Platinum-Free Regimen Falls Short in Cervical Cancer

Krishnansu Tewari, MD

Platinum-taxane combination therapy remains the standard for treatment of advanced cervical cancer, according to results of a randomized trial. The data were presented at the 2013 Annual Meeting of the Society of Gynecologic Oncology (SGO).

The combination of topotecan and paclitaxel failed to meet the primary endpoint of a 30% improvement in survival versus cisplatin-paclitaxel. The platinum-taxane regimen resulted in a median overall survival of 15 months among patients with stage IV resistant/refractory or metastatic cervical cancer. In contrast, the topotecan- paclitaxel combination led to a median survival of 12.5 months.

The 2.5-month survival difference was not statistically significant, meaning that topotecan-paclitaxel was not inferior and might be considered an alternative for selected patients, lead author Krishnansu Tewari, MD, said at the SGO meeting.

“Topotecan-paclitaxel is a treatment alternative for a population that has very few options,” said Tewari, who is an associate professor of Obstetrics and Gynecology at the University of California, Irvine. “Toxicity screening and assessment may identify patients who are less likely to tolerate a platinum-paclitaxel regimen and for whom topotecan- paclitaxel might be considered.”

Members of the Gynecologic Oncology Group (GOG) designed and conducted a randomized trial to determine whether the platinum-free regimen of topotecan and paclitaxel might offer patients an alternative to platinum-taxane therapy. The rationale for the regimen came from concerns related to widespread adoption of cisplatin as a radiosensitizer for patients who received radiation therapy for locally advanced disease.

“We were concerned, due to acquired resistance to platinum, through widespread adoption of cisplatin- based chemoradiation for locally advanced disease, that platinum would be less effective at recurrence,” said Tewari.

The concerns were validated in subsequent GOG trials showing that platinum-based chemotherapy was less effective in patients with recurrent disease after receiving platinum-containing chemoradiation, he added.

The trial involved 452 patients with stage IVB cervical cancer, three-fourths of whom had previously been treated with a platinum-containing regimen. After randomization to topotecan-paclitaxel or cisplatin-paclitaxel, treatment continued until complete response, disease progression, or development of unacceptable toxicity.

Investigators considered a 30% improvement in the survival hazard with the investigational regimen as clinically important.

Instead, survival favored the cisplatin-paclitaxel arm, translating into a hazard ratio (HR) of 1.20 for the topotecan-paclitaxel regimen. The 95% confidence intervals included 1.00, so the investigational arm was not inferior to the standard. However, secondary endpoints showed consistent—and some statistically significant—advantages for progression- free survival (HR = 1.39; P = .0083), response rate (38.4% vs 28.7%; P = .0364), and complete responses (26 vs 16).

The cisplatin regimen demonstrated advantages in response rate among patients with prior exposure to platinum (34% vs 24%; HR = 1.18) and no prior platinum-containing therapy (54% vs 42%; HR = 1.35).

The topotecan regimen was associated with less grade 3-5 nausea, neuropathy, and metabolic disturbances, but more grade ≥3 leukopenia (but not febrile neutropenia).

The trial also evaluated the addition of bevacizumab (Avastin) to each of the chemotherapy regimens. At the recent 2013 Annual Meeting of the American Society of Clinical Oncology, Tewari presented data showing that bevacizumab improved survival by almost 4 months in both treatment arms (http://bit.ly/11thwej). Outcomes with this targeted agent in this trial continue to be analyzed and will be reported at a later date, said Tewari.

Tewari K, Sill M, Monk B, et al. Phase III randomized clinical trial of cisplatin plus paclitaxel vs the nonplatinum chemotherapy doublet of topotecan plus paclitaxel in women with recurrent, persistent, or advanced cervical cancer: a Gynecologic Oncology Group study. Presented at: 2013 Society of Gynecologic Oncology Annual Meeting on Women’s Cancer; March 9-12, 2013; Los Angeles, CA. Abstract 1.