Elsevier

The Lancet Oncology

Volume 3, Issue 9, September 2002, Pages 537-545
The Lancet Oncology

Review
Part II: Chemotherapy for epithelial ovarian cancer-treatment of rcurrent disease

https://doi.org/10.1016/S1470-2045(02)00847-1Get rights and content

Summary

For women with advanced ovarian cancer, rates of response to first-line chemotherapy are high but most patients have relapses and become candidates for further chemotherapy. Chemotherapy for recurrence can palliate symptoms, and there is some evidence that it can also improve survival in this clinical situation. Patients who relapse quickly after first-line therapy should not be given the same drugs as were used initially. However, for patients who have longer intervals from treatment to relapse, the rates of response to a rechallenge with platinum are clinically significant. Several cytotoxic drugs have shown activity in patients whose disease has relapsed after therapy with platinum and a taxane; these drugs include topotecan, etoposide, pegylated liposomal doxorubicin, epirubicin, gemcitabine, altretamine, oxali-platin, and vinorelbine. Recurrent ovarian cancer is also an important setting in which to test investigational agents with promising activity, such as new platinum compounds, new taxanes, and other cytotoxic agents, as well as non-cytotoxic compounds with novel mechanisms of action.

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

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

References (76)

  • P Sorensen et al.

    Phase II study of vinorelbine in the treatment of platinum-resistant ovarian carcinoma.

    Gynecol Oncol

    (2001)
  • M Gore et al.

    A randomised trial of oral versus intravenous topotecan in patients with relapsed epithelial ovarian cancer.

    Eur J Cancer

    (2002)
  • M Markman et al.

    Phase 2 evaluation of topotecan administered on a 3-day schedule in the treatment of platinum– and paclitaxel-refractory ovarian cancer

    Gynecol Oncol

    (2000)
  • BrownJV et al.

    A phase I trial of a 3-day topotecan Q 21 days for recurrent epithelial cancers of the ovary, fallopian tube, and peritoneum.

    Gynecol Oncol

    (2000)
  • M Markman et al.

    Altretamine (hexamethylmelamine) in platinum-resistant and platinum-refractory ovarian cancer: a Gynecologic Oncology Group phase II trial.

    Gynecol Oncol

    (1998)
  • I Pelaez et al.

    Phase II trial of epirubicin at standard dose in relapsed ovarian cancer.

    Eur J Cancer

    (1996)
  • AE Taylor et al.

    Chlorambucil for platinum-refractory ovarian cancer.

    Clin Oncol

    (1994)
  • du BoisA et al.

    Chemotherapy versus hormonal treatment in platinum- and paclitaxel-refractory ovarian cancer: a randomised trial of the Germa Arbeitsgemeinschaft Gynaekologische Onkologie (AGO) study group ovarian cancer.

    Ann Oncol

    (2002)
  • G Bolis et al.

    Carboplatin alone vs carboplatin plus epidoxorubicin as second–line therapy forcisplatin- or carboplatin-sensitive ovarian cancer.

    Gynecol Oncol

    (2001)
  • JE Larson et al.

    Bowel obstruction in patients with ovarian carcinoma: analysis of prognostic factors

    Gynecol Oncol

    (1989)
  • JC Tunca

    Impact of cisplatin multiagent chemotherapy and total parenteral hyperalimentation on bowel obstruction caused by ovarian cancer.

    Gynecol Oncol

    (1981)
  • NR Abu–Rustum et al.

    Chemotherapy and total parenteral nutrition for advanced ovarian cancer with bowel obstruction.

    Gynecol Oncol

    (1997)
  • M Markman et al.

    Tamoxifen in platinum-refractory ovarian cancer: a Gynecologic Oncology Group Ancillary Report.

    Gynecol Oncol

    (1996)
  • BW Yin et al.

    Molecular cloning of the CA125 ovarian cancer antigen: identification as a new mucin, MUC16

    J Biol Chem

    (2001)
  • M Gore

    The treatment of relapsed epithelial ovarian cancer

  • G Blackledge et al.

    Response of patients in phase II studies of chemotherapy in ovarian cancer: implications for patient treatment and the design of phase II trials.

    Br J Cancer

    (1989)
  • M Markman et al.

    Responses to second-line cisplatin-based intraperitoneal therapy in ovarian cancer: influence of a prior response to intravenous cisplatin.

    J Clin Oncol

    (1991)
  • PG Rose et al.

    Prolonged oral etoposide as second-line therapy for platinum-resistant and platinum-sensitive ovarian carcinoma: a Gynecologic Oncology Group study.

    J Clin Oncol

    (1998)
  • ten Bokkel HuininkW et al.

    Topotecan versus paclitaxel for the treatment of recurrent epithelial ovarian cancer.

    J Clin Oncol

    (1997)
  • MA Bookman et al.

    Topotecan for the treatment of advanced epithelial ovarian cancer: an open-label phase II study in patients treated after prior chemotherapy that contained cisplatin or carboplatin and paclitaxel.

    J Clin Oncol

    (1998)
  • FM Muggia et al.

    Phase II study of liposomal doxorubicin in refractory ovarian cancer: antitumor activity and toxicity modification by liposomal encapsulation.

    J Clin Oncol

    (1997)
  • AN Gordon et al.

    Phase II study of liposomal doxorubicin in platinum- and paclitaxel-refractory epithelial ovarian cancer.

    J Clin Oncol

    (2000)
  • B Lund et al.

    Phase II study of gemcitabine (2′,2′-difluorodeoxycytidine) in previously treated ovarian cancer patients.

    J Natl Cancer Inst

    (1994)
  • MD Hauge et al.

    Phase II trial of intravenous hexamethylmelamine in patients with advanced ovarian cancer.

    Invest New Drugs

    (1992)
  • GJ Creemers et al.

    Topotecan, an active drug in the second-line treatment of epithelial ovarian cancer: results of a large European phase II study.

    J Clin Oncol

    (1996)
  • M Gore et al.

    Clinical evidence for topotecan-paclitaxel non-cross-resistance in ovarian cancer.

    J Clin Oncol

    (2001)
  • AN Gordon et al.

    Recurrent epithelial ovarian carcinoma: a randomized phase III study of pegylated liposomal doxorubicin versus topotecan.

    J Clin Oncol

    (2001)
  • J Vermorken et al.

    Multicenter randomized phase II study of oxaliplatin or topotecan in platinum-pretreated epithelial ovarian cancer patients

    Proc Am Soc Clin Oncol

    (2001)
  • Cited by (137)

    • Marine biome-derived secondary metabolites, a class of promising antineoplastic agents: A systematic review on their classification, mechanism of action and future perspectives

      2022, Science of the Total Environment
      Citation Excerpt :

      Alkylating agents modify and crosslink DNA, inhibiting DNA, RNA, and protein production, and killing rapidly dividing cells. Bendamustine is a new alkylating agent with purine analogue characteristics (Harries and Gore, 2002). Bendamustine appears to be particularly effective against B-cell leukemias.

    View all citing articles on Scopus
    View full text