Phase I radiation dose-escalation trial of intensity-modulated radiotherapy (IMRT) with concurrent fixed dose-rate gemcitabine (FDR-G) for unresectable pancreatic cancer

Abstract

4602 Background: Current treatments of non-metastatic, unresectable pancreatic cancer result in poor survival and nearly uniform local persistence of disease. We hypothesized that intensification of local therapy would result in better local control and improve survival. The primary objective of this trial was to determine maximum tolerated radiation dose delivered with IMRT and concurrent FDR-G. Methods: Eligibility included tissue diagnosis of adenocarcinoma, unresectable by radiological criteria, Zubrod performance of 0–2, ANC of ≥ 1500/mm3, platelets ≥ 100,000/mm3, creatinine < 2 mg/dl, bilirubin < 3 mg/dl, ALT and AST ≤ 2.5 x ULN, and informed consent. Patients (pts) received FDR-G (1000 mg/m2, 100-minute infusion) on days -22 and -15. IMRT started day 1 (radiation dose levels [L2-L6] 50, 52.5, 55, 57.5 and 60 Gy, all in 25 fractions) with concurrent FDR-G on days 1, 8, 22, and 29. GTV was defined on pancreas protocol CT in the treatment position. PTV was GTV plus 1 cm expansion. Active Breathing Control was used to reduce breathing motion, except in 3 pts, in whom 4D CT was used to generate an ITV. Post IMRT, up to 4 cycles of FDR-G were given. DLT was defined as GI toxicity ≥ G3, neutropenic fever, or deterioration in Zubrod to ≥3 between day 1 and 126. IMRT dose level was assigned using the Time-to-Event Continual Reassessment Method. With a sample size of 50, the design allows concurrent assessment of efficacy. Results: From 8/06, 27 pts have been accrued. DLTs have been observed in 6 (G3 anorexia, nausea vomiting, and/or dehydration [5 pts]; duodenal bleed [1 pt]). The posterior estimates of probability of DLT are 0.17, 0.21, 0.24, 0.27, and 0.28 for L2 to L6, respectively. The response rate is 52.4% (95% CI 29.8% to 74.3%). The median overall survival and progression-free survival are 23.1 months (95% CI 9–23.1) and 7.2 months (95% CI 5.0–8.0), respectively. Only 1 patient (4%) progressed locally. Two patients have undergone resection (R0), and demonstrated near- and complete pathological responses. Conclusions: High dose radiotherapy and concurrent FDR-G, utilizing the techniques above, is well tolerated and results in highly encouraging response rates, local control rates and overall survival. No significant financial relationships to disclose.