Cancer of the Cervix and Areas of Research

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					Cancer of the Cervix and Areas of Research

                                                                                           the use of weekly neoadjuvant chemotherapy

                                       ervical cancer is the second most common
                                       cause of cancer related death in women              followed by radical chemoradiation for locally
                                       worldwide. The highest levels of disease are        advanced cervical cancer [
                               seen in developing countries [1]. The incidence of          downloads/csg/2009/Gynae%20Annual%20Report%
                               cervical cancer in industrialised nations has fallen        2008-09%20final.pdf, accessed December 2009].
                               dramatically over the last 50 years following the
                               introduction of cervical screening. This has                Chemotherapy - concomitant and metastatic settings
                               facilitated the identification and treatment of pre-        Concomitant chemoradiation with single agent
                               malignant carcinoma-in-situ or cervical intra-              platinum has been the standard of care in the curative
                               epithelial neoplasia.                                       treatment of locally advanced cervical cancer for the
 Katharine Aitken,                Screening has been available in the UK since 1967        last 10 years. The addition of chemotherapy provides
 Specialist Registrar          and is currently offered to women between the ages          a 6% overall survival benefit and an 8% increase in
 Clinical Oncology,            of 25-64 years. The incidence of invasive disease has       five year disease free survival [6].
 Royal Marsden Hospital,       reduced since 1975 and the current lifetime risk of the        Doublet regimes have been investigated in the
                               disease is estimated to be 1 in 136 women. Cervical         treatment of metastatic and recurrent cervical
                               cancer mortality rates in 2007 (2.4 per 100,000             carcinoma. Platinum in combination with paclitaxel
                               population) are nearly 70% lower than they were in          or topotecan has provided the best results [7].
                               the 1970s [2].                                              Combination chemotherapy regimens although yet to
                                  Human papilloma virus and its persistence, is            show an increase in overall survival in comparison
                               thought to be the most important causative factor in        with single agent platinum, have shown an increase
                               the development of the disease [3]. Modifying factors       in progression free survival and response rates[8]. In
                               include cigarette smoking, the oral contraceptive pill      view of this, platinum and paclitaxel is the current
                               and age of first intercourse. An HPV vaccination            standard regimen for palliative systemic therapy[9].
                               programme in girls aged 12-13 years has been started
                               in UK schools with a catch-up programme available           Novel Agents
 Anita Mitra,                  to girls aged 13-18 years.
 Specialist Registrar at the                                                               Agents targeting hypoxia
                                  The histopathology in most cases is squamous cell
 Royal Marsden Hospital
 NHS Foundation Trust.         carcinoma, although the incidence of adenocarcinomas        Necrotic tissue is often found within tumour masses.
                               is increasing, currently making up 15%. Broadly, the        Agents that are activated in a hypoxic environment may
                               staging of invasive cervical cancer is divided into four    therefore target tumour cells. Tirapazamine, a
                               categories where stage 1 represents disease that is         benzotriazine di-N-oxide, is metabolised to free radicals
                               confined to the cervix, stage 2 involving the               in a hypoxic environment. The free radicals cause DNA
                               surrounding tissues, stage 3 disease within the pelvis or   double and single stranded breaks leading to cell death.
                               lower vagina and stage 4 advanced disease which             A Phase 3 randomised trial of chemoradiation versus
                               involves other organs. Five year overall survival varies    chemoradiation with tirapazamine in stage IB2, IIA, IIB,
                               from 80-98% in Stage 1 disease to 20% in stage 4.           IIIB, and IVA cervical carcinoma limited to the pelvis is
                                  Surgery is used to treat early stage disease. Radical    currently being undertaken (Gynaecology Oncology
                               chemo-radiotherapy with external beam radiotherapy          Group 219). Hypoxic cell sensitisers are not currently in
                               followed by brachytherapy is used for those with            routine use.
