result from the fact that
). According to recommendation a            some of PNA-reactive proteins (e.g. the
method of choice for screening is faecal oc-     kD-band and the diffuse bands at the
cult blood tests and colonoscopy in positive    molecular size between  kD and  kD)
cases. Current stool guaiac tests, however,     were present both in normal and malignant
appear to be suboptimal in some respects.       colorectal tissue. e  kD cancer-associ-
   Many cancers and most adenomas do not        ated antigen we have identified is under
bleed and are thus missed (Ahlquist ).      further characterization for development of
e reported sensitivity of serial guaiac        a more specific PNA-test.
based FOBT is only approximately  
(Hardcastle ; Kronborg ). e posi-
                                                Surgical treatment
tive predictive value has been reported to
be –  (Hardcastle ; Kronborg ;
                                                Local recurrence and survival
Winawer ) leading to high number of
unnecessary colonoscopies, as bleeding is       e concept of TME surgery relies on the
not specific for neoplasias (Towler ).      observation that tumour deposits may be
Despite the recent documentation of a           found  to  centimetres distal to the main
significantly reduced mortality by screening    tumour in the lymphovascular mesorectum


32                                                       HUCH, Jorvi Hospital Publications • Series A 01/2005
(Heald ; Wang ). erefore, it has              more frequently after abdominoperineal
been advocated that all cancers of low or              than anterior resection. Wider surgery in-
midrectum should be excised with the me-               cluding removal of the levator muscles en
sorectum intact. e excellence of this ap-             bloc with anal sphincters might reduce the
proach is further supported by the findings            risk (Marr ; Wibe b). In the future,
of Quirke et al. showing that tumour spread            radioactivity-guided sentinel node map-
to the lateral resection margin occurs in up           ping may be one option for finding patients
to   of patients treated with conventional          with lateral spread and thus greater risk for
techniques but in only –  of patients               recurrence (Kitagawa ; Saha ).
treated by TME (Quirke ). Others have
confirmed that the circumferential resection
                                                       Complications
margin involvement is a reliable predictor
of local recurrence, distant metastases and            e overall complication rate of about
survival (Wibe ).                                    in all study periods falls well within
    Since these observations, surgical and             the reported range. Also in line with previ-
pathological workshop projects have been               ous reports, the leakage rate was   with
organized in several countries in Europe               conventional surgery and   in the early
to introduce these new methods. National               phase of TME surgery. Later, when the rou-
studies have shown that TME surgery                    tine use of protective stoma and J-pouch in
improves treatment results in a defined                low anastomoses was adopted, the clinical
population (Kapiteijn ; Martling ;             leakage rate decreased back to  .
Påhlman ; Wibe a).                                ere is some proof that colonic J-pouch
    In our study, the actuarial risk for devel-        anastomosis has better blood supply than
oping a local recurrence decreased from                end-to-end anastomosis and thus may
  to   after the introduction of TME              be less prone to leakage (Hallböök a;
surgery, which is in line with the reports             Hallböök b). Some other studies have
from other centres. Accordingly, cancer-               found a significant correlation between the
specific five-year survival increased from             absence of stoma and anastomotic dehis-
  to   and disease-free five-year                cence (Law ; Peeters ). During the
survival from   to   between the two             TME period between  and  in our
periods.                                               study,  of the  patients ( ) who had a J-
    However, still more than   of the pa-           pouch but no protective stoma, developed
tients with Dukes´ C lesions developed lo-             an anastomotic leak. Of the  patients
cally recurrent disease after TME. As many             with end-to-end anastomosis,  patients
as  of the  Dukes´ C carcinomas in the             ( ) had a leakage. In comparison, only
second period were low rectal tumours and              two of the  patients (. ) who had a
four of the five local recurrences occurred            J-pouch and a protective stoma developed
after resection of low rectal carcinomas.              a leakage. Our results are in line with oth-
It has been shown that some   of low                ers showing leakage rates of   and – 
rectal tumours and   of low Dukes´ C                in patients without and with a protective
tumours spread laterally along the internal            stoma, respectively (Dehni ; Karanjia
iliac vessels (Moriya ), which is outside          ).
the dissection area covered by TME and
thus may explain the high recurrence rates.
                                                       Elderly patients
Besides lateral lymph node involvement, an
inadequate surgical resection despite TME-             An increasing number of rectal cancer pa-
surgery might explain some of the treatment            tients are elderly and have comorbid medi-
failures. Possibly due to tapering of the me-          cal diseases. A question has been raised
sorectum toward levators, circumferential              whether elderly patients with compromised
resection margin involvement still occurs              physical capacity to recover from adverse


