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CHICAGO -- An adjuvant chemotherapy combination almost doubled 5-year survival in operable pancreatic cancer patients compared with use of a standard single drug, a large European trial showed.

Patients who received gemcitabine and capecitabine after surgery had a 5-year survival rate of 28.8% versus 16.3% for gemcitabine. The combination tripled 5-year survival as compared with historical rates for surgery alone.

The 5-year survival somewhat overshadowed the primary endpoint of median overall survival, a statistically significant 3-month difference that also favored the combination arm, as reported here at the American Society of Clinical Oncology (ASCO) 2016 annual meeting.

"Adjuvant gemcitabine with capecitabine is the second-step change [following the introduction of single-agent adjuvant chemotherapy] for resected pancreatic," said , of the University of Liverpool in England. "The regimen was associated with manageable and acceptable toxicity. The 5-year survival increased to 29%, making adjuvant gemcitabine with capecitabine the new standard of care for resected pancreatic cancer."

The should be evaluated within the context of a historically difficult disease that continues to have a poor prognosis for most patients, said , of Massachusetts General Hospital Cancer Center in Boston, who moderated an ASCO press briefing that included the presentation.

"For patients with such a difficult disease like pancreatic cancer, we are going to see steps and incremental gains, and this does provide further statistically significant improvement in survival with a combination therapy that does not add more toxicity," Dizon said. "These are important results."

In most cases, the diagnosis of pancreatic cancer occurs at an advanced stage, when surgery is no longer feasible. For patients with operable disease at diagnosis, adjuvant gemcitabine or other single-agent chemotherapy has been the standard of care for more than a decade.

In the early 1970s, the 1-year survival rate for resectable pancreatic cancer was 10% with surgery alone. That increased to 21% with the adoption of adjuvant chemotherapy with agents such as gemcitabine and capecitabine.

A series of clinical trials conducted by members of the European Study Group for Pancreatic Cancer resulted in step changes in treatment that improved outcomes to the point that discussion of 5-year survival became realistic.

Improvements in surgical technique led to a 5-year survival rate of 8%. The introduction of concurrent chemoradiation therapy increased that to 11% and then to 16% to 18% with use of surgery plus adjuvant fluorouracil or gemcitabine.

"We felt that the combination of gemcitabine and capecitabine might be better than gemcitabine alone, so we designed a trial to test that hypothesis," said Neoptolemos.

On the basis of historical results with existing treatment strategies, statisticians determined that a trial involving more than 700 patients would be required to compare 5-year survival with gemcitabine plus capecitabine versus gemcitabine alone. From January 2008 through July 2014, clinical investigators at 92 sites in six countries subsequently randomized 722 patients with newly diagnosed, resectable pancreatic cancer to receive gemcitabine alone or in combination with capecitabine.

Patients in the study population had a median age of 65, and men accounted for 57% of the total. The patients had good performance status and a median maximal tumor size of 30 mm. Surgery resulted in clear margins in 40% of patients and minimal marginal involvement in the remaining 60%. Neoptolemos said 80% of the patients had node-positive disease, and 40% of the tumors were poorly differentiated.

The primary outcome was overall survival. Secondary endpoints included toxicity, relapse-free survival, and overall survival at 2 and 5 years. The trial ended prematurely when an interim analysis revealed a statistically significant difference between the two treatment groups.

The primary data analysis showed a median survival of 28 months with the two-drug combination and 25 months with gemcitabine, representing a statistically significant 18% reduction in the hazard ratio (HR 0.82, 95% CI 0.68-0.98, P=0.032). The 5-year survival rate was 28.8% with gemcitabine and capecitabine versus 16.3% with gemcitabine alone. Neoptolemos described the difference as statistically significant but did not report the level of significance.

The rates and severity of adverse events were similar between the treatment arms, he said. Overall, one fourth of patients reported treatment-related serious adverse events, including 26% in the gemcitabine arm and 24% in the combination arm.

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