 Peter Blake,
 Consultant Clinical
                               disease beyond the cervix which may be safely
 Oncologist at the Royal       encompassed within a radiation field.                       Epidermal Growth Factor Receptor (EGFR) Inhibitors
 Marsden Hospital NHS             This article provides an overview of some of the         High expression of EGFR is one of the main
 Foundation Trust.             current areas of research in cervical cancer.               mechanisms by which EGFR signalling is increased in
                                                                                           cancer cells. There are two different ways of
 Correspondence:               Chemotherapy                                                pharmacologically targeting EGFR: anti-EGFR
 Peter Blake,                                                                              monoclonal antibodies and inhibitors of the EGFR
 Royal Marsden Hospital,       Neoadjuvant Chemotherapy                                    tyrosine kinase.
 London SW3 6JJ, UK.
                               Neoadjuvant chemotherapy prior to the use of radical           Phase 2 results for tyrosine kinase inhibitors have
                               radiotherapy has not been shown to increase overall         been equivocal. Gefitinib, has been shown to be
                               or disease free survival [4].                               ineffective in refractory cervical cancer [10]. A recent
                                  The benefit of neoadjuvant chemotherapy prior to         study of erlotinib as monotherapy in recurrent
                               surgery is equivocal. Some studies have shown an            cervical cancer did not report a response [11]. Further
                               increased overall survival and others a response rate       investigation is required.
                               of 52% but no associated improvement in the surgical           Preclinical studies of cetuximab, a monoclonal
                               pathological findings[5]. However, confounding              antibody to EGFR, produced significant inhibition in
                               factors in such studies include the non-randomised          all EGFR-positive cervical cancer cell lines tested
                               use of post-operative radiotherapy.                         (range 37%-58%) [12]. The efficacy of single-agent
                                  Neoadjuvant chemotherapy is currently not                cetuximab in patients with persistent or recurrent
                               routinely recommended in the treatment of cervical          cervical cancer is being investigated.
                               squamous cell and adenocarcinomas. The EORTC
                               55994 trial is comparing platinum based neoadjuvant         Anti-angiogenesis
                               chemotherapy followed by surgery with concomitant           Vascular endothelial growth factor (VEGF) is one of
                               chemo-radiotherapy in patients with FIGO IB2, IIA or        the most important factors involved in the regulation
                               IIB cervical cancer. A recently closed phase 2 study        of angiogenesis [13]. The over expression of VEGF is
                               from the NCRI clinical studies group is investigating       associated with poor prognosis [14,15].

192                                                                                                     Volume 4 Issue 6 • January/February 2010
                                                                                                                    disease were using IMRT, the majority in
                                                                                                                    the research setting. Head and neck and
                                                                                                                    urological malignancies were treated with
                                                                                                                    IMRT most commonly, with less than 10%
                                                                                                                    of departments using IMRT in the treatment
                                                                                                                    of gynaecological malignancies[28].
                                                                                                                       Reasons for not implementing IMRT in
                                                                                                                    most departments lay with funding issues
                                                                                                                    and the resulting inadequate physics time
                                                                                                                    and equipment. However there are also
                                                                                                                    concerns that the benefit of reduced
                                                                                                                    morbidity should not be achieved at the cost
                                                                                                                    of decreased local control and overall
                                                                                                                    survival due to movement of the target
                                                                                                                    volume outside of the irradiated field[29-31].
                                                                                                                    Interfractional assessment of organ motion
                                                                                                                    during treatment delivery is required.
                                                                                                                       The IMRT technique will become more
                                                                                                                    widespread in the treatment of cervical
                                                                                                                    malignancies. As it does the opportunities
                                                                                                                    for dose escalation particularly in areas of
                                                                                                                    nodal disease are likely to be investigated.
                                                                                                                       This article reviews some topical areas
                                                                                                                    that are currently under investigation in the
Figure 1: Coronal CT image of intra-uterine and intra-cavitary brachytherapy applicators with a typical radiation   treatment of cervical cancer. These include
dose distribution superimposed.
                                                                                                                    radiosensitisers, biological therapies and
                                                                                                                    technical radiotherapy techniques.
   Bevacizumab is a humanised monoclonal                     3D dose prescription is now becoming a
antibody that recognises and blocks VEGF.                    possibility (Figure 1).