HUCH, Jorvi Hospital Publications • Series A 01/2005                                              33
events can be offered similar treatment than      in Finland were  years of age or older in
younger patients.                                  (Finnish Cancer Registry ). Also,
    In the present study, the crude survival      tumour site and stage distribution are simi-
was significantly lower (  vs.  ) in        lar in both groups, old and young. erefore,
the elderly but the cancer-specific -year        probably a very realistic picture of the
survival rate after curative major surgery        management policy and treatment possi-
for rectal cancer in carefully selected elderly   bilities of the rectal cancer in the elderly is
patients was similar to that found in younger     presented in this study. In future, however,
patients (  vs.  ).                         advancements in laparoscopic surgery may
    e overall postoperative mortality rate       increase the number of patients suitable
including emergency and palliative pro-           for major surgery. Preliminary experience
cedures in our study was . ; .  in          suggests that laparoscopic resections in
the elderly group and .  in the younger        the elderly can be performed more safely
age group. After curative operations,             than standard open surgery (Delgado ;
the mortality in the elderly group was            Reissman ).
  compared with  in the younger age
group. Diligent perioperative care most
                                                  Adjuvant treatments
certainly had an effect on low mortal-
ity rates. Furthermore, all possible efforts      Several different chemotherapeutic regi-
were made to identify and treat comorbid          mens and radiotherapy doses have been
conditions before surgery. e American            used in an effort to increase the percentage
Society of Anaesthesiologists (ASA) clas-         of those responding the treatment. e true
sification of physical health did not help in     impact of the adjuvant treatment on out-
assessing the risk of an individual patient.      come has been difficult to assess because
Perioperative mortality was low irrespec-         of multiple confounding issues such as
tive of ASA score and also, no statistically      variability in tumour stage, different tech-
significant difference in the number of           niques employed among studies, variability
complications between the ASA groups was          in the extent of the follow-up and above all,
noted. According to many reports (Haynes          absence of a uniform method to estimate
; Ranta ) there is considerable in-       the effect. e most used measures such as
ter-observer inconsistency of classification      changes in tumour size, stage or resectabil-
making ASA-scoring alone too imprecise            ity are all subjective and dependent on the
an instrument for treatment decisions.            reliability of preoperative evaluation.
Other more reliable scoring systems like             In the present study, we have shown that
POSSUM score are being developed and              assessment of radiation-induced histopath-
tested (Senagore ).                           ologic changes in tumours is reproducible
    A considerable number of high-risk pa-        and easily available method for examining
tients in our study was not operated on at all    tumour response after preoperative radio-
( ) or underwent local excision ( ),        therapy or chemoradiation. After high-dose
which may contribute to acceptable com-           chemoradiation  patients ( ) showed
plication and mortality figures, and shows        complete regression (TRG ) and marked
the utmost importance of careful patient          response (TRG –) was seen in   of pa-
selection for major surgery. Preoperative         tients, which is in line with previous studies
selection is an aspect often excluded from        (Bouzourene ; Bozzetti ; Dworak
studies in the elderly, even if it is crucial     ; Ruo ). e majority of patients
in the evaluation of long-term results of         ( ) who received a short course PRT in
curative surgery. In our study, proportion of     our study, showed no tumour regression.
elderly patients is consistent with the report    Non-irradiated patients used as a control
of the Finnish Cancer Registry, according         group, were all except one classified in TRG
to which   of all rectal cancer patients       –.


