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Combination therapy did not improve survival in gastric cancer

Issue: February 25, 2008

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Adding irinotecan to S-1 for treatment of advanced gastric cancer was well tolerated, but the combination did not show superiority to S-1 alone in survival.

Hiroshi Imamura, MD, PhD, of the department of surgery at Sakai Municipal Hospital in Osaka, Japan, presented data from the phase-3 trial of first-line gastric cancer treatment.

Imamura and colleagues randomly assigned patients with untreated advanced gastric cancer to S-1, an oral 5-fluorouracil (5-FU) prodrug available in Japan; or to S-1 plus irinotecan (Camptosar, Pfizer). From June 2004 to November 2005, 326 patients were enrolled. Treatment continued until disease progression or unacceptable toxicity.

There was no statistically significant difference in overall survival between the two groups. The median survival was 318 days in the single-agent arm vs. 389 days in the combination arm. The one-year survival was 44.9% in the single-agent arm vs. 52% in the combination arm.

The response rate was significantly better in the combination arm: 41.5% vs. 26.9% in the single-agent arm. Neutropenia, diarrhea, nausea and vomiting were more frequent in the combination arm. – by Emily Shafer

For more information:

• Imamura H, Iishi H, Tsuburaya A, et al. #5. Presented at: 2008 Gastrointestinal Cancers Symposium; Jan. 25-27, 2008; Orlando.

The researchers treated more than 300 patients with metastatic disease, and although there was a significant improvement in response rate for patients on the combination treatment, this did not translate into a significant survival benefit. The study was small but ambitious in that they were looking for a big survival difference. They powered the study to detect a three-month survival difference. They found a 2.5-month survival difference, which some would argue would have been more significant if more patients had been accrued. The study adds to other phase-3 trials of first-line irinotecan combination treatments in gastric cancer that have not shown survival benefits.

The drug S-1 is approved in Japan, where the standard treatment is S-1 plus platinum therapy. This combination is approved in Japan based on phase-3 data that demonstrate a response rate and survival benefit for the combination vs. S-1 alone. A trial was recently completed in the United States and other countries, in which researchers conducted a head-to-head comparison of conventional 5-FU plus platinum vs. S-1 plus platinum. We are waiting for efficacy and toxicity results.

Many irinotecan regimens such as FOLFIRI (leucovorin, 5-FU) appear to be equivalent to standard treatments, but none of the phase-3 trial results have demonstrated a superior survival benefit for irinotecan combination treatments compared with single agents or other combinations. The issue is: How do we position irinotecan in treating gastric cancer? Should we use it as a first-line treatment? Should we use it as a second-line treatment? That is still an area of debate.

For gastric cancer, the standard for patients with a good performance status who can tolerate combination treatments is a two- or three-drug combination. Two-drug regimens would combine a platinum agent with 5-FU, irinotecan or a taxane. Three-drug regimens include ECF and DCF, which combine either epirubicin or docetaxel with cisplatin/5-FU. Only phase-2 data support the use of an irinotecan/platinum regimen.

The two-drug combinations tend to be better tolerated. Research has shown that three-drug regimens like DCF do result in modest improvements of response rate and small improvements in survival but at the cost of a lot greater toxicity.

Their data also suggest that substituting capecitabine or oxaliplatin in the ECF regimen developed by British researchers is equivalent. Many European trials are now using the ECX regimen (epirubicin, cisplatin and capecitabine) both in the advanced disease and adjuvant setting.

Results of phase-3 trials have shown that perhaps there is also a benefit for the double substitution. The EOX (epirubicin, oxaliplatin and capecitabine) arm seemed to have the best survival of the four regimens tested, but the differences were modest. None of these regimens have been home runs in terms of improving outcome when compared with two-drug regimens.

– David H. Ilson, MD

HemOnc Today Editorial Board member