It has been investigated in a small sample                   The benefits of IGBT lie in:
                                                             1) Verification of accurate applicator                 References
of heavily pre-treated women with
recurrent cervical cancer. There was a                           positioning;                                       1. WHO (2006) Comprehensive Cervical Cancer
                                                                                                                       Control: a Guide to Essential Practice Vol.
complete or partial response in 34% of the                   2) Accurate definition of normal tissue                   Accessed 2009.
sample when bevacizumab was used in                              dosimetry;                                         2. Statistics C (2007) Vol. 2009.
combination with 5FU [16]. A Gynaecology                     3) Conformal dose distribution to tumour               3. Wallin KL, Wiklund F, Angstrom T, Bergman F,
Oncology Group (GOG 240) study is                                volume and OAR;                                       Stendahl U, Wadell G, Hallmans G, Dillner J.
currently recruiting into a phase 3 trial of                 4) The potential for dose escalation.                     Type-specific persistence of human
                                                                                                                       papillomavirus DNA before the development of
recurrent, stage IVB or persistent carcinoma                 IGBT also offers the potential for improving              invasive cervical cancer. The New England
of the cervix comparing paclitaxel or                        tumour target (disease) coverage while                    journal of medicine. 1999:341: 1633-8.
topotecan with or without bevacizumab.                       reducing the dose to the OAR [18]. Higher              4. Collaboration NCfLACCM-a Neoadjuvant
                                                             doses are correlated to improved tumour                   chemotherapy for locally advanced cervical
                                                                                                                       cancer: a systematic review and meta-analysis of
New Approaches in Radiotherapy                               control [19,20]. It is possible to increase the           individual patient data from 21 randomised trials.
                                                             dose to the target volume using CT or MRI                 Eur J Cancer. 2003:39: 2470-86.
Image Guided Brachytherapy (IGBT)                            based IGBT [21].                                       5. Eddy GL, Bundy BN, Creasman WT, Spirtos NM,
                                                                                                                       Mannel RS, Hannigan E, O'Connor D. Treatment
Intrauterine and intracavitary brachy-                          IGBT will allow better definition of
                                                                                                                       of ("bulky") stage IB cervical cancer with or
therapy is used after external beam                          radiation dose to malignant tissue and                    without neoadjuvant vincristine and cisplatin
radiotherapy. This technique enables the                     avoidance of OAR. Currently, only a few                   prior to radical hysterectomy and pelvic/para-
                                                                                                                       aortic lymphadenectomy: a phase III trial of the
administration of a high and localised                       centres which treat cervical cancer are
                                                                                                                       gynecologic oncology group. Gynecologic
radiation dose to the cervix and uterus                      using IGBT on a regular basis [21,22].                    Oncology. 2007:106: 362-9.
avoiding organs at risk (OAR). Organs at                     However, 83% of centres hope to be using               6. Joly-Lobbedez F. (2009) [Evidence based of
risk are normal tissue structures adjacent to                this technique in the coming five years [23].             chemoradiotherapy in cervix carcinoma.]. Cancer
                                                                                                                       Radiother. 2009 Oct;13(6-7):503-6. Epub 2009
the disease targeted by radiotherapy.                        The EMBRACE study is currently being
                                                                                                                       Aug 19.
   Inaccurate positioning of the intrauterine                conducted in 12 centres in Europe and is a
                                                                                                                    7. Long HJ, 3rd, Bundy BN, Grendys EC, Jr., Benda
tubes and intracavitary applicators may lead                 vehicle to introduce 3D MRI-based                         JA, McMeekin DS, Sorosky J, Miller DS, Eaton
to uterine perforation. An 8% perforation                    brachytherapy in a multi-centre setting and               LA, Fiorica JV. Randomized phase III trial of
                                                                                                                       cisplatin with or without topotecan in carcinoma
rate has been reported in insertions where                   will prospectively assess local control and               of the uterine cervix: a Gynecologic Oncology
the operator was confident of placement of                   survival (,                    Group Study. J Clin Oncol. 2005:23: 4626-33.
the applicator [17]. Perforation may lead to                 accessed October 2009).                                8. McQuellon RP, Thaler HT, Cella D, Moore DH.