34                                                         HUCH, Jorvi Hospital Publications • Series A 01/2005
   Only   of patients with marked re-               shown that grades – are commonly seen
sponse (TRG –) showed actual downstag-               in patients treated without radiotherapy.
ing according to comparison between uT-                Comparison of grades – with grades –
stage measured by ERUS and pT-stage. On                might have given a more truthful picture of
the other hand, just as many ( ) of those           tumour response.
with no histological response to PRT (TRG                 A more simplified classification combin-
–) seemed to be downstaged. ere was a               ing grades – into two grades and grades
significant discordance (P = .) between             – into one non-responder group has
the methods in assessing the effect of PRT.            been suggested (Wheeler ). ere are
   Downstaging defined as a difference                 preliminary results showing a trend towards
between uT stage and pT stage has been                 increased survival and decreased local
considered a precise method to measure                 recurrence rate in grade  patients when
tumour response to chemoradiation.                     using this three-step classification (Wheeler
However, without preoperative radio-                   ). Furthermore, results from several
therapy, upstaging is more common than                 studies suggest that complete response cor-
downstaging suggesting that assessment of              relates with improved survival (Garcia-
response to radiation with this method over-           Aguilar ; Ruo ; eodoropoulos
estimates the rate of tumour downstaging.              ). Considering that, it seems likely that
Furthermore, its accuracy for assessing the            the new tumour regression grading would
rectal wall invasion is highly user-depen-             help in comparing the results of different
dent varying from   to   (Adams ;            combined-modality therapies and might
Akbari ; Kumar ). us, to estimate             help in choosing the most effective neoad-
the accuracy of downstaging based on the               juvant treatment in the future. Studies on
change of the T stage, the accuracy of ERUS            molecular biomarkers between responders
staging in patients without preoperative               and non-responders might help in reveal-
radiotherapy should be known, whereas tu-              ing the factors correlating with the tumour
mour regression grading (TRG) is a measure             sensitivity for chemoradiotherapy.
independent of preoperative evaluation and
TNM staging.
                                                       Quality of life
   It has not been shown as to yet, whether
histological tumour response translates                Up until ´s most of the patients with
into improved survival. e follow-up time              a carcinoma of the middle or low rectum
in our study is too short and number of                were treated by an abdominoperineal
patients too small to draw any conclusions.            excision, introduced by Sir Ernest Miles in
A study of  patients with T/ tumours,             . Today a variety of surgical techniques
treated preoperatively with . Gy ra-                are available that preserve sphincter func-
diotherapy over . weeks and operated                 tion. Maintaining the normal anatomy has
on within  days, examined correlation of              become one of the main goals in modern
outcome with clinicopathologic variables,              rectal cancer surgery in order to avoid se-
one of which was tumour regression grad-               vere disruption of the quality of life. Indeed,
ing. In the univariate analysis, absence of            a permanent colostomy is rarely necessary
tumour regression (grade ) together with              provided that all presently available tech-
N disease, positive resection margin and              niques of sphincter salvation and restora-
vascular invasion was correlated with ad-              tion are applied. Tumours extending into
verse overall survival and local recurrence            anorectal junction or within the anal canal
rate. In the multivariate analysis absence of          can be treated with ultralow anterior resec-
tumour regression was not an independent               tion or even intersphincteric resection and
prognostic factor (Bouzourene ). In                continuity restored with ultra-low colorec-
that study, patients with grades – were              tal or coloanal anastomosis using colonic
regarded as responders, whereas we have                pouch (Tytherleigh ).


