Pancreatic cancer: are more chemotherapy and surgery needed?

Most patients diagnosed with pancreatic cancer die from the disease. Although mortality from the most common cancers has declined in the past few decades, the mortality for patients with pancreatic cancer has remained high. On the basis of rising incidence, demographic data, and survival projections, pancreatic cancer is predicted to become the second most deadly cancer in the near future. Pancreatic cancer is curable only in a small minority of patients with localised and resectable tumours, which accounts for only 5–10% of the cases, and only 10–20% of patients survive more than 5 years after surgery. With such bleak fi gures, every attempt made to improve the survival rates of patients with pancreatic cancer should be welcomed. This is the aim of the ESPAC-4 trial published in The Lancet. John Neoptolemos and colleag ues report the fi rst results of the ESPAC-4 trial for the pancreatic cancer cohort. This was a multicentre, open-label, randomised trial of gemcitabine alone or in combination with capecitabine in the adjuvant setting for completely resected (R0 or R1) ductal pancreatic adenocarcinoma. The data show a signifi cant improvement of median overall survival with an absolute increase of 2·5 months for the experimental chemotherapy combination group (28·0 months compared with 25·5 months in the standard gemcitabine group; hazard ratio [HR] for overall survival 0·82 [95% CI 0·68–0·98], p=0·032). The 5-year survival rates show an absolute improvement of 12·5%, with 28·8% of patients alive in the combination group versus 16·3% in the gemcitabine group. The toxicities of the combination group were as expected and more pronounced but easily manageable with no detrimental eff ect on quality of life. The authors conclude that the combination of gemcitabine and capecitabine is now the treatment of choice in the adjuvant setting following resection for pancreatic ductal adenocarcinoma. These results open the fi eld to several questions. Can an increase in chemotherapy cure more patients in a cancer considered for more than 60 years to be chemoresistant? Do the fi gures from the ESPAC-4 trial at 5 years really represent patients cured of pancreatic cancer? How can we now improve the survival of patients with pancreatic cancer further? Do we need to give patients more surgery or more chemotherapy? First, the paradigm of pancreatic cancer as a chemoresistant tumour has been largely undermined in the past 5 years. In the metastatic setting, oncologists can now choose between diverse monotherapy or a combination of gemcitabine, fl uorouracil, nab-paclitaxel, oxaliplatin, irinotecan, and liposomal irinotecan. This means there are more chemotherapy drugs available for pancreatic cancer than for colon cancer. A meta-analysis of adjuvant trials in pancreatic cancer published 10 years ago showed that adjuvant chemotherapy gave patients only an extra 3 months of median survival time, without off ering a cure. So does the addition of capecitabine to gemcitabine in the adjuvant setting of pancreatic cancer really translate into more patients being cured? In the ESPAC-4 trial, the 5-year relapse-free survival fi gures were 11·9% (95% CI 7·8–16·9) in the gemcitabine group and 18·6% (13·8–24·0) in the combination group, giving an absolute diff erence of 6·9%, but these were only estimates. The authors also state from the raw data that at the time of analysis, tumour recurrence was observed in 243 (66·4%) patients in the gemcitabine group and 236 (64·8%) in the combination group. Additionally, 43 (11·7%) patients in the gemcitabine group and 35 (9·6%) patients in the combination group died without recurrence. Therefore, the number of patients alive without disease at the end of the analysis was 80 (21·8%) patients in the gemcitabine group and 93 (25·5%) patients in the combination group; an Published Online January 24, 2017 http://dx.doi.org/10.1016/ S0140-6736(17)30126-5