Adjuvant therapy for resectable pancreatic adenocarcinoma: Review of the current treatment approaches and future directions

Less than one out of five patients have resectable disease at the time of initial diagnosis. Nearly 90% are adenocarcinomas (PDAC) arising from the exocrine ductal system. has a very low prognosis, around 3% at 5 yrs. Even if resectable and even with R0 margins, there is high propensaty of recurrance and metastasis in the liver and at the tumor bed. post resection treatment strategies aim to control both micro-metastatic disease as well as loco-regional recurrence. treatments? various trials in the past have compared adjuvant RT and 5-FU to resected pancreatic adeno ca, most have reported mixed results, low accural in patient numbers and differing RT percriptions (i.e. split courses) multicenter trial (ESPAC-1; n = 289) examined the role of both adjuvant chemo (5FU/leucovorin) and CRT (split course 20gy 10# x2). Patients who received CHT [5FU/leucovorin (LCV)] had a significantly improved median OS over no treatment arm (20.1 vs 15.5 mo, respectively; p = 0.009). Surprisingly enough, patients on the CRT arm had a trend towards worse outcome (median OS: 15.9 vs 17.9 mo, respectively; p = 0.05). however this study like most others in the past regarding pancretic trials was criticized because of the suboptimal delivery and dosing of RT that potentially negated any survival benefit conferred by CRT with longer time-to-treatment in the CRT group and inclusion of R1 patients based on other small trials, it has become that adjuvant chemo alone should be the standard of care for either R0 or R1 resections and CRT might only be considered for patients with unfavorable profile. a german trial with gemcitabine compared adjuvant GEM administered for six cycles with observation alone in 368 patients with completely resected PDAC.>>>>> Patients receiving GEM had a near doubling of median disease-free survival (DFS) (13.4 vs 6.9 mo, respectively; p < 0.001), and improved median OS (22.8 vs 20.2 mo, p = 0.005) thus establishing its pivotal role in the management of patients in the AS European Study Group for Pancreatic Cancer (ESPAC) investigators proceeded with another study (ESPAC-3v2) that compared GEM vs 5-FU in the AS without RT. >>>>>> Results showed no differences in DFS and OS between patients receiving GEM and those receiving 5FU (23.6 vs 23.0 mo, respectively), with more grade 3/4 thrombocytopenia observed in patients on the GEM arm and more grade 3/4 stomatitis and diarrhea in patients on the 5FU arm. many other combination of drug have been used but the current best results have been consistency observed when using GEM/5FU In the metastatic setting FOLFIRINOX. A combination of 5FU/Irinotecan and oxaliplatin, was associated with a survival advantage over GEM (11.1 vs 6.8 mo, p < 0.001), offering patients with advanced disease and good performance status . Nab-paclitaxel in a phase II study, showed increased delivery of GEM in the tumor, elimination of PDAC stroma and association with anti-tumor activity. Preliminary reports showed a clear benefit of the combination therapy associated with significantly higher response rate (23% vs 7%), significantly longer median OS (8.5 vs 6.7 mo) and PFS (5.5 vs 3.7 mo) with an acceptable toxicity profile for the setting. This may offer a viable alternative to the above FOLFIRINOX. many other targeted therapies have been studied with little postive results, cetuximab, trastuzumab combinations, Hedgehog inhibitors, VEGF 1,2,3 inhibitors all with Gemcitabine have shown nohting. The used of immunotherapy such as Hyperacute immunotherapy approach (Algenpantucel-L) combined with AT has been tested in the AS demonstrating survival benefit. biomarkers CA19.9 most rountinely used can not be used to govern who will gain most from adjuvant therapy. levels of Human equilibrative nucleoside transport protein 1 (hENT1) alters resistance and predict sensitivity to the treatment. C-X-C chemokine receptor type 4 (CXCR-4) is an independent negative prognostic factor and a predictor of distant relapse suggesting that anti-CXCR4 targeting therapies could be a promising approach in combination with cytotoxic chemotherapy in the AS. concluesion- The optimal adjuvant treatment for PDAC patients remains elusive and there is no worldwide consensus. other directions deserving further evaluation include the role of pre- and perioperative approach Emerging evidence suggests that poor prognosis should at least in part be accounted for by the failure to destroy cancer stem cells (CSC) which may lead to chemo resistance.>>>>argeting signaling pathways that will intercept CSC growth is giving rise to a whole new era of anticancer treatment, albeit questions regarding fundamental cell functions still remain. Ref G. Antoniou, P. Kountourakis, K. Papadimitriou, V. Vassiliou, D. Papamichael, Adjuvant therapy for resectable pancreatic adenocarcinoma: Review of the current treatment approaches and future directions, Cancer Treatment Reviews, Available online 26 June 2013, ISSN 0305-7372, http://dx.doi.org/10.1016/j.ctrv.2013.05.008. (http://www.sciencedirect.com/science/article/pii/S0305737213001229)