Topotecan in Combination With Cisplatin for the Treatment of Stage IVB, Recurrent, or Persistent Cervical Cancer: Review 2

October 1, 2006

Topotecan, a camptothecin analog previously approved for the treatment of ovarian cancer and small-cell lung cancer, was granted regular approval by the US Food and Drug Administration (FDA) on June 14, 2006, for use in combination with cisplatin to treat women with stage IVB, recurrent, or persistent carcinoma of the cervix not amenable to curative treatment with surgery and/or radiation therapy. The purpose of this summary is to review the database supporting this approval.

 Historically, cervical cancer incidence has decreased significantly in industrialized nations with the introduction of routine cytologic screening. Concomitantly, in the past 6 decades, overall mortality has decreased by 70%.[1] A high cure rate can be achieved in early-stage disease with hysterectomy, with or without adjuvant radiation. In this setting, overall 5-year survival rates approach 80% to 90%.[2] In contrast, the 5-year survival for women with advanced disease is a dismal 16%. This has remained unchanged over the past 30 years.

The US Food and Drug Administration (FDA) approval summary regarding "Topotecan in Combination With Cisplatin for the Treatment of Stage IVB, Recurrent, or Persistent Cervical Cancer," by Brave et al, describes a promising new discovery in the treatment of women with advanced or metastatic disease. The authors eloquently describe the results of the phase III trial conducted by the Gynecologic Oncology Group (GOG-0179), which led to FDA approval of combination topotecan/cisplatin for advanced, recurrent, or persistent disease. Key points from the study are highlighted below.

Chemotherapy and Cervical Cancer

The improved survival benefit of cisplatin-based chemotherapy with radiation compared to radiation alone has been well documented in women with early-stage or locally advanced cervical carcinoma.[3-5] The majority of patients with advanced disease, however, will ultimately have a recurrence, and systemic chemotherapy is the mainstay of treatment in this setting. As the authors note, prior to GOG-0179, response rates from cisplatin treatment in the recurrent setting ranged from 20% to 30% with a short median survival of 6 to 7 months.[6-9] In an effort to improve the progression-free interval and overall survival, phase II and III trials began using cisplatin in combination with one or two additional cytotoxic agents.[10-12] These trials produced mixed improvements in the progression-free interval at the expense of significantly increased toxicity, with no improvement in overall survival.

Given promising reports from a phase II trial of cisplatin plus topotecan (with an overall response rate of 28%), the GOG began its phase III superiority trial with single-agent cisplatin vs the combination of cisplatin plus topotecan vs multiagent MVAC (methotrexate, vinblastine, doxorubicin, cisplatin).[13] As the authors point out, the MVAC arm closed early due to increased toxicity. Brave et al note that this is the first randomized phase III trial to illustrate an improvement in overall survival using combination cytotoxic therapy in advanced or recurrent cervical cancer patients.[13] This novel finding prompted FDA approval for the combination of cisplatin plus topotecan in June 2006.

Topotecan, a topoisomerase I inhibitor causing reversible DNA single-strand breaks, is FDA approved for second-line treatment in recurrent ovarian and small-cell lung cancer.[14] The authors describe both treatment arms as well as the background phase I and II data used by the GOG committee to formulate the dose and schedule used in the present study. Respectively, 146 and 147 patients were randomized to single-agent cisplatin (50 mg/m2 over 1 hour on day 1) vs cisplatin plus topotecan (cisplatin 50 mg/m2 over 1 hour on day 1 and topotecan 0.75 mg/m2 over 30 minutes on days 1-3). Each regimen was given every 3 weeks for six cycles. The demographic, histologic, and staging characteristics as well as prior cisplatin exposures were balanced between the two arms.

Improved Overall Survival

The trial results showed an improvement in progression-free survival (PFS), overall response rate (ORR), and overall survival in the cisplatin-plus-topotecan arm. The median PFS was 2.9 vs 4.6 months for single-agent and combination therapy, respectively. Median survival was 6.5 months for single-agent cisplatin and 9.4 months for cisplatin plus topotecan. The ORR was 13% for single-agent cisplatin and 27% for the two agents combined.[13] As the authors explain, the improvements in PFS and ORR were secondary endpoints. These results could not be listed in the marketing claim, as documented tumor measurements were not taken or submitted.

