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 [http://ncrndev.org.uk/
seen in developing countries . 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 .
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 .
the 1970s . 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 . Modifying factors in progression free survival and response rates. 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.
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.
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 . ineffective in refractory cervical cancer . 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 . 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. 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%) . 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 . 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.
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
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radiotherapy. This technique enables the avoidance of OAR. Currently, only a few prior to radical hysterectomy and pelvic/para-
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with resulting long-term complications. Intensity Modulated Radiotherapy allows Gynecologic Oncology Group study. Gynecologic
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to a dose point, most commonly the by targeting the tumour volume more Gynecologic Oncology Group (GOG) study
[abstract]. J Clin Oncol. 2008:26.
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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:
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Volume 4 Issue 6 • January/February 2010 193
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
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