Bull’s-eye! Cutting-edge treatments are aimed squarely at gynaecologic cancers Ovarian cancer is the most common gynaecological malignancy seen at NUH. Radical debulking surgery is performed whenever feasible to achieve optimal status. The ready availability of the colorectal, upper GI and urological specialties, and perioperative support are critical to successful surgical outcome and survival of ovarian cancer patients.    In April 2006, the United States National Cancer Institute (NCI), part of the National Institutes of Health, issued an announcement encouraging the use of intravenous (IV) combined with intra-peritoneal (IP) chemotherapy for the treatment of women with advanced ovarian cancer. The combined treatment method extended overall survival for women with advanced ovarian cancer by about a year. The announcement coincided with the publication in the New England Journal of Medicine of the results of a large clinical trial by Dr Deborah Armstrong, an oncologist and an associate professor at Johns Hopkins Kimmel Cancer Center in Baltimore, Maryland, and her colleagues in an NCI-supported research network known as the Gynecologic Oncology Group (GOG). This is the eighth trial evaluating the use of chemotherapy delivered into the abdomen for ovarian cancer. Together, these trials show a significant improvement in survival for women with advanced ovarian cancer. The Armstrong trial involved 429 women with stage 3 ovarian cancer who were given chemotherapy following the successful surgical removal of ovarian carcinoma. It compared two treatment regimens: 1) IV paclitaxel followed by IV cisplatin and 2) IV paclitaxel followed by IP cisplatin and the subsequent administration of IP paclitaxel.   Ovarian cancer – the top killer The announcement was timely, as ovarian cancer is currently the foremost gynaecological cancer in Singapore women. It has overtaken cervical cancer in incidence, and its age-standardised rate has risen steadily from 6.0/100,000 to 11.0/100,000 over the last 40 years. The most recent statistics show that overall survival is only about 45% at 5 years.   As the condition frequently has mild symptoms (or none at all) until the disease is advanced, only 20% of all cases are detected at an early, localised stage. Standard treatment for women with stage 3 ovarian cancer has been surgical removal of the tumour (debulking), followed by six to eight cycles of IV chemotherapy (carboplatin and paclitaxel) every 3 weeks.   IP chemotherapy – the more effective treatment option? IP chemotherapy allows higher doses and more frequent administration of drugs, and it appears to be more effective in killing cancer cells in the peritoneal cavity, where ovarian cancer is likely to spread or recur first. In the trial, women who received part of their chemotherapy via an IP route had a median survival time 16 months longer than women who received only IV chemotherapy. The 205 women treated via the IP route fared better, even though most of them received fewer than the six planned treatments. Complications associated with the abdominal catheter used to deliver the IP chemotherapy were the main reason why only 86 of the women completed all six IP treatments. Women who received IP chemotherapy had more side effects than those treated with IV chemotherapy alone, but most side effects were temporary and easily managed. One year after treatment, women in both study groups had the same reported quality of life.   At this point in time, the following points should be noted: The NCI recommendation that IP chemotherapy be considered only for patients who are optimally debulked again highlights the importance of referring women with known or suspected ovarian cancer to a gynaecologic oncologist or other physician with special expertise and training in ovarian cancer cytoreductive surgery.   IP chemotherapy – the complications Although there is good evidence that IP chemotherapy increases median survival, it remains unclear whether this translates into higher cure rates. Besides, there is presently no consensus regarding what constitutes the “standard” IP chemotherapy regimen.   Furthermore, as the intensity and toxicity levels of IP chemotherapy are higher than those of IV chemotherapy, IP chemotherapy may not be well-tolerated by patients who do not have an excellent performance status. In view of this, the decision to use IP chemotherapy should be made on a case-by-case basis by each patient and her physician.   The issues and challenges associated with the administration of IP chemotherapy differ from those encountered with IV chemotherapy. Most notably, this includes surgical insertion and maintenance of IP catheters, as well as the management of complications such as catheter obstruction, infection and bowel fistula. In view of this, IP chemotherapy should only be administered by oncologists with appropriate expertise and experience.   The Gynaecologic Oncology Tumour Group (GOTG) at The Cancer Institute (TCI), NUH, provides risk evaluation, and preventive and screening services for women at risk of developing ovarian and uterine cancers. Detailed counselling and gene testing are available for high-risk candidates. Prophylactic surgery is also available for those proven to be at risk of hereditary breast, ovarian or uterine cancers.   