By Robert L. Coleman, MD
Professor, University of Texas; M.D. Anderson Cancer Center, Houston
Dr. Coleman reports no financial relationships relevant to this field of study.
This article originally appeared in the March 2014 issue of OB/GYN Clinical Alert.
SYNOPSIS: Bevacizumab added to chemotherapy, particularly paclitaxel and cisplatin, was efficacious in all response outcomes (objective response, progression-free survival, and overall survival) without diminution in quality of life or unacceptable toxicity.
SOURCE: Tewari KS, et al. Improved survival with bevacizumab in advanced cervical cancer. N Engl J Med 2014;370:734-743.
Patients with metastatic and recurrent cervix cancer typically receive platinum-based therapy in an attempt to control tumor growth. Recently, anti-vascular endothelial growth factor (VEGF) targeted therapies have demonstrated single agent activity in this disease. As use of platinum-based chemoradiation has increased in this setting, expectations of response to platinum at the time of recurrence has decreased, therefore questioning efficacy. This has resulted in an ushering of clinical studies to evaluate the efficacy of non-platinum regimens. GOG-240 was a 2 x 2 factorial designed trial, randomly assigning 452 patients to chemotherapy (paclitaxel/cisplatin or paclitaxel/topotectan) with or without bevacizumab at a dose of 15 mg/kg. Cisplatin was dosed at 50 mg/m2, with paclitaxel at a dose of 135 or 175 mg/m2; and topotecan at a dose of 0.75 mg/m2, days 1 to 3, plus paclitaxel at a dose of 175 mg/m2 on day 1. Cycles were repeated every 21 days until disease progression, the development of unacceptable toxic effects, or a complete response was documented. The primary endpoint was overall survival; a reduction of 30% in the hazard ratio for death was considered clinically important. The treatment cohorts were well balanced with respect to age, histologic findings, performance status, previous use or non-use of a radiosensitizing platinum agent, and disease status. In an interim evaluation, topotecan-paclitaxel was not found to be superior to cisplatin-paclitaxel (hazard ratio [HR] for death, 1.20). After collapsing the chemotherapy regimens for analysis, the addition of bevacizumab to chemotherapy was associated with increased overall survival (17.0 months vs. 13.3 months: HR, 0.71; 95% confidence interval [CI], 0.54-0.95; p = 0.004 in a one-sided test), increased progression-free survival (8.2 months vs. 5.9 months: HR, 0.67; 95% CI, 0.54-0.82; two-sided p = 0.002), and higher response rates (48% vs. 36%, p = 0.008). Bevacizumab, as compared with chemotherapy alone, was associated with an increased incidence of hypertension of grade 2 or higher (25% vs. 2%), thromboembolic events of grade 3 or higher (8% vs. 1%), and gastrointestinal fistulas of grade 3 or higher (3% vs. 0%). The authors concluded that the addition of bevacizumab to combination chemotherapy in patients with recurrent, persistent, or metastatic cervical cancer was associated with an improvement of 3.7 months in median overall survival.
Cancer of the uterine cervix is the second most common cancer afflicting women worldwide and is a major cause of preventable mortality. It also disproportionately impacts underserved and under-resourced populations. However, about half of cervix cancer cases diagnosed in the United States each year are at advanced stages or metastatic at presentation. Primary treatment with chemoradiotherapy provides modest tumor control for many, but those women whose tumors are not amenable to curative intervention are left with few therapeutic options. The investigative story of chemotherapy for metastatic and recurrent cervix cancer has been methodical and deliberative, moving from non-platinum agents to platinum single agents to platinum-doublets and triplets and finally to the introduction of chemotherapy with anti-angiogenesis agents.1 The progress, albeit slow, has been significant, moving anticipated overall survival 25 years ago of approximately 6 months to now nearly 18 months. This trial represents a significant advance forward and breaks a therapeutic ceiling reached in the previous GOG study (protocol 204), which was unable to identify a survival gain among any of the four platinum-based doublets tested.2
Many relevant observations in this trial add to the credibility of the overall conclusions. First, the control arm’s performance was as expected; both the platinum and non-platinum-based doublets were associated with progression-free survival and response as anticipated and consistent with previous contemporary (since 1999) trials. This suggests a stable patient population, particularly with regard to the proportion of patients exposed to prior platinum-based chemoradiation (70% in the current trial). A previous phase III trial of single-agent cisplatin vs. cisplatin and topotecan demonstrated substantially lower response rates to single-agent platinum when platinum-based chemoradiation was used in prior therapy.3,4 Second, biological and clinical rationale supports the use of anti-VEGF-based therapy. The GOG and others have demonstrated that VEGF targeting as a single agent has clinical activity in recurrent cervix cancer.5 Biologically, de-repression of E6/E7 leads to increased VEGF expression and vulnerability to anti-VEGF-based therapy. Third, the evaluated outcome variables were enhanced in the experimental cohort (response, progression-free survival, and overall survival) and were favorably impacted by the addition of bevacizumab, including consistent findings for objective response regardless of measurable disease within a radiated field. It previously has been observed in many trials that metastatic extrapelvic disease has nearly doubled the response rate of intrapelvic (and infield) disease. However, the current trial demonstrated equal efficacy in the experimental arm. Finally, quality of life was not hampered by the increase in (expected) toxicity.
With the publication of this study, it is likely that a new standard will be supported for women with metastatic and recurrent cancer of the cervix by the FDA. However, the greatest burden of disease resides in areas of the world where this expensive therapy is not within reach. Further work and drug availability will be needed to continue to reduce the impact of this disease, which globally wreaks havoc on young women and their families.
- Coleman RL, Gynecologic Oncology Group. The Gynecologic Oncology Group's role in the treatment of recurrent cervix cancer: Current clinical trials. Gynecol Oncol 2008;110(Suppl 2):S77-S80.
- Monk BJ, 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 2009;27:4649-4655.
- Moore DH, et al. Prognostic factors for response to cisplatin-based chemotherapy in advanced cervical carcinoma: A Gynecologic Oncology Group study. Gynecol Oncol 2010;116:44-49.
- Long HJ 3rd, 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 2005;23:4626-4633.
- Monk BJ, 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 2009;27:1069-1074.