May 4, 2011 — Adding gemcitabine to cisplatin chemoradiotherapy, compared with the current standard of care, improves survival outcomes for patients with locally advanced cervical cancer, according to the results of a large international trial.
Among patients who received gemcitabine, a statistically significant benefit was observed for the 3 main survival end points: progression-free survival at 3 years, overall progression-free survival, and overall survival.
The results of this study were initially presented at the 2009 meeting of the American Society of Clinical Oncology (ASCO), and were reported by Medscape Medical News at that time. The study was published in the May 1 issue of the Journal of Clinical Oncology.
In an accompanying editorial, Gillian Thomas, MD, from the Sunnybrook Odette Cancer Centre, University of Toronto, Ontario, Canada, says that this trial is an important addition to the field. She also congratulates the researchers on completing the study "undoubtedly under some difficult circumstances," as it was conducted in 8 developing nations (Argentina, Bosnia and Herzegovina, India, Mexico, Pakistan, Panama, Peru, and Thailand).
"This study represents clear evidence that large phase 3 randomized controlled trials can be conducted in a rapid fashion in the developing world if sufficient commitment, expertise, and financial support is available in countries where the disease is so rampant," Dr. Thomas notes.
It also highlights the importance of using therapies that are accessible and affordable in the developing world, she explains.
Limitations and Unanswered Questions
Although the results of this study are encouraging, with the authors reporting a 9% improvement in progression-free survival at the fixed time point of 3 years of follow-up, Dr. Thomas points out that there are limitations.
"It is impossible to understand the actual impact of this more intense and toxic therapy on long-term overall survival from the data provided," she notes. It is also unclear whether the treatment in the study group "simply delayed recurrence or cured more patients."
She points out that since accrual was completed 6 years ago, sufficient time has elapsed that if further follow-up had been conducted, an accurate assessment of overall survival rates could have been reported.
"The trial does not explain the possible mechanisms by which the observed gain in progression-free survival was achieved," she adds.
Dr. Thomas cites a number of questions raised by this study. Can patients with stage IIB and stage III disease also benefit from this combination therapy? Is the contribution of gemcitabine specifically unique, or could agents with less toxicity also be considered?
"It is currently unclear whether this new treatment, specifically with gemcitabine and cisplatin, will be widely implemented without confirmatory studies to determine the magnitude and relative benefits of intensifying pelvic treatment and adding further systemic therapy," she writes.
Improved Survival End Points
In this study, led by 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, 515 chemotherapy- and radiotherapy-naive patients with stage IIB to IVA disease were randomly assigned to 1 of 2 study groups.
Patients in the gemcitabine group received cisplatin 40 mg/m2 and gemcitabine 125 mg/m2 weekly for 6 weeks with concurrent external-beam radiotherapy 50.4 Gy in 28 fractions, followed by brachytherapy 30 to 35 Gy in 96 hours, and then 2 adjuvant 21-day cycles of cisplatin 50 mg/m2 on day 1, plus gemcitabine 1000 mg/m2 on days 1 and 8).
Patients in the standard-therapy group received cisplatin and concurrent external-beam radiotherapy followed by brachytherapy only (dosing was the same as in the gemcitabine group).
At 3 years, progression-free survival was 74.4% with gemcitabine and 65.0% with standard therapy (P = .029).
The authors also observed that patients in the gemcitabine group had improved overall progression-free survival, compared with the standard-therapy group (hazard ratio [HR], 0.68; P = .0227), and improved overall survival (HR, 0.68; P = .0224). Time to disease progression was also superior in the gemcitabine group (HR, 0.54; P = .0012).
The tumor response rate was 95.8% in the gemcitabine group and 93.4% in the standard-therapy group; the between-treatment difference was not statistically significant (P = .249).
Higher Toxicity
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 during his presentation at ASCO. "However, the rates of grade 3/4 events were low overall and considered to be clinically acceptable and manageable."
"Further studies are required to define optimal patient selection for this combination and to delineate the specific contributions of multiagent chemoradiotherapy and adjuvant chemotherapy phases to survival outcomes," the authors conclude.
The study was funded by Eli Lilly. Several of the authors report a financial relationship with Eli Lilly, as noted in the paper.
