Clinical Newswire, November 20, 2009-Gemcitabine (GEM) has been the standard of care for advanced pancreatic cancer but combining the drug with other therapeutic agents to improve survival has largely been unsuccessful. A study published in the November, 2009 edition of the Journal of Clinical Oncology has found that capecitabine (CAP) in combination with GEM significantly improved response rate (RR) and progression-free survival (PFS) in locally advanced and metastatic pancreatic cancer.
The open-label randomized phase III study compared GEM vs. the combination of GEM and CAP in 508 patients with pancreatic carcinoma. Primary outcome measure was overall survival (OS) and secondary outcomes included PFS, objective response rate (ORR), toxicity, QoL and pain assessment. All patients had histologically proven ductal adenocarcinoma or metastatic disease (World Health Organization performance status of 0,1 or 2) and had not undergone previous chemotherapy, radiotherapy or other investigational drug treatment. Patients were 1:1 randomly assigned to receive GEM (1,000 mg/m2 intravenously weekly X 7 with 1 week rest, followed by weekly X 3 every 4 weeks) or GEM-CAP (intravenous GEM at 1,000 mg/m2 weekly X 3 every 4 weeks; oral CAP at 1,660 mg/m2/d (830mg/m2 twice daily) for 3 weeks followed by 1 week rest). Patients were stratified at randomization based on disease extent and performance status. Pain assessment was made at baseline and every 6 weeks, while QoL assessment was performed at baseline and 12 weeks. Patient baseline characteristics were well balanced between arms. A retrospective analysis pooling the OS results of this study along with two additional smaller randomized controlled trials comparing GEM and GEM-CAP was also performed.
Patients in the GEM-CAP arm had significantly improved best achieved response rate compared with the GEM arm (19.1% vs. 12.4%, respectively; P=0.03). GEM-CAP was also associated with significantly improved PFS (HR, 0.78; 95% CI, 0.66-0.93; P=0.004). Median PFS for GEM-CAP was 5.3 months, while that for GEM alone was 3.8 months. At 12 months, PFS rate was 13.9% for GEM-Cap and 8.4% for GEM alone. OS trended higher in the GEM-CAP arm compared with GEM (HR, 0.86; 95%CI, 0.72-1.02, P=0.08). Median survival of patients treated with GEM-CAP was 7.1 months, compared to 6.1 months for GEM alone. One year OS rates were 24.3% for GEM-CAP and 22% for GEM. The trend toward better survival with GEM-CAP was evident even after adjusting for stratification factors at randomization (HR, 0.86;95%CI, 0.72-1.02, P=0.077). A meta-analysis performed on pooled OS data from the present study and 2 previous phase III trials (total patients=935) showed a significant improvement in OS in favor of GEM-CAP (HR, 0.86;95%CI,0.75-0.98, P=0.02). The improved survival in the GEM-CAT arm was not at the expense of QoL; there was no significant difference in QoL within 12 months between the 2 treatment arms.
Both treatments were well tolerated, with similar incidences of nausea, vomiting, diarrhea and stomatitis. Neutropenia was more prevalent in the GEM-CAP arm vs. the GEM arm (35%; 87/251 patients vs. 22%; 54/247, respectively), however, this did not result in more febrile neutropenia.
The researchers concluded that combination GEM-CAP significantly improves ORR and PFS and is associated with an increased OS trend compared to GEM alone. The authors indicate that although survival increases with the drug combination were modest, they were much larger than those seen with erlotinib-GEM combination (median survival 6.24 months for GEM-erlotinib and 5.91 months for GEM alone), the only other regimen that appears to improve survival in patients with advanced pancreatic cancer. The authors recommend GEM-CAP to be considered as one of the standard first-line options in locally advanced and metastatic pancreatic cancer.
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