The group is actively researching the proteomic and genomic profiles of ovarian cancers, which are now believed to be key to early detection, as well as participating in a phase 3 randomised trial of a novel chemotherapeutic agent for second-line treatment of relapsed ovarian, tubal and peritoneal carcinoma.   Cervical cancer screening The second commonest gynaecological malignancy seen here is cervical carcinoma. The incidence of cervical carcinoma in Singapore has been gradually declining, in part due to opportunistic screening, and more recently due to the launch of CervicalScreen Singapore. However, the rates in Singapore continue to be higher than most of Europe and the US, and lower than parts of Asia, Africa and Latin America. Cervical cytology screening is well known to represent the “ideal” screening test for a cancer that has a well-defined pre-malignant phase of many years. But it is by no means perfect, given its false negative rates ranging from 15% to 30% for high-grade pre-cancers, and up to 50% for invasive cancers (due to the obscuring effect of blood and necrotic exudates).   The Pap test using liquid-based cytology (LBC) is now the de facto standard at NUH. In this method, samples are collected in the usual manner from the cervix but are then transferred directly into the fixative solution rather than dispersed on a slide. The liquid is then passed through a filter and the cells are transferred to a slide as a monolayer. The slide is then processed like a conventional pap test. The ability to interpret the slide is improved because the cells are more evenly distributed and there is less artifactual material such as blood and mucus, thus reducing the incidence of unsatisfactory reports. The ability to test LBC specimens for HPV DNA and other sexually transmitted organisms further enhances the clinical appeal of this technology.   For the evaluation of abnormal smears and the investigation of vulvar diseases, digital colposcopy is used at the GOTG Colposcopy Clinic. This technology enables colposcopic images and video to be captured on digital media at a very high resolution within the database to allow more accurate evaluation, image comparisons, data archiving, practice audit and, in the future, tele-colposcopy. Outpatient treatments using the CO2 laser, loop diathermy and cold coagulation are also available at the Colposcopy Clinic.   Treatment options The central etiologic role of human papilloma viruses (HPV) in the pathogenesis of cervical cancer has spawned the development of vaccines to immunise against HPV as a primary prevention strategy for cervical cancer. A proof-of-principle study of a monovalent HPV vaccine has confirmed a high rate of seroconversion, with none of the vaccinated subjects developing HPV-16 infection or HPV-16-related CIN. Subsequent studies have culminated in a quadrivalent HPV vaccine that has now won FDA approval, and in time to come, HSA approval for use in Singapore. The group is currently participating in a multi-centre trial on another bivalent HPV vaccine. These vaccines may herald the eradication of cervical cancer in the near future.   For patients diagnosed with invasive cervical carcinoma, the traditional Wertheim (or radical) hysterectomy may be performed for early stage disease. Locally advanced disease is treated on-site with concurrent chemo-radiation at TCI’s Cancer Centre and Radiotherapy Centre.   The group is collaborating closely with NUS bioengineers to develop a high-speed fluorescent spectroscopy system for non-invasive detection of cervical pre-cancers and cancer. Research is also being carried out at the molecular level to investigate the role of molecular diagnostics in early detection of cervical carcinoma.   Fortunately, endometrial carcinoma presents at an early stage in most cases. Many patients can therefore be treated with minimally invasive surgery. As such, a laparoscopic hysterectomy and node dissection can be performed for many of these patients. This will afford them quicker post-surgical recovery and earlier return to work. This is made possible by modern endoscopic surgery at NUH. In the later part of 2006, robotic surgery using the famous Da Vinci system will also become available. The robot-assisted endoscopic surgery will further increase surgical precision and increase patient safety.   This article is courtesy of the Gynaecologic Oncology Tumour Group at The Cancer Institute, National University Hospital. The GOTG comprises gynaecologic oncologists, radiation and medical oncologists, pathologic and oncologic radiologists providing one-stop, comprehensive, state-of-the-art care for women with gynaecological cancers. The gynaecological cancer services are supported by the multidisciplinary clinical and para-clinical services at NUH and The Cancer Institute. This is complemented by the biomedical research infrastructure at the National University of Singapore (NUS) and Biopolis, and the South African National Bioinformatics Institute.