Toxicity

The authors accurately report the toxicities and adverse events in each treatment arm. As would be expected with combination therapy, significantly more toxicity was seen with the cisplatin-plus-topotecan regimen, mostly related to hematologic toxicity, specifically neutropenia (70% vs 1.4%) and febrile neutropenia (18% vs 8%). These were managed with dose reductions, filgrastim (Neupogen), and antibiotics as needed. Further data regarding the number of patients requiring stem-cell support and the algorithm for dose reduction would be helpful in guiding clinicians using these agents.

Quality of Life

A secondary endpoint not included in the FDA summary that warrants a brief mention is the quality-of-life outcome. Given the increased toxicity with cisplatin plus topotecan, it is noteworthy that quality-of-life scores were similar between the two treatment groups.[15] This finding remained consistent not only during treatment but also 9 months after randomization.[15]

Future Directions

Brave et al comprehensively and accurately summarize the salient portions of GOG-0179, which formed the basis for FDA approval of cisplatin plus topotecan in advanced, recurrent, or persistent cervical cancer. They concisely describe the rationale behind dose regimens, resultant toxicities, and treatment outcomes. As the authors of GOG-0179 report, "…although a 2.9-month improvement in median survival is short, the survival curve demonstrates a separation of 2 months that seems to be sustained until 18 months from study entry, suggesting a durable benefit of this combination on long-term survival for patients."[13] These data provided the foundation for the ongoing GOG 204 phase III trial evaluating cisplatin in combination with one of four agents-topotecan, paclitaxel, gemcitabine (Gemzar), or vinorelbine-as these other agents have shown promising improvements in overall survival during phase II trials.

Quality of life is an important primary study endpoint given the overall poor survival rate associated with advanced or recurrent disease. Additionally, with the advent of exciting targeted biologics, the future remains bright for incorporating these agents into clinical trials for the treatment of advanced and recurrent cervical cancer.

-Sharyn N. Lewin, MD
-Nadeem R. Abu-Rustum, MD

Disclosures:

The authors have no significant financial interest or other relationship with the manufacturers of any products or providers of any service mentioned in this article.

References:

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3. Keys HM, Bundy BN, Stehman FB, et al: Cisplatin, radiation, and adjuvant hysterectomy compared with radiation and adjuvant hysterectomy for bulky stage IB cervical carcinoma. N Engl J Med 340:1154-1161, 1999.

4. Morris M, Eifel PJ, Lu J, et al: Pelvic radiation with concurrent chemotherapy compared with pelvic and para-aortic radiation for high-risk cervical cancer. N Engl J Med 340:1137-1143, 1999.

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11. Buxton E, Meanwell C, Hiton C, et al: Combination bleomycin, ifosfamide, and cisplatin chemotherapy in cervical cancer. J Natl Cancer Inst 81:359-361, 1989.

12. Moore DH, Blessing JA, McQuellon RP, et al: Phase III study of cisplatin with or without paclitaxel in stage IVB, recurrent of persistent squamous cell carcinoma of the cervix: A Gynecologic Oncology Group study. J Clin Oncol 22:3113-3119, 2004.

13. Long HJ, Bundy BN, Grendys EC, et al: Randomized phase III trial of cisplatin with or without topotecan in carcinoma of the uterine cervix: A Gynecologic Oncology Group study. J Clin Oncol 23:4626-4633, 2005.

14. Brave M, Dagher R, Farrell A, et al: FDA approval summary: Topotecan in combination with cisplatin for the treatment of stage IVB, recurrent, or persistent cervical cancer. Oncology (Williston Park) 20:1401-1410, 2006.

15. Monk BJ, Huang HQ, Cella D, et al: Quality of life outcomes from a randomized phase III trial of cisplatin with or without topotecan in advanced carcinoma of the cervix: A Gynecologic Oncology Group study. J Clin Oncol 23:4617-4625, 2005.