HUCH, Jorvi Hospital Publications • Series A 01/2005                                               35
   However, sphincter preservation without      Physical functioning tended to be worse af-
good function is of questionable benefit.       ter APR than LAR. Of note is that sphincter-
e functional result after low anterior re-     saving surgery resulted in significantly better
section may be disappointing because of an      physical functioning in those patients who
increased frequency of defecation, urgency      did not have any major problems with bowel
and faecal leakage (Renner ). With the      function or continence. e QoL of patients
addition of radiation therapy the results       with such problems was similar to that of the
may be further compromised (Hallböök            patients who had undergone APR.
b; Marijnen ). In this study, major        Social functioning was significantly
bowel dysfunction (urgency, frequency,          worse in patients with major bowel dysfunc-
incontinence or constipation) occurred in       tion compared with that of patients who did
  of patients after high or low anterior     not have such problems. Also urinary dys-
resection, which is in line with previous re-   function impaired social functioning and
ports (Camilleri-Brennan ).                 impotence physical and social functioning
   Urogenital dysfunction is also common        scores. Consequently, the same age general
after surgery for rectal cancer (Camilleri-     population scored significantly better in
Brennan ). However, with modern             social functioning compared with rectal
operation techniques permanent major uri-       cancer patients. In other dimensions the
nary dysfunction is rare (Enker ; Maas      QoL of the patient group was not impaired
). Also in this study, the urinary symp-    compared with that of general population.
toms were similar to those encountered          In contrast, the patients reported better
commonly in general population of same          health perception than the population.
age. No major incontinence or neurogenic           According to our results, organ dys-
bladder requiring catheterization was en-       function is a crucial factor in determining
countered. e incidence of sexual dysfunc-      quality of life after rectal cancer surgery.
tion has been reported to be higher after       Preoperative information about potential
APR than AR (Allal ; Engel ). In line   side effects is mandatory to make a patient’s
with that, impotence occurred in   and       expectations realistic, and to help to cope
  after LAR and APR in our study.            with the consequences. Refining surgical
   Overall, the differences in the QoL of       techniques to minimize the incidence of
patients after sphincter-sacrificing and        treatment-related adverse effects is prob-
sphincter-preserving surgery seem to be         ably at least as important as aiming to
small (Pachler ). In the present study,     sphincter-sparing surgery in an attempt to
no significant difference between the treat-    improve the quality of life after rectal cancer
ment groups in the quality of life was seen.    surgery.




36                                                       HUCH, Jorvi Hospital Publications • Series A 01/2005
CONCLUSIONS




                  On the basis of the present study, the following conclusions can be
                  drawn:

                  . A single PNA-test in its present form is as sensitive indicator of
                     colorectal neoplasia as Hemolex completed over three days but
                     lacks specificity, making it less suitable for screening purposes.
                     e  kD cancer-associated antigen under further character-
                     ization might help in developing a more specific PNA-test.

                  . Total mesorectal excision technique (TME) technique in
                     low and midrectal cancers results in improved survival and
                     decreased local recurrence rate compared with conventional
                     surgery. Despite an increased number of anastomotic compli-
                     cations TME technique is safe. e use of covering stoma and
                     colonic J-pouch seems to reduce the incidence and severity of
                     anastomotic complications.

                  . Identification and treatment of comorbid conditions before
                     surgery for rectal cancer is mandatory to keep morbidity and
                     mortality rates acceptable. In carefully selected elderly patients
                     similar survival rates to those found in younger patients are
                     obtained.

                  . In assessing tumour response to preoperative adjuvant therapy,
                     histologic tumour regression grading (TRG) seems to offer a
                     more accurate means than uT-downstaging, which did not cor-
                     relate with TRG results.

                  . Bowel and urinary dysfunction and impotence have a major
                     adverse impact on the quality of life after rectal cancer surgery.
                     ese adverse effects need to be discussed with the patient and
                     preoperative function needs to be taken into account when
                     choosing between treatment options. Refining surgical tech-
                     niques to minimize the incidence of treatment-related adverse
                     effects is probably at least as important as aiming to sphincter-
                     sparing surgery in an attempt to improve the quality of life after
                     rectal cancer surgery.




