Evolving Panorama of Treatment for Metastatic Pancreas Adenocarcinoma

Pancreas adenocarcinoma in contradistinction to other common solid tumor malignancies such as breast, lung, prostate, and colorectal cancer, has both rising incidence and mortality rates, emphasizing the major public health problem this disease incurs. Nonetheless, the last several years have also seen improved understanding of the molecular pathogenesis and the biology of pancreas adenocarcinoma and tangible progress has been made in the area of therapeutics for advanced disease. Notably, the multiagent cytotoxic regimen of irinotecan, oxaliplatin, fluorouracil, and leucovorin (FOLFIRINOX) and more recently the combination of gemcitabine combined with albumin-bound paclitaxel, have demonstrated superiority over single-agent gemcitabine in front-line therapy for untreated advanced pancreas adenocarcinoma. Both of these regimens are undergoing and/or have planned evaluation in localized resectable and unresectable pancreas adenocarcinoma and there is potential promise for improved outcomes in these settings. These regimens also provide a platform for combination with new agents and will spur a new generation of clinical trials in advanced pancreas cancer. In the article that accompanies this editorial, Ueno et al in their randomized phase III Gemcitabine and S1 Trial (GEST) provide support for the emerging role of the oral fluoropyrimidine, S-1 (TS-1; Taiho Pharmaceutical, Tokyo, Japan) in the treatment of pancreas adenocarcinoma. This phase III study was designed to evaluate both the noninferiority of S-1 and the potential superiority of a gemcitabine and S-1 combination compared with gemcitabine alone in untreated locally advanced or metastatic pancreas adenocarcinoma. Eight hundred and thirty-four patients with an Eastern Cooperative Oncology Group performance status of 0 to 1 were randomly allocated on a 1:1:1 basis to either gemcitabine at a conventional dose and schedule of 1,000 mg/m/d on days 1, 8, and 15, repeated on an every-28-day schedule, or to S-1 alone at a dose of 80 to 120 mg/d on days 1 through 28, repeated on an every-42-day schedule, or to the combination with gemcitabine administered on days 1 and 8 and S-1 60 to 100 mg/d on days 1 through 14, repeated on an every-21-day schedule. For the primary end point of overall survival the outcomes were 8.8 months for gemcitabine alone, 9.7 months for S-1 alone, and 10.1 month for the combination. The trial results confirmed noninferiority for S-1 to gemcitabine (hazard ratio [HR], 0.96; 97.5% CI, 0.78 to 1.18; P .001), however superiority for the combination was not met (HR, 0.88; 97.5% CI 0.71 to 1.08; P .15). S-1 is an oral agent with three components: tegafur, a prodrug of fluorouracil, gimeracil (5-chloro-2,4 dihydropyridine), which inhibits dihydropyrimidine dehydrogenase enzyme activity, and oteracil (potassium oxonate). S-1’s benefit has been established in the treatment of gastric cancer and has been investigated in other malignancies, and extensive investigation has been underway in pancreas adenocarcinoma in multiple disease settings with results suggesting utility. The results of the GEST trial, which was a thoughtfully conceived, wellconducted, and clearly reported randomized phase III trial, provide additional support for the role of fluoropyrimidine therapy in pancreas adenocarcinoma and suggest that for certain patient populations single-agent monotherapy with S-1 is a suitable therapeutic intervention with anticipated toxicities being mostly gastrointestinal. Additional support for the utility of S-1 in pancreas cancer further emerges from the preliminary results of the Japan Adjuvant Study Group of Pancreatic Cancer (JASPAC) 01 study comparing S-1 and gemcitabine in the adjuvant setting. This trial was also designed with noninferiority intent; however, preliminary results suggest superiority of S-1 over gemcitabine may be met with the HR for S-1 to gemcitabine (0.56; 95% CI, 0.42 to 0.74; P .0001 for noninferiority and P .001 for superiority) and with 2-year survival being 70% for S-1% and 53% with gemcitabine. Where do the collective results of these phase III trials leave us with regard to the use of S-1 in the global treatment of pancreas adenocarcinoma, in particular given that S-1 is available only in Asia and the pathway to approval in the United States is far from clear? Much has been discussed regarding the importance of pharmacogenetic considerations in drug metabolism, efficacy, and heightened potential for toxicity of therapeutics in different patient populations, considerations that are relevant to the other widely used oral fluoropyrimidine, capecitabine in pancreas adenocarcinoma. The ongoing European Study Group for Pancreatic Cancer (ESPAC) Trial 4, a randomized phase III trial in patients with resected pancreas cancer, evaluating the addition of capecitabine to gemcitabine, will to some extent test the hypothesis of the utility of the addition of a fluoropyrimidine in the adjuvant setting in a non-Asian population, however, multiple randomized trials in a similar patient population have not shown superiority for such a combination in the metastatic disease using a variety of oral and bolus fluoropyrimidine schedules combined with gemcitabine. Based on the evidence to date, further investigation of S-1 in non-Asian populations is warranted with a keen focus on pharmacogenomic evaluation. JOURNAL OF CLINICAL ONCOLOGY E D I T O R I A L VOLUME 31 NUMBER 13 MAY 1 2013