Despite availability of primary and secondary prevention measures, cervical cancer persists as one of the most common cancers among women around the world. Although early-stage disease can be cured with radical and even fertility-sparing surgery, patients with metastatic and recurrent cervical cancer have poor prognosis with historically limited treatment options and incurable disease. Significant advances in cervical cancer treatment have emerged as the result of clinical trials that have sought to determine the best therapy to prolong overall and progression-free survival. Most recently, trials that have involved angiogenesis blockade in addition to standard chemotherapy have demonstrated improved overall and progression-free survival. This review serves to highlight pivotal trials in chemotherapy development for advanced, metastatic, and recurrent cervical cancer that includes the paradigm-shifting work that demonstrates increased overall survival with angiogenesis blockade.
Cervical cancer is diagnosed in 528,000 women annually and results in 266,000 deaths worldwide each year. The American Cancer Society estimates that there will be 12,900 new diagnoses and 4100 cervical cancer-related deaths in the United States in 2015. Cervical cancer is 1 of many cancers caused by human papillomavirus (HPV) infection, but it is the only cancer for which HPV has been demonstrated to be the necessary precursor. Risk factors for cervical cancer are those associated with HPV exposure, such as an increased number of sexual partners, although cigarette smoking and immunosuppression increase risk of HPV persistence. Despite high efficacy and availability of HPV vaccines and the recommendation for routine vaccination, completion of the vaccine series among adolescent girls 13-17 years old in the United States remains <40%. Given difficulties of the achievement of widespread compliance with HPV vaccination and the inability to include all oncogenic subtypes in the vaccines, the importance of continued secondary prevention remains. Most women who are diagnosed with cervical cancer report an inability to recall when they last had a Papanicolaou smear or that it was at least 10 years earlier; however, even among women compliant with screening guidelines, cervical cancer may develop.
Although the goals for HPV vaccination, Papanicolaou smears, and HPV testing are prevention and early diagnosis, approximately 5% of women who are diagnosed with cervical cancer in North America have stage IV disease with 5-year survival rates of 9.3-21.6%. Even among women with earlier stages at diagnosis, 15-61% will experience metastatic disease, usually within the first 2 years of completing treatment. For women who are diagnosed with recurrent disease, 5-year survival is <5%. This review focuses on changes in systemic treatment for women with metastatic or recurrent cervical cancer.
Development of standard chemotherapy
Single-agent cisplatin was established as the backbone of chemotherapy treatment for advanced cervical cancer >30 years ago when a phase II trial of cisplatin 50 mg/m 2 demonstrated a 44% objective response rate (RR) in 25 treatment-naïve patients. In a Gynecologic Oncology Group (GOG) phase III study of cisplatin with or without paclitaxel for stage IVB, recurrent or persistent squamous cell carcinoma of the cervix (GOG 169) is an objective response that occurred in 19% of patients who received cisplatin vs 36% of patients who received cisplatin with paclitaxel ( Table 1 ). There was a significant increase in median progression-free survival (PFS); however, there was no difference in overall survival (OS), and patients in the doublet arm experienced increased grade 3-4 anemia and neutropenia.