the positioning of the applicators close to                                                                            Quality of life (QOL) outcomes from a
                                                                                                                       randomized trial of cisplatin versus cisplatin plus
bowel and potential overdose to this organ                   Intensity Modulated Radiotherapy (IMRT)                   paclitaxel in advanced cervical cancer: a
with resulting long-term complications.                      Intensity Modulated Radiotherapy allows                   Gynecologic Oncology Group study. Gynecologic
Verification of the applicator position will                 an external beam radiotherapy dose                        Oncology. 2006:101: 296-304.
avoid this complication.                                     distribution to conform very precisely to the          9. Monk BJ, Sill M, McMeekin S, al. E. A
                                                                                                                       randomized phase III trial of 4 cisplatin (CIS)
   Brachytherapy prescription has remained                   treatment volume. This means that there is                containing doublet combinations in stage IVB,
unchanged for the last 20 years. Prescribing                 great potential for sparing of normal tissues             recurrent or persistent cervical carcinoma: a
to a dose point, most commonly the                           by targeting the tumour volume more                       Gynecologic Oncology Group (GOG) study
                                                                                                                       [abstract]. J Clin Oncol. 2008:26.
Manchester point A is undertaken                             accurately. Sparing normal tissues (bowel,
                                                                                                                    10. Goncalves A, Fabbro M, Lhomme C, Gladieff L,
regardless of tumour distribution and the                    bladder and rectum) in the treatment of                    Extra JM, Floquet A, Chaigneau L, Carrasco AT,
organs at risk. With the advent of High                      gynaecological malignancies should reduce                  Viens P. A phase II trial to evaluate gefitinib as
Dose Rate brachytherapy, artefact-free CT                    long-term morbidity [24-27].                               second- or third-line treatment in patients with
                                                                                                                        recurring locoregionally advanced or metastatic
and MRI compatible applicators and the                          A recent national survey revealed that                  cervical cancer. Gynecologic Oncology. 2008:108:
accessibility of modern imaging techniques,                  46% of centres which treat malignant                       42-6.

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11. Erlich E, Carmo CC, Viegas C, al. e (2008) Erlotonib combined with
    cisplatin and radiotherapy for patients with locally advanced squamous
    cell cervical cancer: a phase II trial. J Clin Oncol. 2008:26.
12. Bellone S, Frera G, Landolfi G, Romani C, Bandiera E, Tognon G, Roman
    JJ, Burnett AF, Pecorelli S, Santin AD. Overexpression of epidermal
                                                                                   Meet the Editorial Team
    growth factor type-1 receptor (EGF-R1) in cervical cancer: implications for
    Cetuximab-mediated therapy in recurrent/metastatic disease. Gynecologic              Professor Denys Wheatley is Editor, and is Director of BioMedES. He has strong
    Oncology. 2007:106: 513-20                                                           research ties in Albany, Davis, Auckland, Valencia, Detroit, Budapest, St Petersburg,
13. Lee JS, Kim HS, Park JT, Lee MC, Park CS. Expression of vascular                     Heidelberg, Zürich and Hong Kong. He is eager to establish strong interaction with cancer
    endothelial growth factor in the progression of cervical neoplasia and its           and cell biology teams worldwide, and initiate programmes in the areas in which his
    relation to angiogenesis and p53 status. Analytical and quantitative                 expertise lies. His work in cancer research, other scientific fields, with IFCB, and in
    cytology and histology / the International Academy of Cytology [and]                 publishing and scientific communication has led to his receiving awards in recent years.
    American Society of Cytology 2003:25: 303-11.
14. Gaffney DK, Haslam D, Tsodikov A, Hammond E, Seaman J, Holden J,
    Lee RJ, Zempolich K, Dodson M. Epidermal growth factor receptor
                                                                                         Professor Patrick J Bradley (Associate Editor), is a Head and Neck Oncologic
    (EGFR) and vascular endothelial growth factor (VEGF) negatively affect
                                                                                         Surgeon at the University Hospital, Nottingham. He is a member of numerous journals’
    overall survival in carcinoma of the cervix treated with radiotherapy.
