EDITORIAL
JOP. J Pancreas (Online) 2014 Mar 10; 15(2):84-86.
Pancreatic Cancer in 2014
Serafim Kaltsas1, Konstantinos N Syrigos1, Muhammad Wasif Saif2
1University of Athens School of Medicine. Athens Greece. 2Tufts Medical Center. Boston, MA, USA
Pancreatic adenocarcinoma remains a therapeutic challenge. The American Cancer Society’s estimates [1] for pancreatic cancer in the United States for 2014 are:
· about 46,420 people will be diagnosed with pancreatic cancer;
· about 39,590 people will die of pancreatic cancer.
On the side of targeted agents, including bevacizumab, cetuximab, and erlotinib has been dismal except a modest benefit with erlotinib [4, 6]. Though statistically significant in the erlotinib study, this difference was not considered clinically significant. Recent data was also disappointing about IPI926, CO-101, AMG479, vismodegib and sorafenib. These disappointing results again underlined the difficulty of treating patients with pancreatic cancer. Currently, novel agents targeting numerous pathways are under study, such as histone deacetylases, insulin-like growth factor 1 receptor, mammalian target of rapamycin, transforming growth factor β type I receptor, PIK3/AKT, Notch, prostate stem cell antigen (PSCA), and SRC. A promising approach under evaluation in clinical studies is the development of pegylated recombinant human hyaluronidase 20 (PEGPH20). Preliminary data from a phase Ib study in combination with gemcitabine for the treatment of patients with stage IV metastatic pancreatic cancer showed a promise [7]. In this trial, both progression free survival and overall survival data suggest a potential clinical benefit of using PEGPH20 with gemcitabine in patients with high levels of tumor associated hyaluronan (hyaluronic acid; HA). Multiple regimens are under testing with PEGPH20 such as combination with nab-paclitaxel and gemcitabine, as well as, combination with 5-flouorouracil, leucovorin and oxaliplatin (FOLFOX) and FOLFIRINOX.
NAPOLI 1 (NCT01494506) is a global, randomized, open label phase III trial testing MM-398 as a monotherapy and MM-398 in combination with 5-fluorouracil and leucovorin (5-FU/LV) compared with the shared control arm of 5-FU/LV [10]. MM-398 is a novel nanoliposomal encapsulation of irinotecan sucrosofate. MM-398 is designed to optimize the delivery of irinotecan by extending the duration of circulation in the body and preferentially activating the drug within the tumor to achieve higher levels of the active cytotoxic irinotecan (SN-38). In another phase II trial, known as the Ruxolitinib in Pancreatic Cancer Patients (RECAP; NCT01423604) trial, patients with metastatic pancreatic cancer who had failed first-line treatment with gemcitabine, or another chemotherapy agent if they were ineligible to receive gemcitabine, received capecitabine 2,000 mg/m2 or 1,000 mg/m2 twice a day and were randomized to receive either ruxolitinib 15 mg twice a day or a placebo [11]. Ruxolitinib is a potent and selective oral Janus kinases 1 and 2 (JAK1 and JAK2) inhibitor that was approved by the FDA in 2011 for the treatment of myelofibrosis. Glufosfamide versus 5-FU/LV is being tested in second-line metastatic pancreatic cancer [12].
Despite progress in the development of new cytotoxic and biological drugs for the treatment of pancreatic cancer the outcome remains grim. The conclusions from the recent 2014 ASCO Gastrointestinal Cancers Symposium are that we are awaiting for new chemotherapy combinations. Data are emerging for the benefit of second-line regimens. Also new targets are in development, as anticancer stem cell agents, immunotherapy and gene therapy, for this very deadly malignant tumor. Patients with any stage of pancreatic cancer should be considered candidates for clinical trials.
Keywords Carcinoma; Pancreas; Pancreatic Neoplasms; Therapeutics /toxicity
Abbreviations 5-FU/LV: 5-fluorouracil and leucovorin; FOLFIRINOX: 5-fluorouracil, leucovorin, irinotecan, and oxaliplatin; FOLFOX: 5-flouorouracil, leucovorin and oxaliplatin; HA: hyaluronic acid; JAK: Janus kinase; MM-398: irinotecan sucrosofate; MPACT: Metastatic Pancreatic Adenocarcinoma Clinical Trial; PARP: poly (ADP-ribose) polymerase; PEGPH: pegylated recombinant human hyaluronidase; PSCA: prostate stem cell antigen; SN-38: active metabolite of irinotecan; SPARC: secreted protein acidic and rich in cysteine
Conflict of interest The authors have no potential conflicts of interest
Correspondence
Muhammad Wasif Saif
Department of Medicine and Cancer Center
Tufts Medical Center
800 Washington Street Box 245
Boston, MA 02111
USA
Phone: +1-617.636.5627
Fax: +1-617.636.8535
E-mail: wsaif@tuftsmedicalcenter.org
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