Effect of oxaliplatin-containing neoadjuvant chemotherapy on tumor volume in locally advanced rectal cancer and sensitivity of surviving tumor cells to radiotherapy.

Abstract

3547 Background: The use of oxaliplatin (OXA) is well established in adjuvant and palliative treatment of colorectal cancer (CRC), but its role in neoadjuvant treatment of locally advanced rectal cancer (LARC) is controversial. Data from the ACCORD 12/0405, STAR-01 and NSABBP R-04 trials suggest no additional clinical benefit of adding OXA to fluoropyrimidine-based preoperative chemoradiotherapy (CRT) in LARC. However, the possibility of reducing risk of systemic recurrence and the use of OXA-containing neoadjuvant chemotherapy (NACT) in liver metastasis warrant further clarification of the role of OXA in neoadjuvant treatment of LARC. Methods: We report results from a non-randomized phase II trial of neoadjuvant treatment of 72 LARC patients, receiving two courses of the Nordic FLOX regimen prior to CRT (25 x 2 Gy; weekly OXA; daily capecitabine). Tumor volumes were calculated from MRI scans taken before and after NACT and 4 weeks after CRT completion. Using OXA resistant human CRC cell lines, the impact of previous OXA exposure on radiosensitivity (1-5 Gy) was examined. Results: Median baseline tumor volume was 16.6 cm3 (1.1-293 cm3). All tumors, except one, responded to NACT, leaving a median tumor volume of 5.3 cm3 (0.2-157 cm3), representing a median volume reduction of 63%. In all but three patients, additional tumor volume reduction was observed following subsequent CRT (median tumor volume 5.3 cm3; 0.02-119 cm3; median volume reduction of 68%). Exposure of cell lines to increasing concentrations of OXA resulted in resistance towards the drug. OXA resistant models exhibited increased radiosensitivity compared to OXA sensitive counterparts. Conclusions: OXA-containing NACT led to substantial tumor volume reduction. Additional tumor volume reduction was observed in almost all cases, suggesting that pretreatment with OXA-containing NACT did not preclude tumor response to CRT. Results from experimental models rather suggest that pretreatment with OXA might enhance radiosensitivity of surviving OXA resistant cells. Taken together, our results are in favor of continued exploration of OXA-containing NACT in LARC. Clinical trial information: NCT00278694.