Adjuvant therapy for pancreatic cancer

Pancreatic cancer is a challenging malignancy to treat, as less than one-fifth of diagnosed cases are resectable, surgery is complex and postoperative recovery slow, treated patients tend to relapse and overall survival rates are low. It is one of the leading causes of cancer-related mortality. Adjuvant therapy has been employed in resectable disease, to target micrometastases and improve prognosis. Chemotherapy, chemoradiotherapy (chemoRT) and chemoradiotherapy (chemoRT) followed on by chemotherapy have been evaluated in randomised controlled trials. The European Study Group for Pancreatic Cancer (ESPAC)-1 and CONKO-001 trials clearly established the survival advantage of adjuvant chemotherapy with 5 fluorouracil (5FU) plus folinic acid and gemcitabine respectively over no chemotherapy. The ESPAC-3 (version 2) trial demonstrated equivalence between 5FU plus folinic acid and gemcitabine in terms of survival parameters, though gemcitabine had a better toxicity profile. The results of these key studies, together with smaller ones have been subjected to meta-analyses, with confirmation of improved survival with adjuvant systemic chemotherapy. The EORTC-40891 and ESPAC-1 trials found no survival advantage with adjuvant chemoRT compared to observation, and this has been reflected in a subsequent meta-analysis. The popularisation of chemoRT, with follow on chemotherapy (versus observation) was based on the small underpowered GITSG trial. The ESPAC-1 trial was unable to find a survival benefit for chemoRT, with follow on chemotherapy compared to observation. The RTOG-9704 trial assessed chemoRT with follow on chemotherapy in both arms and found no difference between survival in the gemcitabine and 5FU arms. There has never been a published head-to-head randomised comparison of adjuvant chemotherapy to chemoRT, with follow on chemotherapy. Ongoing randomised trials are looking into adjuvant combination chemotherapy, chemotherapy with follow on chemoRT, and neoadjuvant therapy. Novel agents continue to be assessed in early phase trials with a major emphasis on predictive and prognostic biomarkers. Based on the available evidence, adjuvant chemotherapy with gemcitabine or 5FU/folinic acid is the current recommended gold standard in the management of resected pancreatic cancer.