Added text about multiple randomized trials using postoperative chemotherapy, which have historically established that adjuvant gemcitabine monotherapy (cited Oettle et al. as reference 21) or adjuvant 5-fluorouracil (5-FU) monotherapy improves overall survival (OS) for 6 months after surgical resection compared with surgery alone. Also added that more recent studies have looked at newer combination regimens that might further improve outcomes after surgical resection.
Added text about evidence-producing postoperative chemotherapy trials, including the European Study Group for Pancreatic Cancer (ESPAC-4) trial that randomly assigned 732 patients with resected pancreatic cancer to receive either six cycles of gemcitabine alone or oral capecitabine (cited Neoptolemos et al. as reference 22 and level of evidence 1iiA). Added statistical data from ESPAC-4 to verify that the adjuvant combination of gemcitabine and capeticabine should be the new standard of care after a resection for pancreatic cancer. Included data about gemcitabine/capecitabine yielding improvement in estimated 5-year OS, the lack of a significant difference in overall rates of grade 3/4 toxicities between treatment arms, and the lack of significant effects on quality of life in the treatment groups.
Added text about the Japan Adjuvant Study Group of Pancreatic Cancer (JASPAC-01) study, a phase III, multicenter, noninferiority trial in Japan that randomly assigned 385 patients to receive either gemcitabine for six cycles or S-1 (cited Uesaka et al. as reference 23 and level of evidence 1iiA). Added data from JASPAC-01 about an early interim analysis and results that were associated with a 5-year OS of 24.4% in the gemcitabine group and 44.1% in the S-1 group; the differences between the groups in grade 3/4 toxicities, and an explanation of the effect of S-1 on Eastern and Western populations. Stated that S-1 is an effective treatment in Japan but needs further study in non-Asian populations and approval by the U.S. Food and Drug Administration in the United States.
Added text to state that for patients with good performance status, adjuvant gemcitabine/capecitabine should be considered; however, for older patients or patients with marginal performance status, adjuvant gemcitabine or 5-FU monotherapy can be considered.
Revised text to state that because of the low objective response rate and limited efficacy of palliative chemotherapy regimens, enrollment into clinical trials should be considered for all newly diagnosed patients. Multiagent chemotherapy combinations have recently been shown to prolong outcomes compared with single-agent gemcitabine.
Added text about second-line chemotherapy evidence and included the NAPOLI-1 trial that evaluated the role of nanoliposomal irinotecan in patients with metastatic pancreatic cancer who were previously treated with gemcitabine-based therapies. Described nanoliposomal irinotecan as an encapsulated formulation of irinotecan designed to increase intratumoral levels of irinotecan and its active metabolite. Added statistical data from the study of 417 patients who were randomly assigned to either nonliposomal irinotecan monotherapy, 5-FU and folinic acid, or nanoliposomal irinotecan and folinic acid (cited Wang-Gillam et al. as reference 11 and level of evidence 1iiD) that included a comparison of the two groups regarding median OS, which on a multivariate analysis, concluded that nanoliposomal irinotecan plus 5-FU and folinic acid was associated with improved OS, grade 3/4 adverse events, and quality of life. Concluded by stating that there is a lack of clarity about the benefit of using nanoliposomal irinotecan rather than unencapsulated irinotecan because the regimen for the control arm of this study was 5-FU/folinic acid; additionally, the value of using nanolipisomal irinotecan after FOLFIRINOX (leucovorin calcium, fluorouracil, irinotecan hydrochloride, and oxaliplatin) in the first-line setting is not clear.
Added text about folinic acid, fluorouracil, oxaliplatin (FOLFOX) versus 5-FU/leucovorin (LV) after gemcitabine chemotherapy by including statistical data about the PANCREOX study, a prospective, multicenter trial that randomly assigned 108 patients with advanced pancreatic cancer who had previously received first-line gemcitabine-based chemotherapy to receive 5-FU/LV either with or without oxaliplatin, which was administered as modified FOLFOX (mFOLFOX)-6 (cited Gill et al. as reference 12 and level of evidence 3iA). The statistical data about the two groups included the median progression-free survival rates, the lack of difference in response rate and quality of life, the overall incidence of grade 3/4 adverse events, the lack of benefit with the addition of oxaliplatin, administered in the mFOLFOX-6 regimen, versus infusional 5-FU/LV among patients with advanced pancreatic cancer after first-line gemcitabine-based chemotherapy, suggesting that oxaliplatin-based regimens for metastatic pancreatic cancer may yield the greatest benefit in the first-line setting.
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