                                                                                         UK Editorial Boards; Journal of Laryngology and Otology, Oral Oncology, and International
    International journal of radiation oncology, biology, physics. 2003:56: 922-
                                                                                         Journals: Laryngoscope, Head and Neck, Acta Otolaryngologica Scandinavia, as well as
                                                                                         Section Editor of Head and Neck Oncology, and Current Opinions ORL-HNS.
15. Loncaster JA, Cooper RA, Logue JP, Davidson SE, Hunter RD, West CM.
    Vascular endothelial growth factor (VEGF) expression is a prognostic
    factor for radiotherapy outcome in advanced carcinoma of the cervix.
    British journal of cancer. 2000:83: 620-5.
                                                                                         Dr Richard J Ablin (Associate Editor), is Research Professor of Immunobiology and
16. Wright JD, Viviano D, Powell MA, Gibb RK, Mutch DG, Grigsby PW,
                                                                                         Pathology, University of Arizona College of Medicine and a Member of the Arizona Cancer
    Rader JS. Bevacizumab combination therapy in heavily pretreated,
                                                                                         Center, Tucson, Arizona. He received the First Award for scientific excellence from The
    recurrent cervical cancer. Gynecologic Oncology. 2006:103: 489-93.
                                                                                         Haakon Ragde Foundation for Advanced Cancer Studies. Dr Ablin discovered prostate-
17. Barnes EA, Thomas G, Ackerman I, Barbera L, Letourneau D, Lam K,                     specific antigen (PSA) in 1970. A pioneer of cryosurgery and cryoimmunotherapy, he has
    Makhani N, Sankreacha R. Prospective comparison of clinical and                      extensive experience in cancer research.
    computed tomography assessment in detecting uterine perforation with
    intracavitary brachytherapy for carcinoma of the cervix. Int J Gynecol
    Cancer. 2007:17: 821-6.
18. Potter R, Fidarova E, Kirisits C, Dimopoulos J. Image-guided adaptive
                                                                                        Dr Tom Lynch is Assistant Editor – Imaging, and is a Radiologist and Lead Nuclear
    brachytherapy for cervix carcinoma. Clinical oncology (Royal College of             Medicine Physician in the Northern Ireland Cancer Centre based at the Belfast City Hospital.
    Radiologists (Great Britain)) 2008:20: 426-32.                                      Tom specialises in PET/CT scanning and nuclear medicine with a special interest in
                                                                                        paediatric nuclear medicine.
19. Choy D, Wong LC, Sham J, Ngan HY, Ma HK. Dose-tumor response of
    carcinoma of cervix: an analysis of 594 patients treated by radiotherapy.
    Gynecologic Oncology. 1993:49: 311-7.
20. Eifel PJ, Thoms WW, Jr., Smith TL, Morris M, Oswald MJ. The
    relationship between brachytherapy dose and outcome in patients with
    bulky endocervical tumors treated with radiation alone. International               Dr Heidi Sowter is Assistant Editor – Web Review, and is a Lecturer in Forensic
    journal of radiation oncology, biology, physics. 1994:28: 113-8.                    Science and Biology, at the Faculty of Education, Health and Science, University of Derby.
                                                                                        Heidi continues to pursue her research interests in gynaecological and breast cancer.
21. Potter R, Knocke TH, Fellner C, Baldass M, Reinthaller A, Kucera H.
    Definitive radiotherapy based on HDR brachytherapy with iridium 192 in
    uterine cervix carcinoma: report on the Vienna University Hospital
    findings (1993-1997) compared to the preceding period in the context of
    ICRU 38 recommendations. Cancer Radiother. 2000:4:159-72.
22. Tan LT, Coles CE, Hart C, Tait E. Clinical impact of computed tomography-
    based image-guided brachytherapy for cervix cancer using the tandem-                Ms Kathleen Mais is Assistant Editor – Nursing, and is a Nurse Clinician in Head &
    ring applicator - the Addenbrooke's experience. Clinical oncology (Royal            Neck Oncology at Christie Hospital, Manchester. Kathleen qualified as a nurse in
    College of Radiologists (Great Britain)) 2009:21: 175-82.                           Newcastle-upon-Tyne. Kathleen is a nurse-prescriber and runs a nurse-led chemotherapy
                                                                                        clinic as well as continuing her work in clinical research.
