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Second-Line Chemotherapy for Gastric Cancer

Summary and Comment |
January 21, 2014

Second-Line Chemotherapy for Gastric Cancer

  1. David H. Ilson, MD, PhD

Two trials demonstrate a modest survival benefit in metastatic disease.

  1. David H. Ilson, MD, PhD

Survival of patients treated with chemotherapy for metastatic gastric cancer usually does not exceed 1 year. Randomized trials have shown a potential modest survival benefit from second-line chemotherapy with taxanes or irinotecan. Now, investigators report the results of two studies in this setting that compared docetaxel versus best supportive care and irinotecan versus paclitaxel.

Ford and colleagues conducted a phase III, multicenter, randomized, open-label (COUGAR-02) trial of second-line docetaxel (75 mg/m2 once every 3 weeks) plus supportive care versus supportive care alone. The study involved 168 patients in the U.K. with metastatic esophagogastric cancer that progressed during chemotherapy (43%) or within 3 months (32%) or 6 months (25%) of chemotherapy with a fluorinated pyrimidine and a platinum agent. Most patients had a performance status of 0 or 1 (83%–86%), and equal numbers in each treatment group had gastric cancer (44%–46%) and esophageal/esophagogastric junction cancer (54%–56%).

After a median follow-up of 12 months, median overall survival (OS; the primary endpoint) was modestly improved with docetaxel plus supportive care compared with supportive care alone (5.2 vs. 3.6 months; hazard ratio, 0.67; P=0.01). Responses were seen in 7% of assessable patients receiving docetaxel. Grade 3 and 4 toxicities in docetaxel recipients were manageable, including neutropenia (15%) leading to rare neutropenic fever (7%). Health-related quality-of-life measurements indicated no detrimental effect of chemotherapy and potential improvements in pain and nausea.

Hironaka and colleagues conducted a phase III, multicenter, randomized, open-label (WJOG 4007) trial of second-line irinotecan (150 mg/m2 every 2 weeks) versus paclitaxel (80 mg/m2 weekly for 3 of every 4 weeks). The study involved 219 patients in Japan with metastatic or recurrent gastric cancer that progressed after fluorinated pyrimidine/platinum chemotherapy. Nearly all patients had performance status of 0 or 1 (96%), most had the primary tumor still in place (65%–66%), most had received prior S-1 plus cisplatin (79%–84%), and equal numbers of patients had intestinal or diffuse histology. Patients with large volume ascites, ileus, or bowel obstruction due to carcinomatosis were excluded.

After a median follow-up of 17.6 months, OS (the primary endpoint) was similar with paclitaxel and irinotecan (9.5 and 8.4 months, respectively), as was progression-free survival (3.6 and 2.3 months), and response rate (21% and 14%). More paclitaxel recipients received third-line chemotherapy (90% vs. 72%; P= 0.001). Toxicities from both treatments were manageable. Irinotecan recipients experienced more grade 3 or 4 neutropenia (39% vs. 29%) and diarrhea (5% vs. 1%); paclitaxel recipients experienced more grade 3 or 4 sensory neuropathy (7% vs. 0%).

Comment

These two trials add to the accumulating evidence supporting a modest survival benefit for second-line chemotherapy in metastatic gastric cancer. The Ford trial indicates a measurable survival improvement for docetaxel over best supportive care alone, and the Hironaka trial and a previously reported trial by Kang (NEJM JW Oncol Hematol Apr 3 2012) indicate similar survival benefits for a taxane versus irinotecan. The superior overall survival in the Hironaka trial likely reflects patient selection. The recently reported results for the use of the VEGFr2 targeted agent ramucirumab (NEJM JW Oncol Hematol Oct 28 2013), which improved survival as a second-line agent in gastric cancer over best supportive care, compares favorably to the use of chemotherapy, and approval of this agent will herald the option of a biologic agent as a second-line therapy. Although second-line treatment now represents a standard of care in gastric cancer, the limited benefit of available therapies reinforces the need for ongoing clinical trials.

  • Disclosures for David H. Ilson, MD, PhD at time of publication Consultant / Advisory board Clovis; Eli-Lilly; ImClone Speaker's bureau Genentech Grant / research support Bayer Editorial boards HemOnc Today; Journal of Clinical Oncology

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