HUCH, Jorvi Hospital Publications • Series A 01/2005                                      37
ACKNOWLEDGEMENTS




e present study was carried out at the          Professor Jyrki Mäkelä, MD, for their con-
Fourth Department of Surgery, the Helsinki       structive comments in accomplishing the
University Central Hospital and the              manuscript to its final form.
Jyväskylä Central Hospital. Analyzing the            e colleagues at the Jorvi Hospital have
data and writing the papers were done while      a special place in my heart as well. Above all,
I was working at the Jorvi Hospital.             I am deeply indebted to Jorma Nieminen,
   I wish to thank Professor Krister             MD, the Surgeon-in-Chief, for his encour-
Höckerstedt, MD, and the late Professor          aging, trusting and supporting attitude that
Juhani Ahonen, MD, and all the colleagues        helped enormously in bringing this thesis to
with whom I have worked at the Fourth            its conclusion. Also, I am very grateful to the
Department of Surgery. e stimulating            wonderful staff at the Day Surgery Unit, who
conversations and fine attitude towards          had to put up with me in good and bad days
both clinical and scientific work created the    during this process.
ground for this thesis.                              I owe thanks to the staff at the patient
   Above all, I wish to express my deepest       archives of the Surgical Hospital, the
gratitude to my supervisor, docent Ilmo          Helsinki University Central Hospital and the
Kellokumpu, MD, whose skills as a surgeon        Jyväskylä Central Hospital, for their prompt
and researcher I highly respect. He guided       assistance and positive attitude when I was
me to the world of science and provided          collecting data from patient files. Many
resources and subjects for this study. I could   warm thanks go also to Mrs Tuula Boström
not have imagined having a better advisor        for her always so helpful attitude in litera-
and mentor and without his knowledge and         ture haunt, to Mr Jari Simonen for handling
perceptiveness I might have never finished       the lay-out of this thesis, and to Mrs Sari
this work. His commitment to good quality        Karesvuori and Mrs Eila Karonen for their
work will always inspire me.                     invaluable help in organizing practical
   I owe sincere thanks to all my co-authors     things for the dissertation.
of the published manuscripts for their im-           My special thanks go to my cousin and
portant contribution. Especially I wish to ex-   very dear friend Mrs Tarja Sarvi for help-
press my gratitude to docent Leena Halme,        ing me with the English language. My
MD, whose patience and determination in          warmest thanks go also to Mrs Jutta Gröhn
solving problems connected to comput-            with whom I shared hilarious moments in
ers and statistics was of great help during      the miraculous world of science, and her
the early phases of this work. Gratefully        husband Mr Heikki Pikkarainen as well as
acknowledged is also Peter Sainio, MD,           Mrs and Mr Helle and Erkki Päiviö, who all
PhD, who showed me the importance                took a great interest in the study. anks
of preciseness in scientific work. Docent        are due to my dear colleague and friend
Matti Kairaluoma, MD, Matti Juhola, MD,          Pia Nordström who was a great source of
and Sakari Kellokumpu, PhD, are sincerely        strength all through this work. Collectively, I
thanked for collecting data, for examining       am deeply grateful to all my dear friends and
histopathologic samples and for laboratory       relatives for their caring, support and always
analyses in PNA-tests, respectively.             so refreshing company. Special thanks are
   My sincere thanks are due to the review-      due to each one of them who kept asking
ers, Professor Heikki Järvinen, MD, and          me all these years: ”Have you finished your


38                                                        HUCH, Jorvi Hospital Publications • Series A 01/2005
thesis yet?” Silencing that question was a             ing attitude to keep me going. is work is
prime motivation when other interests in               dedicated to them all.
life enticed.                                             is study was financially supported by
    I wish to thank my dear mother Maria               the Jorvi Hospital scientific foundation,
for always believing in me. My warmest                 the University of Helsinki, the Finnish
thanks go also to my wonderful children                Medical Society Duodecim and the Finnish
Eveliina and Aleksi for their patience and             Research Foundation of Gastroenterology,
interest in what I was doing throughout this           which I gratefully acknowledge.
work. Finally, I owe my most loving thanks                Looking forward to new challenges
to my husband Pekka who so often during
many lonely hours spent at the computer                                             Jaana Vironen
nourished me with a hot cup of tea and lov-                            Espoo, th September 




HUCH, Jorvi Hospital Publications • Series A 01/2005                                          39
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