Pancreatic adenocarcinoma (PAC) is the fourth leading cause of cancer death in U.S.A. and the 7th in Europe. The prognosis remains dismal for all stages with 5-year overall survival of less than 5%, while >95% of those affected die of the disease . Surgical resection followed by adjuvant therapy offers the only curative option. However, less than 15% of the patients present with resectable disease. In the adjuvant setting, 6 months of gemcitabine (GEM) or 5-fluorouracil (5-FU) chemotherapy is considered to be the standard of care. Chemo radiation is another proposed therapeutic approach but its role remains controversial. Unfortunately, the 5-yr survival rate of resected PAC cases remains low (˜20%), despite the implementation of multimodality approaches. Hence, further efforts to improve the adjuvant treatment outcome are mandatory.
In the case of advanced disease, FOLFIFRINOX has lately emerged as the regimen with the best results in a randomized phase III trial (response rate: 31%; median overall survival of 11.1 months) but this is reserved to patients with good performance status due to the increased toxicity . Otherwise, gemcitabine (either alone or in combination with other agents) serves as the backbone for palliative treatment.
The chemoresistance of PAC has led to a continuing search for new therapeutic targets or optimization of the existing treatment approaches. Recently, two Phase III randomized trials have been published for both adjuvant and advanced therapy in PAC [3, 4].
The first study was based on the impressive results of a phase II study that showed 55% five-year-OS survival when the combination cisplatin, FU, interferon alfa-2b (IFNa -2b), and external-beam radiotherapy was implemented . Schmidt et al. randomly assigned 132 R0/R1 resected patients to receive either fluorouracil (FU), cisplatin, and interferon alfa-2b plus radiotherapy followed by two cycles of FU (arm A, n= 64) or to six cycles of FU monotherapy (arm B, n = 68) . Median overall survival (mOS) for all patients was 26.5 months in arm A and 28.5 months in arm B. (Hazard ratio (HR) was 1.04; 95% CI, 0.66 to 1.53; P= .99). Median survival for those who received at least one dose of the study medication was 32.1 months in arm A and 28.5 months in arm B (P = .49). Higher percentage of the patients in Arm A experienced grade 3 or 4 toxicity (85% vs. 16% in Arm B) which temporarily affected their quality of life. Although no statistical difference could be observed in the two arms it is of interest that the mOS is the highest reported till now. If this has to do with selection bias or due to the high surgical volume centre effect remains a question.
In the second study, Gonçalves et al. tested the combination of gemcitabine and sorafenib in comparison with gemcitabine/placebo in the first line treatment of locally advanced or metastatic PAC . The primary outcome was progression-free survival (PFS). 104 patients were enrolled on the study (52 pts in each arm). The median and the 6-month PFS were 5.7 months and 48% for gemcitabine/ placebo and 3.8 months and 33% for gemcitabine/sorafenib (P = 0.902), respectively. Similarly the combination of Gem/sorafenib did not improve response rate, mOS and clinical benefit. The results of this trial are in concordance with two phase II studies [6,7], that failed to prove any benefit from the addition of sorafenib to gemcitabine or to the combination of gemcitabine/cisplatin, respectively. Despite the encouraging preclinical and Phase I data, as well as the scientific rationale of targeting the angiogenesis and K-RAS driven BRAF/MEK/ERK pathway by sorafenib, it seems that this multitarget inhibitor has limited , if any, effect in the management of advanced PAC.
Despite the negative results, these trials can teach us a lot. Up to date, chemoradio-immunotherapy seems to have no proven efficacy in the adjuvant setting. In addition, we should interpret early-phase trials’ results very cautiously. It is a frequent phenomenon the initial excitement, experienced from impressive early phase studies’ results, to be followed by disappointing outcomes from the randomized trials. Nevertheless, there are many studies ongoing , especially in advanced PAC, and we anticipate the actual results of two phase III trials suggesting survival benefit in metastatic PAC with the combination of gemcitabine with either nab-paclitaxel or masitinib (a tyrosine kinase inhibitor that targets mast cells) .
Definitely, pancreatic cancer is an aggressive disease hard to treat with not many therapeutic options. Hence, physicians should be highly motivated to enrol pancreatic cancer patients into clinical trials.
- Seufferlein T, Bachet JB, Van Cutsem E, Rougier P; ESMO Guidelines Working Group. Pancreatic adenocarcinoma: ESMO-ESDO Clinical Practice Guidelines for diagnosis, treatment and follow-up. Ann Oncol. 2012 Oct;23 Suppl 7:vii33-40
- Conroy T, Desseigne F, Ychou M et al. FOLFIRINOX versus gemcitabine for metastatic pancreatic cancer. N Engl J Med 2011; 364: 1817–1825
- Schmidt J, Abel U, Debus J, et al. Open-Label, Multicenter, Randomized Phase III Trial of Adjuvant Chemoradiation Plus Interferon Alfa-2b Versus Fluorouracil and Folinic Acid for Patients With Resected Pancreatic Adenocarcinoma. J Clin Oncol. 2012 Nov 20;30(33):4077-83
- Gonçalves A, Gilabert M, François E, et al. BAYPAN study: a double-blind phase III randomized trial comparing gemcitabine plus sorafenib and gemcitabine plus placebo in patients with advanced pancreatic cancer. Ann Oncol. 2012 Nov;23(11):2799-805
- Picozzi VJ, Kozarek RA, Traverso LW: Interferon based adjuvant chemoradiation therapy after pancreaticoduodenectomy for pancreatic adenocarcinoma. Am J Surg 185:476-480, 2003
- El-Khoueiry AB, Ramanathan RK, Yang DY et al. A randomized phase II of gemcitabine and sorafenib versus sorafenib alone in patients with metastatic pancreatic cancer. Invest New Drugs 2011
- Berardi R, Sobrero A, Labianca R et al. Sorafenib does not improve the results of chemotherapy in advanced pancreatic cancer: a GISCAD randomised phase II trial. Ann Oncol 2010; 21: viii225–viii249
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