Phase I Study of Hyperfractionated Radiation Therapy with Protracted 5-Fluorouracil Infusion in Patients with Locally Advanced Pancreatic Cancer

Abstract

Objective: This study investigated the maximum-tolerated dose of hyperfractionated radiation therapy with protracted 5-fluorouracil (5-FU) infusion in patients with locally advanced, unresectable pancreatic cancer. Methods: Five cohorts of patients were scheduled to receive escalating doses of hyperfractionated radiation therapy (range, 45.6–64.8 Gy). All patients received two fractions of 1.2 Gy each (separated by 6 h) per day for 5 days a week, and received protracted 5-FU infusion (200 mg/m²/day) during the radiation course. The maximum-tolerated dose was defined as one dose level below the dose at which more than one third of 3–6 patients experienced dose-limiting toxicity. Results: Twenty-nine patients were enrolled in this study. The most common toxicities were nausea/vomiting and anorexia. Although 1 patient developed bleeding from a gastric ulcer 3 months after the completion of chemoradiotherapy, the maximum-tolerated dose was not reached even at the highest dose level (level 5, 64.8 Gy). The median survival time was 12.2 months and the 1-year survival rate was 55.0%. Conclusion: The toxicity associated with our regimen was tolerable up to dose level 5 (64.8 Gy). We are currently conducting a phase II study of this hyperfractionated radiation therapy with protracted 5-FU infusion at a dose of 64.8 Gy.

A systematic methodology review of phase I radiation dose escalation trials

“…In addition to lung cancer, a large number of phase I RT trials (n = 17) were performed to improve the treatment of brain (n = 4) [28][29][30][31][32], pancreas (n = 7) [33][34][35][36][37][38][39] and prostate cancers (n = 6) [40][41][42][43][44][45][46][47] (for details per study see Appendix 3). The majority of these studies (n = 11, 65% [29,30,[33][34][35]39,40,42,43,45,46]) re- ported only safety and toxicity data. In general, the trials were performed as multicentre studies (n = 10, 59%) [28,29,[31][32][33][34][35][36]38,43] in the Northern America (n = 12, 71%) [28][29][30][33][34][35][36]…”

“…In general, the trials were performed as multicentre studies (n = 10, 59%) [28,29,[31][32][33][34][35][36]38,43] in the Northern America (n = 12, 71%) [28][29][30][33][34][35][36][37]40,[44][45][46][47][48] (Table 1). Seven (41%) used the modified Fibonacci design for RT dose escalation [30,33,34,[37][38][39]41]; in the other ten (59%) no specific design was used [28,29,31,32,35,36,40,42,43,45,46]. Dose escalation was performed in nine of these studies by increasing the number of fractions (53%) [31,34,36,38,39,41,43,…”

“…Seven (41%) used the modified Fibonacci design for RT dose escalation [30,33,34,[37][38][39]41]; in the other ten (59%) no specific design was used [28,29,31,32,35,36,40,42,43,45,46]. Dose escalation was performed in nine of these studies by increasing the number of fractions (53%) [31,34,36,38,39,41,43,46,47], and in five studies by increasing the dose per fraction (29%) [28,30,33,35,37]. In two studies, both the number of fractions and the dose per fraction were increased (12%) [29,32,40].…”

“…Late toxicity in almost all studies was defined as occurring 3 months or more after treatment (n = 14, 82%). The MTD was defined in nine (53%) studies [30,33-35,37-39, 41,43], and the DLT in ten (59%) [29,30,[33][34][35][37][38][39]41,43]. In only two studies (12%) late toxicity was used to define the MTD [39,45].…”

Recent Advances in Combined Modality Treatment for Locally Advanced Pancreatic Cancer

“…The median survival was 12.2 months and the 1-year survival rate was 55.0%. The authors concluded that the toxicity was tolerable up to a dose of 64.8 Gy and conducted a phase II study testing this regimen [27].…”