| Trial | Lead author | Eligibility | Arms | Relative risk (%) | Mean overall survival, mo | Mean progression-free survival, mo | Conclusion |
|---|---|---|---|---|---|---|---|
| Gynecologic Oncology Group | |||||||
| 169 | Moore | Stage IVB, recurrent or persistent SCC | Cisplatin 50 mg/m 2 | 19 | 8.8 | 2.8 | Combined regimen superior for response rate and progression-free survival without detriment to quality of life |
| Cisplatin 50 mg/m 2 + paclitaxel 135 mg/m 2 | 36 | 9.7 | 4.8 | No change in overall survival | |||
| 179 | Long | Stage IVB, recurrent or persistent | Cisplatin 50 mg/m 2 | 13 | 6.5 | 2.9 | Improved overall survival with doublet |
| Cisplatin 50 mg/m 2 + topotecan 0.75 mg/m 2 day 1-3 | 26 | 9.4 | 4.6 | Results most favorable for patients with no previous radiosensitizing cisplatin | |||
| Methotrexate 30 mg/m 2 days 1, 15, 22 + vinblastine 3 mg/m 2 days 2, 15, 22 + doxorubicin 30 mg/m 2 day 2 + cisplatin 70 mg/m 2 day 2 | N/A | N/A | N/A | ||||
| 204 | Monk | Stage IVB, recurrent or persistent | Cisplatin 50 mg/m 2 + paclitaxel 135 mg/m 2 | 29 | 12.9 | 5.8 | Closed for futility |
| Cisplatin 50 mg/m 2 + topotecan 0.75 mg/m 2 days 1-3 | 23.4 | 10.3 | 4.7 | ||||
| Cisplatin 50 mg/m 2 + gemcitabine 1000 mg/m 2 | 22.3 | 10.3 | 4.6 | ||||
| Cisplatin 50 mg/m 2 + vinorelbine 30 mg/m 2 | 25.9 | 10 | 4.0 | ||||
| Japan Clinical Oncology Group Study 0505 | Kitagawa | Stage IVB, recurrent or persistent | Cisplatin 50 mg/m 2 + paclitaxel 135 mg/m 2 | 58.8 | 18.3 | 6.9 | Noninferiority of carboplatin/paclitaxel doublet except in platinum-naïve patients |
| Carboplatin AUC 5 mg/mL/min + paclitaxel 175 mg/m 2 | 62.6 | 17.5 | 6.2 |
Phase II reports of high RR with the use of methotrexate, vinblastine, doxorubicin and cisplatin (MVAC) prompted the development of GOG 179, a randomized phase III trial that compared MVAC with cisplatin plus topotecan or cisplatin alone. The MVAC arm was closed by the Data Safety Monitoring Board because of 4 treatment-related deaths among 63 patients. Among the remaining patients who were assigned randomly to cisplatin or cisplatin plus topotecan, patients who received the doublet had improved RR (27% vs 13%), median PFS (4.6 vs 2.9 months), and median OS (9.4 vs 6.5 months) and more grade 3 and 4 hematologic toxicity, although without detriment to quality of life. This seminal study was the first randomized phase III trial to demonstrate statistically significant increased survival with combined chemotherapy over cisplatin alone for treatment of advanced or recurrent cervical cancer.
After phase II trials showed promise for a doublet of vinorelbine plus cisplatin, a phase III trial (GOG 204) was planned with 2 arms that compared paclitaxel-cisplatin with vinorelbine-cisplatin; however, 2 additional arms that compared gemcitabine-cisplatin and topotecan-cisplatin were added when phase II data for gemcitabine-cisplatin and phase III data for topotecan-cisplatin became available. After a planned interim analysis, the study was closed for futility. This phase III trial showed that vinorelbine-cisplatin, gemcitabine-cisplatin, and topotecan-cisplatin were not superior to paclitaxel-cisplatin in RR, OS, or PFS and that there was no difference in quality of life between study arms.
Despite improvements in cisplatin-based combination chemotherapy, RR remained low for advanced cervical cancer, which prompted a multivariate logistic regression analysis of data from GOG 110, 169, and 179 that identified 5 risk factors for poor response to therapy: black race, performance status >0, pelvic disease, previous radiosensitizer, and time interval from diagnosis to first recurrence <1 year. The authors developed a simple prognostic index that combined risk factors to create 3 groups: low risk (0-1 risk factor), mid risk (2-3 risk factors) and high risk (4-5 risk factors) and validated the index with the use of data from GOG 149.
It has been suggested that therapeutic equivalency of cisplatin-paclitaxel (PT) and carboplatin-paclitaxel (CT) that is demonstrated in ovarian cancer may be extrapolated to cervical cancer. To evaluate this hypothesis, the Japanese Clinical Oncology Group developed a multicenter, open label, randomized phase III trial to evaluate efficacy, safety, and quality of life of CT compared with PT. Median OS was 18.3 months for PT vs 17.5 months for CT (hazard ratio [HR], 0.994; 90% confidence interval [CI], 0.79–1.25), which demonstrated the noninferiority of CT with significantly longer proportion of nonhospitalization periods for patients who receive CT ( P < .001). Median PFS was 6.9 months for PT vs 6.2 months for CT (HR, 1.041; 95% CI, 0.803–1.351). Among patients with no previous cisplatin treatment, OS was shorter with CT (13.0 vs 23.2 months; HR, 1.571; 95% CI, 1.06–2.32), which indicates that cisplatin remains superior for platinum-naïve patients.
