The results from the ESPAC-4, a multicenter, international, open-label randomised controlled phase III trial of adjuvant combination chemotherapy of gemcitabine / capecitabine versus monotherapy gemcitabine in patients with resected pancreatic ductal adenocarcinoma show a statistically significant 2.5 months improvement in survival in favour of combination regimen. The results were presented in the oral abstract session on Gastrointestinal (Noncolorectal) Cancer by Dr John Neoptolemos during the ASCO Annual Meeting 2016 (3-7 June, Chicago US).
Gemcitabine is the standard of care in this setting. Previously, the ESPAC-3 trial compared adjuvant gemcitabine with 5-fluorouracil / folinic acid (5-FU/FA) for resected pancreatic cancer; gemcitabine regimen achieved similar survival with less toxicity. ESPAC-4 aimed to determine whether combination chemotherapy with gemcitabine / capecitabine improve survival compared to gemcitabine alone.
In the ESPAC-4 study, patients with pancreatic ductal adenocarcinoma were randomised within 12 weeks of surgery to either six cycles of gemcitabine alone or gemcitabine / capecitabine. They were stratified for R0/R1 resection margin status and country. Eligibility criteria foreseen no ascites, liver or peritoneal metastasis, or any other abdominal or extra-abdominal organ spread; no previous or concurrent malignancy diagnoses; WHO performance status ≤ 2; life expectancy of more than 3 months; and fully informed consent.
The primary endpoint was overall survival; secondary endpoints were toxicity, relapse free survival, 2- and 5-year survival and quality of life.
Between November 2008 and September 2014, 732 patients were randomised with 730 included in the full analysis set (366 gemcitabine, 364 gemcitabine / capecitabine). Median age was 65 years, 57% were men. WHO performance status was 0, 1 or 2 in 42% 55% and 3% respectively. Postoperative median CA19-9 was 19 kU/L. Median maximum tumour size was 30 mm, 60% were R1 resections, 80% were node positive and 40% were poorly differentiated.
In December 2015 the Independent Trial Steering Committee requested that the trial proceed to full analysis. The data freeze was on 2 March 2016.
Median survival for patients treated with gemcitabine / capecitabine was 28.0 months and 25.5 months for those treated with gemcitabine. Stratified log-rank analysis revealed an hazard ration of 0.82 [95% CI, 0.68 – 0.98]; p = 0.032.
In total, 196 out of 366 gemcitabine patients in the safety set reported 481 grade 3/4 adverse events, while 226 out of 359 gemcitabine / capecitabine patients reported 608 grade 3/4 adverse events, with non-significant difference. In term of grade 3/4 adverse events, diarrhoea and hand-foot syndrome were more frequent in combination arm.
Dr Neoptolemos concluded that median survival for patients treated with combination regimen was significantly better than with gemcitabine alone (28 vs 25.5 months). The estimated 5-year survival rate was superior with combination regimen than gemcitabine monotherapy (28.8% vs 16.3%). The 5-year survival rate with combination treatment (28.8%) was superior to previous ESPAC trial arms including no chemotherapy (8%), chemoradiotherapy (10.8%), 5-FU/FA (15.9%). There was slightly more toxicity in the gemcitabine / capecitabine arm but overall this was manageable and not significant (serious adverse events 24% vs 26% / combination vs monotherapy).
Dr Neoptolemos concluded that marginal benefit of active agents in advanced pancreatic cancer can translate into a much bigger effect in the adjuvant setting. All patients with pancreatic cancer should be offered entry into randomised trials; biomarkers must be evaluated (hENT1, etc). Adjuvant gemcitabine / capecitabine is the new standard of care for resected pancreatic cancer.
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