Incorporation of bevacizumab in the treatment of recurrent and metastatic cervical cancer: A phase III randomized trial of the Gynecologic Oncology Group
Reporter: J Taylor Whaley, MD
The Abramson Cancer Center of the University of Pennsylvania
Last Modified: June 5, 2013
Presenter: Krishnansu Sujata Tewari, MD Presenter's Affiliation: University of California, Irvine, Medical Center, Orange, CA
Cervical cancer is the 12th most common cancer that women develop, and the 14th most common cause of cancer death for women in the U.S.
There has been a 75% decrease in incidence and mortality from cervical cancer in the United States over the past 50 years. Most of this decrease is attributed to the effective institution of cervical cancer screening programs.
Although metastatic disease is infrequently seen at the time of diagnosis for cervical cancer, up to 50% of patients are at risk for developing metastatic or recurrent disease.
Metastatic cervical cancer presents a significant challenge as it generally develops within 2 years of the initial diagnosis and is incurable.
Patients with local recurrences or limited metastatic disease can be offered potentially definitive treatments with either surgical resection or radiation; however, if local therapy is not possible or extensive metastatic disease is present, chemotherapy is the only palliative option.
Despite aggressive therapy, patients with metastatic cervical cancer have a poor prognosis with observed survival typically <12 months when treated with the current standard of care with Cisplatin and Paclitaxel.
A recent trial performed by the Gynecologic Oncology Group (GOG 204) evaluating alternate traditional combination chemotherapies was unsuccessful and closed for futility.
Therefore, there is a significant need for novel therapeutics in this group of patients.
Angiogenesis is known to play a central role in cervical cancer progression from pathologic studies. Vascular endothelial growth factor (VEGF) promotes angiogenesis, a mediator of disease progression in cervical cancer.
Bevacizumab is a humanized anti-VEGF monoclonal antibody that binds to and inhibits the activity of vascular endothelial growth factor (VEGF). This prevents the VEGF from interacting with its receptor on endothelial cells. This, in turn, inhibits the formation of new blood vessels, slowing down the growth of tumors.
Initial single arm Phase II studies of Bevacizumab (GOG 227c) demonstrated activity in the setting of metastatic cervical cancer, creating excitement for future randomized trials.
Additionally, previous data has demonstrated synergy for combination Topotecan/Paclitaxel.
The current Phase III trial, GOG 240, was undertaken to evaluate Bevacizumab as well as combination Topotecan/Paclitaxel as first line therapy for the metastatic and recurrent cervical cancer.
Materials and Methods
This was a randomized, multi-center, international trial conducted by the Gynecologic Oncology Group.
Entry criteria for the trial are as follows:
Measurable recurrent or metastatic cervical cancer
ECOG PS 0-1
No prior systemic doses of chemotherapy (patients could have previously received cisplatin as a radiosensitizer)
Using a 2x2 factorial design, patients were randomly assigned to the standard of care, Cisplatin/Paclitaxel or Topotecan/Paclitaxel. A second randomization was then followed with or without Bevacizumab 15 mg/kg.
The chemotherapy regimens included cisplatin 50 mg/m2 plus paclitaxel 135-175 mg/m2 and topotecan 0.75 mg/m2 plus paclitaxel 175 mg/m2.
Cycles were repeated every 21 days until disease progression, unacceptable toxicity, or complete response.
Overall survival (OS) was the primary endpoint with a reduction in the hazard of death by 30% using anti-VEGF therapy considered important and improvement in median survival from 12 to 16 months.
Secondary endpoints included progression free survival, objective tumor response by RECIST criteria, quality of life, pooled risk factors, and effect of nicotine on treatment response.
Target accrual was 450 patients.
Final analysis was planned when 346 deaths were observed. Analysis was performed by intent to treat.
452 patients were accrued from 4/6/09 to 1/3/12.
A total of 225 patients received combination chemotherapy alone and 227 patients received chemotherapy plus Bevacizumab.
The randomized treatment groups were similar with regard to age, histology, race, stage, performance status, previous platinum as a radiosensitizer, and recurrence, persistence, or advanced disease.
Median age was 46 years old.
The scheduled interim analysis occurred after 174 patients had died and showed that the Topotecan-Paclitaxel backbone was not superior to the Cisplatin-Paclitaxel backbone with a hazard ratio of 1.2.
A second interim analysis was conducted after 271 deaths.
The Bevacizumab -to-no- Bevacizumab hazard ratio (HR) of death was 0.71 (p=0.0035), which is highly statistically significant.
Median survival was 17 months (chemotherapy plus Bevacizumab) and 13.3 months (chemotherapy alone). Median progression free survival was 8.2 vs. 5.9 months.
The RR were 47% (chemotherapy plus Bevacizumab) and 27% (chemotherapy alone) (p=0.0078).
Bevacizumab showed a benefit across all subgroups of prognostic factors.
Patients with recurrent disease in a previously irradiated pelvis also showed a benefit to Bevacizumab.
Treatment with Bevacizumab was associated with more grade 3-4 bleeding (5 vs 1%) thrombosis/embolism (9 vs 2%), and GI fistula (3 vs 0%). In the Bevacizumab groups, 25% of patients had grade 2+ hypertension, 35% of patients had grade 2+ neutropenia, 8% of patients had thromboembolism, and 6% of patients developed a fistula.
In each group, four patients had fatal events while on treatment. No patient needed to stop Bevacizumab for treatment-related toxicity.
Patients who received Bevacizumab did not document a decreased in quality of life over the course of the trial.
For the first time, a targeted agent significantly improved OS in gynecologic cancer. The study met the primary endpoint with a clinically significant improvement in overall survival.
The second interim analysis crossed the boundary for efficacy, warranting early release of this information.
The nearly 4-month increase in median overall survival with the addition of Bevacizumab to chemotherapy in women with recurrent cervical cancer is considered to be clinically significant. The benefit was seen across all subgroups of patients.
Bevacizumab was associated with increased adverse events as expected at a rate of 3-8%. However, the use of Bevacizumab was not associated with a decrease in quality of life.
Combination chemotherapy with Bevacizumab appears to represent the new standard of care for patients with metastatic and/or recurrent cervical cancer.
The authors presented a phase III randomized, international, placebo-controlled study evaluating the use of combination chemotherapy and Bevacizumab to patients with recurrent and metastatic cervical cancer. This was a well-designed and well-performed study that met its primary endpoints with a 4-month improvement in overall survival.
This phase III study effectively changes the standard of care in metastatic cervical cancer to include Bevacizumab to combination chemotherapy. The regimen was well-tolerated with expected toxicity and provided significant survival benefit.
Numerous previous attempts to improve outcomes for metastatic cervical cancer have been ineffective in improving survival. The results of this trial, with overall survival of 17 months, are the best ever seen in this patient population.
It should be noted that the control arm performed well and no crossover was allowed on the trial, further validating the results; however, it should also be noted that only 17% of patients had metastatic disease with the vast majority of patients having recurrent disease in the pelvis.
Several issues remain with respect to this regimen, including cost-effectivness associated with this treatment. Future studies will hopefully evaluate other targeted inhibitors of angiogenesis, including the tyrosine kinase inhibitors.