Recurrent Cervical Cancer
No standard treatment is available for patients with recurrent cervical cancer that has spread beyond the confines of a radiation or surgical field. For locally recurrent disease, pelvic exenteration can lead to a 5-year survival rate of 32% to 62% in selected patients.[1-3] These patients are appropriate candidates for clinical trials testing drug combinations or new anticancer agents.
The Gynecologic Oncology Group (GOG) has reported on several randomized phase III trials, (GOG-0179 [NCT00003945], GOG-0240 [NCT00803062]) in this setting. Single-agent cisplatin administered intravenously at 50 mg/m² every 3 weeks was the most-used regimen to treat recurrent cervical cancer since it was initially introduced in the 1970s.[4,5]
Various combinations containing cisplatin [4,5] failed to reach their primary endpoint of improving survival, however, a doubling of the cisplatin dose-rate did improve survival. Combinations with paclitaxel and with ifosfamide improved response rates (RR), but they did so at a cost of much greater toxicity, especially with the latter drug. A survival advantage over cisplatin was obtained with the cisplatin + topotecan (CT) doublet  leading to approval of this indication for topotecan by the U.S. Food and Drug Administration. However, in this study, cisplatin underperformed because many patients had received this drug earlier as a radiosensitizer. (Refer to Stages IIA, IIB, III, and IVA for more information on chemoradiation and the drug cisplatin, in particular.) Therefore, cisplatin plus paclitaxel (CP) was the reference arm in GOG-0204 (NCT00064077).
The GOG has reported on sequential randomized trials dealing with chemotherapy for stage IVB, recurrent, or persistent cervical cancer.[5-9] In the initial trial, the primary endpoint of exceeding the survival observed with cisplatin alone was not reached. However, in these trials:
- The ifosfamide + cisplatin combination was superior to cisplatin alone in the secondary endpoint of RR but at the cost of increased toxicity.
- The paclitaxel + cisplatin (PC) combination, similarly, was superior in RR and progression-free survival (PFS), and its toxicity was similar to the single agent except in patients with GOG performance status 2 (scale: 0, asymptomatic–4, totally bedridden).
- The CT doublet combination had a significant advantage in overall survival (OS) compared with cisplatin alone, but cisplatin alone underperformed in this trial because as many as 40% of the patients had already received cisplatin up front as a radiosensitizer.
GOG-0204 enrolled 513 patients, leading to an early closure because no one experimental arm was likely to significantly lower the hazard ratio of death (HRdeath) relative to PC:1.15 (95% confidence interval [CI], 0.79–1.67) for vinorelbine + cisplatin (VC), 1.32 (95% CI, 0.91–1.92) for gemcitabine plus cisplatin (GC), and 1.27 (95% CI, 0.90–1.78) for CT. Trend in RR, PFS, and OS favored CT.[Level of evidence: 1iiA] The patients in the various arms of the study differed in the extent of neutropenia, infection, and alopecia that they experienced, but none of the patients in the study arms differed in health-related quality of life during treatment. However, there were more neurologic side effects for PC.
Interim results for GOG-0240 (NCT00803062) were presented in abstract form and showed that 452 patients with stage IVB, recurrent, or persistent cervical cancer were randomly assigned to chemotherapy versus chemotherapy plus bevacizumab-containing regimens. The chemotherapy regimens were cisplatin (50 mg/m2) plus paclitaxel (135–175 mg/m2) and topotecan (0.75 mg/m2 d1–d3) plus paclitaxel (175 mg/m2 d1). The bevacizumab dose was 15 mg/kg, and cycles were every 21 days unless toxicity, progression, or complete response were noted.
Preliminary results showed the topotecan-paclitaxel combination was not superior to the cisplatin-paclitaxel combination. The addition of bevacizumab led to improved median OS when compared with chemotherapy alone (17 months versus 13.3 months, respectively). The HRdeath was 0.71 when regimens were compared with and without bevacizumab [97.6% CI, 0.54–0.95; 1-sided P = .0035]. The bevacizumab-containing regimens were associated with more grade 3 or 4 bleeding, thrombosis and embolism, and gastrointestinal fistula.[Level of evidence: 1iiA]
Standard treatment options:
- For recurrence in the pelvis following radical surgery, radiation therapy in combination with chemotherapy (fluorouracil with or without mitomycin) may cure 40% to 50% of patients.
- Chemotherapy can be used for palliation. Tested drugs include the following:
- Cisplatin (15%–25% RR).
- Ifosfamide (15%–30% RR).[14,15]
- Paclitaxel (17% RR).
- Irinotecan (21% RR in patients previously treated with chemotherapy).
- Bevacizumab (11% RR, 24% survived progression free for at least 6 months; as seen in GOG-0227C [NCT00025233]).
- Ifosfamide + cisplatin.[7,19]
- PC (46% RR).
- GC (41% RR).
- CT (27% RR).
- VC (30% RR).
Treatment options under clinical evaluation:
- New anticancer drugs in phase I and phase II clinical trials.
Information about ongoing clinical trials is available from the NCI Web site.Current Clinical Trials
Check for U.S. clinical trials from NCI's list of cancer clinical trials that are now accepting patients with recurrent cervical cancer. The list of clinical trials can be further narrowed by location, drug, intervention, and other criteria.