J Clin Oncol. 2011;29:1654-1656, 1678-1685. Thomas full text, Dueñas-González et al abstract
Among patients who received gemcitabine, a statistically significant benefit was observed for the 3 main survival end points: progression-free survival at 3 years, overall progression-free survival, and overall survival.
The results of this study were initially presented at the 2009 meeting of the American Society of Clinical Oncology (ASCO), and were reported by Medscape Medical News at that time. The study was published in the May 1 issue of the Journal of Clinical Oncology.
In an accompanying editorial, Gillian Thomas, MD, from the Sunnybrook Odette Cancer Centre, University of Toronto, Ontario, Canada, says that this trial is an important addition to the field. She also congratulates the researchers on completing the study "undoubtedly under some difficult circumstances," as it was conducted in 8 developing nations (Argentina, Bosnia and Herzegovina, India, Mexico, Pakistan, Panama, Peru, and Thailand).
"This study represents clear evidence that large phase 3 randomized controlled trials can be conducted in a rapid fashion in the developing world if sufficient commitment, expertise, and financial support is available in countries where the disease is so rampant," Dr. Thomas notes.
It also highlights the importance of using therapies that are accessible and affordable in the developing world, she explains.
Limitations and Unanswered Questions
Although the results of this study are encouraging, with the authors reporting a 9% improvement in progression-free survival at the fixed time point of 3 years of follow-up, Dr. Thomas points out that there are limitations.
"It is impossible to understand the actual impact of this more intense and toxic therapy on long-term overall survival from the data provided," she notes. It is also unclear whether the treatment in the study group "simply delayed recurrence or cured more patients."
She points out that since accrual was completed 6 years ago, sufficient time has elapsed that if further follow-up had been conducted, an accurate assessment of overall survival rates could have been reported.
"The trial does not explain the possible mechanisms by which the observed gain in progression-free survival was achieved," she adds.
Dr. Thomas cites a number of questions raised by this study. Can patients with stage IIB and stage III disease also benefit from this combination therapy? Is the contribution of gemcitabine specifically unique, or could agents with less toxicity also be considered?
"It is currently unclear whether this new treatment, specifically with gemcitabine and cisplatin, will be widely implemented without confirmatory studies to determine the magnitude and relative benefits of intensifying pelvic treatment and adding further systemic therapy," she writes.
Improved Survival End Points
In this study, led by 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, 515 chemotherapy- and radiotherapy-naive patients with stage IIB to IVA disease were randomly assigned to 1 of 2 study groups.
Patients in the gemcitabine group received cisplatin 40 mg/m2 and gemcitabine 125 mg/m2 weekly for 6 weeks with concurrent external-beam radiotherapy 50.4 Gy in 28 fractions, followed by brachytherapy 30 to 35 Gy in 96 hours, and then 2 adjuvant 21-day cycles of cisplatin 50 mg/m2 on day 1, plus gemcitabine 1000 mg/m2 on days 1 and 8).
Patients in the standard-therapy group received cisplatin and concurrent external-beam radiotherapy followed by brachytherapy only (dosing was the same as in the gemcitabine group).
At 3 years, progression-free survival was 74.4% with gemcitabine and 65.0% with standard therapy (P = .029).
The authors also observed that patients in the gemcitabine group had improved overall progression-free survival, compared with the standard-therapy group (hazard ratio [HR], 0.68; P = .0227), and improved overall survival (HR, 0.68; P = .0224). Time to disease progression was also superior in the gemcitabine group (HR, 0.54; P = .0012).
The tumor response rate was 95.8% in the gemcitabine group and 93.4% in the standard-therapy group; the between-treatment difference was not statistically significant (P = .249).
Higher Toxicity
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 during his presentation at ASCO. "However, the rates of grade 3/4 events were low overall and considered to be clinically acceptable and manageable."
"Further studies are required to define optimal patient selection for this combination and to delineate the specific contributions of multiagent chemoradiotherapy and adjuvant chemotherapy phases to survival outcomes," the authors conclude.
The study was funded by Eli Lilly. Several of the authors report a financial relationship with Eli Lilly, as noted in the paper.
J Clin Oncol. 2011;29:1654-1656, 1678-1685. Thomas full text, Dueñas-González et al abstract
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