Over the past 30 years, cisplatin-based combination chemotherapy has been shown to produce the best PFS and OS for most patients with advanced and recurrent cervical cancer, with exceptions for those with high risk for nonresponse to cisplatin based on criteria of Moore et al. Despite extensive research to improve chemotherapy for advanced and recurrent cervical cancer, OS continues to be measured in months. For this reason, investigations in recent years have delved into other pathways in the hope of eliciting improved response to treatment with prolongation of survival.
Angiogenesis blockade
Historically, options have been limited for patients with persistent or recurrent cervical cancer after platinum-based chemotherapy. Angiogenesis, the process of new blood vessel formation, is essential not only for growth of new tissue, wound healing, and embryogenesis but also is fundamental for tumor proliferation. Vascular endothelial growth factor (VEGF) is the major mediator of tumor angiogenesis. Neovascularization correlates directly with disease spread and inversely with survival. Ferrara et al developed bevacizumab, a humanized anti-VEGF monoclonal antibody that bound with an affinity comparable with that of the original antibody. Bevacizumab was the first angiogenesis inhibitor to be approved by the Food and Drug Administration (FDA) for cancer treatment.
Angiogenesis blockade
Historically, options have been limited for patients with persistent or recurrent cervical cancer after platinum-based chemotherapy. Angiogenesis, the process of new blood vessel formation, is essential not only for growth of new tissue, wound healing, and embryogenesis but also is fundamental for tumor proliferation. Vascular endothelial growth factor (VEGF) is the major mediator of tumor angiogenesis. Neovascularization correlates directly with disease spread and inversely with survival. Ferrara et al developed bevacizumab, a humanized anti-VEGF monoclonal antibody that bound with an affinity comparable with that of the original antibody. Bevacizumab was the first angiogenesis inhibitor to be approved by the Food and Drug Administration (FDA) for cancer treatment.
Bevacizumab
In a retrospective case series of 6 patients with heavily pretreated recurrent cervical cancer, 5 of the 6 patients received 5-fluorouracil in combination with bevacizumab, and 1 of the 6 patients received capecitabine with bevacizumab ( Table 2 ). Among these 6 patients, complete response (17%; n = 1), partial response (17%; n = 1), or stable disease (33%; n = 2) was seen among 67% (n = 4), which demonstrates encouraging antitumor activity with minimal grade 4 adverse events (1 patient experienced neutropenic sepsis). Among the 4 patients whose condition demonstrated clinical benefit, median PFS was 4.3 months.
| Case series | Lead author | Pathologic condition | Arms | Response rate, % | Overall survival, mo | Mean progression-free survival, mo | Conclusion |
|---|---|---|---|---|---|---|---|
| Wright | SCC, AS | 5-fluorouracil 250-500 mg IV every week + bevacizumab 5-15 mg/kg IV every 2-3 wks | 33 | 5.1 | None reported | Bevacizumab is well-tolerated and displays antitumor activity in recurrent cervical cancer | |
| Capecitabine 2000 mg orally twice daily + bevacizumab 5-15 mg/kg IV every 2-3 wks | |||||||
| Gynecologic Oncology Group 227C | Monk | SCC, AS | Bevacizumab 15 mg/kg IV every 3 wks | 35 | 7.3 | 3.4 | Bevacizumab is well-tolerated and active as second- and third-line therapy for recurrent cervical cancer and warrants a phase III trial |
| Radiation Therapy Oncology Group 0417 | Schefter | SCC | Cisplatin 40 mg/m 2 + RT + brachytherapy + bevacizumab 10 mg/kg every 2 wks for 3 cycles | None reported | 3-year; 81.3% | 3-year; 68.7% | Bevacizumab in addition to standard chemoradiation for locally advanced cervical cancer is feasible and safe |
| Zighelboim | SCC, AC | Cisplatin 50 mg/m 2 day 1 + topotecan 0.75 mg/m 2 days 1-3 + bevacizumab 15 mg/kg day 1 every 3 wks | 35 | 13.2 | 7.1 | Addition of bevacizumab to cisplatin and topotecan produces an active by highly toxic regimen | |
| Gynecologic Oncology Group 240 | Tewari | SCC, AS, or AC | Cisplatin 50 mg/m 2 + paclitaxel 135 or 175 mg/m 2 | 14.3 | 5.9 | Bevacizumab resulted in 3.7-month increased overall survival (17 mo compared with 13.3 mo) | |
| Cisplatin 50 mg/m 2 + paclitaxel 135 or 175 mg/m 2 + bevacizumab 15 mg/kg | 17.5 | 8.2 | |||||
| Topotecan 0.75 mg/m 2 days 1-3 + paclitaxel 175 mg/m 2 | 12.7 | ||||||
| Topotecan 0.75 mg/m 2 days 1-3 + paclitaxel 175 mg/m 2 + bevacizumab 15 mg/kg | 16.2 |
An early case series by Wright et al suggested that bevacizumab in combination with chemotherapy was active in recurrent cervical cancer. A phase II study to evaluate bevacizumab monotherapy in this population was activated through the Gynecologic Oncology Group (ie, GOG 227C). Among the 46 women who were enrolled, 82.6% (n = 38) had received previous radiation, and 1 (n = 34; 73.9%) or 2 (n = 12; 26.1%) previous cytotoxic regimens for recurrent disease. Eleven of the 46 patients (23.9%; 2-sided 90% CI, 14–37%) achieved PFS for at least 6 months, and another 5 patients (10.9%; 2-sided 90% CI, 4–22%) achieved partial response. Median PFS of 3.40 months (95% CI, 2.53–4.53 months) and OS of 7.29 months (95% CI, 6.11–10.41 months) with bevacizumab compared favorably with other phase II trials for persistent or recurrent disease, which prompted the development of a phase III trial.
