Preoperative radiation and irinotecan in combination with 5 fluorouracil (5-FU) and low-dose leucovorin (LV) in locally advanced rectal cancer (LARC)

Abstract

3576 Background: The aim of this study is to determine maximum tolerated dose (MTD) and recommended scheduled dose of irinotecan on days 1–5 and 29–33, in combination with LV 20mg/m2 and 5-FU 350mg/m2 (1 hour infusion) synchronously with pre-operative radiotherapy (RT) days 1–5, 29–33. Methods: Toxicity and effectiveness of the schedule is studied in LARC. Escalating dose levels of 2 mg/m2 irinotecan were used starting at 6 mg/m2. Preoperative pelvic RT comprises 45Gy in 25 fractions (1.8Gy per fraction), and is CT planned and delivered with patients prone using a 3/4 field technique. Surgery is performed 6–8 weeks later. Results: The MTD was determined when dose-limiting toxicity (DLT) of grade 3 diarrhoea was experienced in Cohort 8 (20 mg/m2 x 5) in 3/4 patients. All 4 patients at this dose level completed treatment as per protocol. The median age is 62 (range 44–73). A further 14 patients will be treated at 18mg/m2. 41/43 patients completed RT without interruption and 40/43 without chemotherapy dose reduction. 5 patients did not proceed to surgery due to a persistant inoperable mass (3) and presence of metastatic disease(2). To date 34 patients have had surgical resection. Histopathology demonstrated pCR 8/34 (24%), Tmic 3/33 (9%), pCR+ Tmic 11/33 (33%), pT0–2 14/34 (41%) and histologically confirmed clear CRM in 29/34 (85%). Conclusions: DLT with irinotecan given days 1–5 and 29–33 when added to the described 5FULV and 45Gy radiation pre-operatively is 20mg/m2. The toxicity and compliance at 18mg/m2 may be suitable for testing in future phase II studies. This study has successfully integrated irinotecan into the EORTC 22921 CRT trial regimen. Acceptable low levels of acute toxicity were seen in the first seven cohorts and the high histologically confirmed CRM -ve rate is encouraging. Author Disclosure Employment or Leadership Consultant or Advisory Role Stock Ownership Honoraria Research Funding Expert Testimony Other Remuneration Aventis Aventis Aventis