Gemcitabine Alone vs Gemcitabine Plus Radiotherapy in Patients with Locally Advanced Pancreatic Cancer: An Eastern Cooperative Oncology Group Trial
Gemcitabine Alone vs Gemcitabine Plus Radiotherapy in Patients with Locally Advanced Pancreatic Cancer: An Eastern Cooperative Oncology Group Trial
Abstract & Commentary
By Samir P. Kanani, MD, Associate Clinical Professor of Neurosurgery and Radiation Oncology, George Washington University; Radiation Oncology, Inova Fairfax Hospital. Dr. Kanani reports no financial relationships relevant to this field of study.
Synopsis: In a muti-institutional prospective trial conducted from 2003-2005, 74 patients with unresectable pancreatic adenocarcinoma were randomly assigned to receive GEM alone (at 1,000 mg/m2/wk for weeks 1-6, followed by 1 week rest, then for 3 of 4 weeks) or GEM (600 mg/m2/wk for weeks 1-5, then 4 weeks later 1,000 mg/m2/wk for 3 of 4 weeks) plus radiotherapy for a total of 50.4 Gy. Measurement of quality of life also was performed. Patients enrolled in Arm B (GEM plus radiation) had a higher incidence of grades 4 and 5 toxicities (41% vs 9%), but grades 3 and 4 toxicities combined were similar in both arms. No statistical difference was noted in quality of life. The primary endpoint of survival was improved with the addition of radiotherapy with 11.1 months for Arm B and 9.2 months for Arm A.
Source: Loehrer P, et al. Gemcitabine alone versus gemcitabine plus radiotherapy in patients with locally advanced pancreatic cancer: An Eastern Cooperative Group Trial. J Clin Oncol 2011;29:4105-4112.
For patients with advanced pancreatic cancer, systemic therapy with radiotherapy has been the standard of care in the United States for decades, with median survival measured in months.1 European trials have demonstrated no significant benefit to the addition of radiotherapy and 5FU to gemcitabine.2 Numerous Phase 1 and Phase 2 trials have demonstrated the safety and efficacy of concurrent gemcitabine with radiotherapy. This intergroup trial was designed to test the hypothesis that concurrent radiotherapy and gemcitabine would improve survival and provide additional quality-of-life benefits when compared to gemcitabine alone.
Eligibility was limited to patients who were deemed surgically unresectable with an ECOG performance status of 0-2. The proposed sample size was 316 patients; however, the study was closed early because of poor accrual. The 74 enrolled patients were stratified according to performance status and weight loss and randomized to either gemcitabine or gemcitabine and radiotherapy. Patients were followed radiographically with CT scans, and quality of life was assessed using a validated FACT-hepatobiliary questionnaire.
Patients receiving combined GEM and radiotherapy experienced more grade 4 and 5 toxicity (41% vs 9%). Both arms had one grade 5 toxicity. Patients treated with GEM and radiotherapy experienced more problems with appetite and cramps, but FACT-hepatobiliary analysis demonstrated no statistical differences. Median number of cycles delivered were 3 in both arms. Overall 30% of patients received all panned chemotherapy. Nearly 1 in 4 patients (24%) received less than 45 Gy of radiotherapy. Median progression-free survival was similar in both arms at 6 months. Overall survival was improved with the addition of radiotherapy from 9.2 months to 11.1 months (P = 0.017).
Commentary
GEM is currently the most active single agent in pancreatic cancers. A number of trials have been conducted utilizing the radiosensitization of GEM concurrent with radiotherapy. Many of these trials used alternative fractionation of radiotherapy and smaller non-traditional radiotherapy fields because of the potent sensitizing power of GEM.3 The current trial is the first trial utilizing a more "standard" radiotherapy portal and dose fractionation with GEM. It is also the first trial to show a survival advantage in a randomized fashion. The survival advantage comes with a price of increased grade 4 toxicity. In treating pancreatic cancers, the clinician must weigh the competing risks of local disease progression vs the risk of distant metastatic disease, thus weighing the importance of radiotherapy and chemotherapy. The authors conclude that radiotherapy concurrent with GEM is an important component in first-line therapy for managing unresectable pancreatic cancers. I would argue that a 41% risk of grade 4 and 5 toxicity is prohibitive in community practice, and caution should be used when trying to apply the results of this clinical trial. Treatment should be individualized for each clinical scenario. A patient with a small tumor deemed unresectable because of vascular encasement is certainly different than a patient with bulky pancreaticoduodenal adenopathy. Perhaps a combination approach of GEM alone combined with a hypofractionated course of radiotherapy with higher biologic equivalent dose directed at gross tumor could provide a tolerable balance between local control and distant metastatic control. Additional studies certainly are needed, as current standard therapy for advanced unresectable pancreatic cancer is palliative at best. Future directions will definitely involve testing novel chemotherapeutic agents in large populations. I believe that radiotherapy will play an important role in these studies as this trial points out.
References
1. Klassen DJ, et al. Treatment of locally unresectable cancer of the stomach and pancreas: A randomized comparison of 5FU alone eith radiation plus concurrent and maintenance 5FUan ECOG study. J Clin Oncol 1985;3:373-378.
2. Chauffert B, et al. Phase III trial comparing intensive induction chemoradiotherapy followed by maintenance gemcitabine with gemcitabine alone for locally advanced unresctable pancreatic cancer: Definitive results of the 2000-01 FFCD/SFRO study. Ann Oncol 2008;19:1592-1599.
3. Blackstock AW, et al. Phase I trial of twice weekly gemcitabine and concurrent radiation in patients with advnced pancreatic cancer. J Clin Oncol1999;17:2208-2212.
In a muti-institutional prospective trial conducted from 2003-2005, 74 patients with unresectable pancreatic adenocarcinoma were randomly assigned to receive GEM alone (at 1,000 mg/m /wk for weeks 1-6, followed by 1 week rest, then for 3 of 4 weeks) or GEM (600 mg/m /wk for weeks 1-5, then 4 weeks later 1,000 mg/m /wk for 3 of 4 weeks) plus radiotherapy for a total of 50.4 Gy. Measurement of quality of life also was performed. Patients enrolled in Arm B (GEM plus radiation) had a higher incidence of grades 4 and 5 toxicities (41% vs 9%), but grades 3 and 4 toxicities combined were similar in both arms. No statistical difference was noted in quality of life. The primary endpoint of survival was improved with the addition of radiotherapy with 11.1 months for Arm B and 9.2 months for Arm A.Subscribe Now for Access
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