General information about clinical trials is also available from the NCI Web site.References
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- Tumors of the cervix. In: Morrow CP, Curtin JP: Synopsis of Gynecologic Oncology. 5th ed. New York, NY: Churchill Livingstone, 1998, pp 107-151.
- Schmidt AM, Imesch P, Fink D, et al.: Indications and long-term clinical outcomes in 282 patients with pelvic exenteration for advanced or recurrent cervical cancer. Gynecol Oncol 125 (3): 604-9, 2012. [PUBMED Abstract]
- Tewari KS, Monk BJ: Gynecologic oncology group trials of chemotherapy for metastatic and recurrent cervical cancer. Curr Oncol Rep 7 (6): 419-34, 2005. [PUBMED Abstract]
- Long HJ 3rd, Bundy BN, Grendys EC Jr, 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 (21): 4626-33, 2005. [PUBMED Abstract]
- Thigpen JT, Blessing JA, DiSaia PJ, et al.: A randomized comparison of a rapid versus prolonged (24 hr) infusion of cisplatin in therapy of squamous cell carcinoma of the uterine cervix: a Gynecologic Oncology Group study. Gynecol Oncol 32 (2): 198-202, 1989. [PUBMED Abstract]
- Omura GA, Blessing JA, Vaccarello L, et al.: Randomized trial of cisplatin versus cisplatin plus mitolactol versus cisplatin plus ifosfamide in advanced squamous carcinoma of the cervix: a Gynecologic Oncology Group study. J Clin Oncol 15 (1): 165-71, 1997. [PUBMED Abstract]
- Moore DH, Blessing JA, McQuellon RP, et al.: Phase III study of cisplatin with or without paclitaxel in stage IVB, recurrent, or persistent squamous cell carcinoma of the cervix: a Gynecologic Oncology Group study. J Clin Oncol 22 (15): 3113-9, 2004. [PUBMED Abstract]
- Tewari KS, Monk BJ: Recent achievements and future developments in advanced and recurrent cervical cancer: trials of the Gynecologic Oncology Group. Semin Oncol 36 (2): 170-80, 2009. [PUBMED Abstract]
- Monk BJ, Sill MW, McMeekin DS, et al.: Phase III trial of four cisplatin-containing doublet combinations in stage IVB, recurrent, or persistent cervical carcinoma: a Gynecologic Oncology Group study. J Clin Oncol 27 (28): 4649-55, 2009. [PUBMED Abstract]
- Cella D, Huang HQ, Monk BJ, et al.: Health-related quality of life outcomes associated with four cisplatin-based doublet chemotherapy regimens for stage IVB recurrent or persistent cervical cancer: a Gynecologic Oncology Group study. Gynecol Oncol 119 (3): 531-7, 2010. [PUBMED Abstract]
- Tewari K, Sill M, Long H, et al.: Incorporation of bevacizumab in the treatment of recurrent and metastatic cervical cancer: A phase III randomized trial of the Gynecologic Oncology Group. [Abstract] J Clin Oncol 31 (Suppl) A-3.
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- Sutton GP, Blessing JA, McGuire WP, et al.: Phase II trial of ifosfamide and mesna in patients with advanced or recurrent squamous carcinoma of the cervix who had never received chemotherapy: a Gynecologic Oncology Group study. Am J Obstet Gynecol 168 (3 Pt 1): 805-7, 1993. [PUBMED Abstract]
- McGuire WP, Blessing JA, Moore D, et al.: Paclitaxel has moderate activity in squamous cervix cancer. A Gynecologic Oncology Group study. J Clin Oncol 14 (3): 792-5, 1996. [PUBMED Abstract]
- Verschraegen CF, Levy T, Kudelka AP, et al.: Phase II study of irinotecan in prior chemotherapy-treated squamous cell carcinoma of the cervix. J Clin Oncol 15 (2): 625-31, 1997. [PUBMED Abstract]
- Monk BJ, Sill MW, Burger RA, et al.: Phase II trial of bevacizumab in the treatment of persistent or recurrent squamous cell carcinoma of the cervix: a gynecologic oncology group study. J Clin Oncol 27 (7): 1069-74, 2009. [PUBMED Abstract]
- Buxton EJ, Meanwell CA, Hilton C, et al.: Combination bleomycin, ifosfamide, and cisplatin chemotherapy in cervical cancer. J Natl Cancer Inst 81 (5): 359-61, 1989. [PUBMED Abstract]
- Rose PG, Blessing JA, Gershenson DM, et al.: Paclitaxel and cisplatin as first-line therapy in recurrent or advanced squamous cell carcinoma of the cervix: a gynecologic oncology group study. J Clin Oncol 17 (9): 2676-80, 1999. [PUBMED Abstract]
- Burnett AF, Roman LD, Garcia AA, et al.: A phase II study of gemcitabine and cisplatin in patients with advanced, persistent, or recurrent squamous cell carcinoma of the cervix. Gynecol Oncol 76 (1): 63-6, 2000. [PUBMED Abstract]
- Morris M, Blessing JA, Monk BJ, et al.: Phase II study of cisplatin and vinorelbine in squamous cell carcinoma of the cervix: a Gynecologic Oncology Group study. J Clin Oncol 22 (16): 3340-4, 2004. [PUBMED Abstract]