23. RCR (2008) Implementing Image Guided Brachytherapy for Cevix Cancer
    in the UK Vol. 2009.
24. Chen MF, Tseng CJ, Tseng CC, Kuo YC, Yu CY, Chen WC. Clinical
    outcome in posthysterectomy cervical cancer patients treated with
    concurrent Cisplatin and intensity-modulated pelvic radiotherapy:
    comparison with conventional radiotherapy. International journal of                 Marilena Loizidou is Assistant Editor – Colorectal, and is a Non-Clinical Senior
    radiation oncology, biology, physics. 2007:67: 1438-44.                             Lecturer in the Department of Surgery, UCL. Her research program focuses on aspects of
                                                                                        colorectal cancer and liver metastases, from the basic underlying biology to new potential
25. Kavanagh BD, Schefter TE, Wu Q, Tong S, Newman F, Arnfield M,
                                                                                        treatments. The current focus of research is the contribution of the peptide endothelin-1 to
    Benedict SH, McCourt S, Mohan R. Clinical application of intensity-
                                                                                        tumour growth and progression in the bowel. Additional research areas include breast and
    modulated radiotherapy for locally advanced cervical cancer. Seminars in
                                                                                        bladder cancer.
    radiation oncology. 2002:12: 260-71.
26. Mundt AJ, Lujan AE, Rotmensch J, Waggoner SE, Yamada SD, Fleming G,
    Roeske JC. Intensity-modulated whole pelvic radiotherapy in women with
    gynecologic malignancies. International journal of radiation oncology,              Alan Cooper is Assistant Editor – Urology, and is Lead Scientist with the urology
    biology, physics. 2002:52: 1330-7.                                                  research group in Southampton University Hospitals and senior lecturer (albeit with virtually
                                                                                        no lecturing burden) in the Department of Biomedical Sciences at Portsmouth University.
27. Mundt AJ, Mell LK, Roeske JC. Preliminary analysis of chronic
    gastrointestinal toxicity in gynecology patients treated with intensity-
    modulated whole pelvic radiation therapy. International journal of
    radiation oncology, biology, physics. 2003:56: 1354-60.
28. Jefferies S, Taylor A, Reznek R. Results of a national survey of
    radiotherapy planning and delivery in the UK in 2007. Clinical oncology
    (Royal College of Radiologists (Great Britain)) 2009:21: 204-17.                    Dr S Gokul is Assistant Editor - Journal Reviews, and is a Consultant Medical
29. Kim RY, McGinnis LS, Spencer SA, Meredith RF, Jennelle RL, Salter MM.               Oncologist at The James Cook University Hospital, Middlesbrough. His areas of interest are
    Conventional four-field pelvic radiotherapy technique without computed              lung and gynaecological cancer.
    tomography-treatment planning in cancer of the cervix: potential
    geographic miss and its impact on pelvic control. International journal of
    radiation oncology, biology, physics. 1995:31: 109-12.
30. Thomas L, Chacon B, Kind M, Lasbareilles O, Muyldermans P, Chemin A,
    Le Treut A, Pigneux J, Kantor G. Magnetic resonance imaging in the
    treatment planning of radiation therapy in carcinoma of the cervix treated            Helen Evans is a Journal Reviewer for Oncology News. Helen recently worked as a
    with the four-field pelvic technique. International journal of radiation              Senior Lecturer in Cancer Nursing at the Institute of Nursing and Midwifery, University of
    oncology, biology, physics. 1997:37: 827-32.                                          Brighton, but following the birth of her son has returned to clinical practice as a Clinical Nurse
31. Weiss E, Eberlein K, Pradier O, Schmidberger H, Hess CF. The impact of                Specialist at St. Wilfrid's Hospice in Chichester.
    patient positioning on the adequate coverage of the uterus in the primary
    irradiation of cervical carcinoma: a prospective analysis using magnetic
    resonance imaging. Radiother Oncol. 2002:63: 83-7.

194                                                                                                                          Volume 4 Issue 6 • January/February 2010

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