Published and unpublished data for this review were identified by searches of Medline, the web of science, the National Cancer Institute register of clinical trials, and abstracts for the annual meetings of the American Society of Clinical Oncology and the American Association of Cancer Research, as well as discussions with experienced investigators who study ovarian cancer. In searching databases, we did not limit the year of publication, but only articles published in English were
ReviewPart II: Chemotherapy for epithelial ovarian cancer-treatment of rcurrent disease
Section snippets
Timing of treatment
The basic principles of palliative chemotherapy should be an important guide when advising patients about treatment and when designing trials. Treatment should aim to relieve cancer-related symptoms, optimise quality of life, delay the time to symptomatic disease progression, and prolong overall survival. It could be argued, therefore, that treatment is not required until the patient has symptoms and that follow-up should be based on symptom-directed investigations alone. However, analysis of
Rising CA-125
Most women with ovarian carcinoma have high serum concentrations of the antigen CA-125 at the time of diagnosis, and this antigen is also a sensitive marker of relapse with a median lag time of 3–9 months before disease becomes evident macroscopically.2, 3 Patients who have symptoms and a rising CA-125 concentration should start treatment. However, there is no evidence that early treatment of relapse is of any benefit to patients without symptoms, and randomised controlled trials addressing
CA-125 non-secretors
There are patients whose tumours do not secrete CA-125 and who did not have high concentrations at the time of diagnosis; this group accounts for 10–20% of patients. Our practice for such women is to monitor with routine scans to detect early relapse before the tumour becomes too bulky. A more vigilant follow-up policy is advocated for patients with early-stage disease for whom there is no evidence of a raised CA-125 concentration at diagnosis and who have been managed by observation only since
Prediction of response
The first consideration that influences the choice of treatment is the time from previous chemotherapy. This treatment-free interval has consistently been the most important factor in prediction of future response.5, 6, 7 Two groups of patients can be differentiated: patients who relapse on or within a few months of first-line treatment and those who relapse later. The first group, generally defined as those who relapse within 6 months, have disease that is likely to be resistant to the
Drugs with activity in relapsed ovarian cancer
Several compounds have activity in relapsed ovarian cancer, with most drugs having a response rate in the range of 15–20% for patients with a treatment-free interval of less than 12 months. The main drugs are discussed below and their single-agent activity is summarised in table 1.8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21
There have been no randomised controlled trials to compare chemotherapy with best supportive care for relapsed disease. However, in a recent multicentre study of 266
Topotecan
The topoisomerase I inhibitor topotecan has now become an established drug in relapsed ovarian cancer and in the UK has been approved for this use by the National Institute of Clinical Excellence. In a large multicentre phase II study,23 topotecan 1·5 mg/m2 daily was administered intravenously by a 30 min infusion for 5 days repeated every 3 weeks and was active in relapsed disease. As with other drugs in this setting, there were large differences in the response rates between patients who had
Epirubicin
The role of conventional anthracyclines in relapsed ovarian carcinoma remains controversial. Before the advent of the taxanes, doxorubicin was commonly used for relapsed disease and in the 1980s was investigated in several first-line studies. Epirubicin, in phase II studies, has shown response rates that vary from zero to 27%17, 35 In Vermorken and colleagues' phase I and phase II studies of high-dose epirubicin,18, 36, 37 there was significant activity with a response rate of 20% (95% CI
Combination chemotherapy for relapsed disease
There have been few randomised trials comparing combination therapy with single-agent treatment for relapsed disease. Colombo42 reported that treatment with cyclophosphamide, doxorubicin, and cisplatin did not result in significantly higher response rates than treatment with single-agent paclitaxel (54% vs 49%) but that there was an advantage for the combination in median progression-free survival (18·9 vs 7·3 months, p=0·014) and overall survival (24·3 vs 20·3 months, p=0·03).42 In that study,
Chemotherapy for patients with bowel obstruction
One of the most common problems faced by patients with end-stage ovarian cancer is bowel obstruction. This difficult clinical situation should be managed by a multidisciplinary team with input from nurses, palliative-care specialists, dietitians, surgeons, and medical oncologists. Much thought and discussion are needed before patients undergo surgery, because the reported perioperative mortality rate (within 8 weeks of surgery) is 10–15%, and 35–38% of patients do not gain any clinical benefit.
Endocrine agents
Endocrine therapy has long been used for patients with refractory ovarian cancer. The overall response rate to progestagens and antioestrogens is low (10–15%), but a large GOG study reported an 18% response rate, including a 10% complete remission rate, for tamoxifen administered at a dose of 20 mg twice daily by mouth.53 An updated analysis of this study suggested a response rate of 13% in patients with platinum-resistant disease (defined in this study as progression during or within 6 months
Platinum analogues
Several platinum analogues are being investigated for activity in ovarian cancer. ZD0473 is a sterically hindered platinum drug designed to circumvent platinum resistance caused by high concentrations of glutathione.56 It is being tested in a phase II study in patients with relapsed ovarian cancer and appears to be active.57 BBR3464, a novel cationic triplatinum complex, has non-cross-resistance with cisplatin in preclinical models and is also now undergoing clinical trials.58
New taxanes
Taxoprexin is a covalent conjugate of paclitaxel and the essential fatty acid docosahexaenoic acid that may have a better pharmacokinetic and toxicity profile than paclitaxel. Taxoprexin is under evaluation as a single agent in phase II studies and in combination with carboplatin in phase I studies. BMS-184476 is a taxoid with potentially less toxicity and greater solubility than paclitaxel, which is being assessed in phase II clinical trials.59
Other cytotoxic agents
The activity of some new cytotoxic agents is being investigated in patients with relapsed ovarian cancer: NX211 (a liposomal formulation of lurtotecan),60 epothilones,61 and ecteinascidin-743.62
Signal-transduction inhibitors
Several new drugs targeting molecular pathways that are altered in cancer cells are being developed and tested. These include inhibitors of farnesyl transferase, which prevent the post-translational modification of RAS, RAF-kinase inhibitors, rapamycin analogues that inhibit the synthesis of several signalling molecules including m-TOR, inhibitors of protein kinase C, and inhibitors of epithelial-growth-factor-receptor (EGFR) tyrosine kinase.63
Iressa (ZD1839), an inhibitor of EGFR tyrosine
Conclusion
A patient with relapsed ovarian carcinoma should be assessed according to her treatment-free interval, the bulk of disease, symptoms, performance status, and her preference. Patients with a 6-month or longer interval since first-line therapy should be considered for rechallenge with a platinum-based regimen at some stage. Several drugs have activity in platinum-resistant disease, and this is also an ideal setting for testing of new agents. Non-cytotoxic approaches and strategies designed to
Search strategy and selection criteria
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