June 2, 2009 (Orlando, Florida) —The addition of gemcitabine (Gemzar) to cisplatin-based chemotherapy and radiation appears to improve overall and progression-free survival in women with locally advanced cervical cancer.
"To our knowledge, the data from this trial represent the first finding of significantly improved survival outcomes for locally advanced cervical cancer treated with combination chemotherapy and concurrent radiation, over single-agent cisplatin with concurrent radiation," said lead author Alfonso Dueñas-González, MD, PhD, a cancer researcher at the National Cancer Institute of Mexico and the Instituto of Biomedical Research UNAM in Mexico City.
Dr. Dueñas-González presented his research at an oral session here at the American Society of Clinical Oncology 45th Annual Meeting.
At a median follow-up of 3 years, progression-free survival was 74% in patients who received gemcitabine, compared with 65% in those who received standard therapy, and this improvement reached statistical significance, explained Dr. Dueñas-González.
An improvement in overall survival was observed in the gemcitabine group (78% vs 69%; log-rank P = .0224), and time to progressive disease was also significantly improved (log-rank P = .0008).
This improvement in both progression-free and overall survival is "remarkable," commented Robert L. Coleman, MD, during the daily Highlights session. "Gemcitabine combination therapy is a challenge to standard chemotherapy."
Dr. Coleman, a professor in the Department of Gynecologic Oncology at the University of Texas MD Anderson Cancer Center in Houston, noted that distant failure was much lower in the gemcitabine group. "Distant failure contributes to two thirds of failure in cervical cancer patients and is a significant contributor to mortality," he said.
Improved Therapy Needed
Cisplatin-based chemoradiation is now the standard of care for most patients with locally advanced cervical carcinoma, but the 5-year relative survival rate for such patients is 57.7%. "This suggests a need for improved therapy," said Dr. Dueñas-González.
Previous studies have suggested that gemcitabine is useful in the management of recurrent or advanced cervical cancer when used concurrently with cisplatin. The current trial aimed to improve outcomes by capitalizing on the synergistic activity of gemcitabine, cisplatin, and radiotherapy, as well as the potential value of adjuvant therapy.
In this phase 3 multinational trial (conduced in Argentina, Mexico, India, Bosnia and Herzegovina, Pakistan, and Panama), 515 women were randomized to 1 of 2 treatment groups. The gemcitabine group received cisplatin 40 mg/m2 followed by gemcitabine 125 mg/m2 weekly x 6 doses with concurrent external beam radiation (50.4 Gy in 28 fractions [1.8 Gy 5 days a week]), followed by brachytherapy (30–35 Gy) and then 2 adjuvant 21-day cycles of gemcitabine (1000 mg/m2 on days 1 and 8) plus cisplatin (50 mg/m2 on day 1). The standard-therapy group received cisplatin 40 mg/m2 weekly x 6 doses with concurrent external beam radiation followed by brachytherapy, given as in the gemcitabine group.
Participants had bulky stage IIB to IVA carcinoma of the cervix and were chemotherapy and radiotherapy naïve, with a Karnofsky performance status score of 70 or higher.
Higher Rate of Toxicity With Gemcitabine
The incidence of grade 3/4 toxicities was significantly higher in the gemcitabine group than in the standard-therapy group (86.5% vs 46.3%). In the gemcitabine group, 2 patients died of causes that were probably related to their treatment; in the standard-therapy group, no patients died.
"As expected, the addition of a second therapeutic agent increased hematologic and nonhematologic toxicities," said Dr. Dueñas-González. "However, the rates of grade 3/4 events were low overall and considered to be clinically acceptable and manageable."
"We conclude that the inclusion of gemcitabine significantly improves survival outcomes for patients with locally advanced cervical cancer, with increased but clinically acceptable and manageable toxicity," he said.
The data from this study are very important to the international community, especially in countries where cervical cancer is more prevalent, said Amit M. Oza, Bsc, MBBS, MD, senior staff physician and professor of medicine at Princess Margaret Hospital, University of Toronto, in Ontario. "For the future, we have to see if the progression-free survival is maintained and the toxicity is acceptable."
Dr. Oza, who was not involved in the study, pointed out that the question of whether 2 drugs are better than 1 is being addressed by trials that are currently ongoing and looking at different combinations of agents.
The issue of the added toxicity also has to be addressed, he said. "Is the toxicity acceptable? Toxicity was considerably increased in the experimental arm, resulting in hospitalizations and discontinuations," he said, and "there were 2 toxic deaths, [but] none in the control arm."
Despite the added toxicity, he noted, most patients were able to complete radiation therapy. "The results of this study are plausible and compelling, judging by the magnitude of benefit," Dr. Oza said.
Dr. Dueñas-González has received honoraria from Eli Lilly. Dr. Coleman has consulted and/or served in an advisory role for Celgene, Genentech, GlaxoSmithKline, Merck, and Morphotek; and has received research funding/honoraria from GlaxoSmithKline, Lilly, Ortho Biotech, Sanofi-Aventis, and Novartis. Dr. Oza has consulted, served in an advisory role, and/or received honoraria from Abbott, Thallion, and Nicholas Piramal; and has received research funding from Merck, Novartis, AstraZeneca, EntreMed, Sanofi-Aventis, and Roche.
American Society of Clinical Oncology (ASCO) 45th Annual Meeting: Abstract CRA5507. Presented May 31, 2009.
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