Because bevacizumab had demonstrated clinical activity in pretreated populations, the Radiation Therapy Oncology Group designed a phase II single-arm study (protocol 0407) of bevacizumab in addition to standard chemoradiation for bulky stage IB-IIIB cervical cancer to investigate efficacy and safety. Among the 60 patients enrolled, 49 cases were evaluable and had a median follow-up time of 12.4 months (range, 4.6–31.4 months) with no serious adverse events. This study was not powered for PFS or OS analysis; however, in a report of secondary endpoints, over a median follow-up time of 3.8 years (range, 0.8–6.0 years), the 3-year OS was 81.3% (95% CI, 67.2–89.8%), and the PFS was 68.7% (95% CI, 53.5–79.8%). This phase II trial indicated that further study of bevacizumab for treatment of locally advanced disease is warranted.
In a multicenter phase II trial that evaluated a regimen of topotecan, cisplatin, and bevacizumab for persistent or recurrent cervical cancer, 27 patients with no previous chemotherapy for recurrence received a median of 3 treatment cycles (range, 1–19 cycles) and a median of 10 months (range, 1.7–33.4 months) of follow up. Among the 26 evaluable cases, 59% (80% CI, 46–70%) experienced 6-month PFS; 1 patient (4%; 80% CI, 0.4–14%) experienced complete response, and 8 patients (31%; 80% CI, 19–45%) experienced partial response that lasted a median of 4.4 months. Median PFS was 7.1 months (80% CI, 4.7–10.1 months), and median OS was 13.2 months (80% CI, 8.0–15.4 months). Unfortunately, grade 3-4 hematologic toxicity was common with high incidence (78%) of unanticipated hospitalizations.
The first phase III randomized trial (GOG 240) of bevacizumab for advanced cervical cancer randomly assigned women to 1 of 4 arms: (1) cisplatin plus paclitaxel, (2) cisplatin, paclitaxel, and bevacizumab, (3) topotecan plus paclitaxel, and (4) topotecan, paclitaxel, and bevacizumab. Inclusion criteria included adequate hepatic, bone marrow, and renal function and good nutritional status. Most of the study group (75%) previously had received platinum and were distributed evenly between the 2 backbones. Addition of bevacizumab to chemotherapy resulted in a 3.7-month increase in median OS (17.0 vs 13.3 months; Figure 1 ) and higher RR (48% vs 36%; P = .008). Subanalysis showed beneficial effects of bevacizumab in patients who had been exposed previously to platinum and among those with recurrent or persistent disease. Additionally, benefits of bevacizumab were demonstrated in patients with recurrent disease in a previously irradiated field. Grade 2 or higher hypertension, grade 3 or higher gastrointestinal, or genitourinary fistulas and grade 3 or higher thromboembolic events were all significantly higher among patients who received bevacizumab, but quality-of-life scores indicated that the addition of bevacizumab did not affect health-related quality of life adversely. In the final protocol-specified OS analysis, bevacizumab improved OS to 16.8 months vs 13.3 months for chemotherapy alone (HR, 0.765; 95% CI, 0.62–0.95; P = .0068).
