While the early analysis of the trial showed a higher pathological CR rate, reduction in positive circumferential margins and increased downstaging at surgery in the CMT arm, further analysis revealed that among the two groups, there were no significant benefits in terms of sphincter preservation, OS, DFS, LC, or rate of late toxicity (41). In addition, the preoperative CMT arm had a significantly higher rate of acute toxicity (18.2% versus

3.2%; p<0.001). Sequencing of adjuvant therapy Preoperative Inhibitors,research,lifescience,medical radiation therapy (with or without systemic therapy) offers certain theoretical advantages that postoperative radiation therapy or CMT does not. In lesions of the distal rectum, preoperative therapy may allow for sphincter preservation. And for locally advanced (T4) lesions that may be otherwise unresectable, preoperative therapy may allow for the possibility of tumor downstaging and resection. Preoperative radiation therapy also Inhibitors,research,lifescience,medical allows for better definition of gross tumor volumes during radiation planning and may allow for smaller treatment portals. With preoperative radiation therapy, the perineum is often avoided from treatment and potentially less small bowel is irradiated since it is more mobile, and the anastomosis is not in the treatment field. In addition radiation before surgery can potentially sterilize

the Inhibitors,research,lifescience,medical Inhibitors,research,lifescience,medical operative field, thus decreasing the risk of tumor cells spilling during surgery. Irradiating preoperatively has increased radiosensitivity compared to postoperative therapy due to preserved vasculature thus allowing for better tumor oxygenation (25). Therefore,

preoperative radiation should theoretically improve the therapeutic ratio over postoperative therapy (25)-(27). Three large randomized trials were designed to compare preoperative and postoperative CMT in stage II/III rectal cancer. All three used conventional doses of daily radiation and concurrent 5-FU-based chemotherapy Inhibitors,research,lifescience,medical with pretreatment assessment of the planned surgical procedure. Two of the trials (NSABP R-03 and Intergroup 0147) were closed early due to low accrual and also thus the data from these INCB024360 order studies is limited. Preliminary results of the NSABP R-03 trial demonstrated that 23% of patients treated neoadjuvantly had a clinical CR and a larger proportion of neoadjuvant patients underwent sphincter sparing operations compared to patients treated postoperatively (42). The third study, the German Rectal Cancer Trial CAO/ARO/AIO-94, reached targeted accrual (43). In this study, stage II/III patients in the neoadjuvant arm received 50.4 Gy in 28 fractions while receiving 5-FU as 120-hour continuous venous infusion (CVI) of 1000 mg/m2/day during the 1st and 5th week of treatment. TME was then scheduled 4-6 weeks after completion of preoperative therapy.