Neoadjuvant therapy for rectal cancer Mature results from NSABP protocol R-04

SUMMARY: The American Cancer Society's estimates 40,000 new cases of rectal cancer in the United States for 2014. Rectal cancer diagnosed at an early stage such as Stage II (T3-T4, N0) or Stage III (Node positive disease without distant metastases) is potentially curable with a combination of neoadjuvant (preoperative) chemoradiation, surgery and postoperative chemotherapy. Unlike colon cancer, the risk of locoregional recurrence is high in rectal cancer due to its close proximity to the surrounding pelvic organs and difficulty in obtaining a clear surgical margins. Further, there is no serosal tissue surrounding the rectum. For all these reasons, preoperative Radiation Therapy (RT) with concurrent fluoropyrimidine based chemotherapy as a radiosensitizer followed by postoperative chemotherapy (total of 6 months of perioperative chemotherapy) has been the standard intervention. Infusional 5 Fluorouracil (5-FU) is often incorporated with concurrent radiation. This however is cumbersome and inconvenient for the patients. The NSABP protocol R-04 trial is a four arm phase III trial in which 1608 patients with clinical stage II or III rectal cancer undergoing preoperative RT were randomly assigned to one of four chemotherapy regimens – Continuous Infusion (CI) 5-FU 225mg/m2 over 24 hours, 5 days a week x 5 weeks (N=477), CI 5-FU with IV Oxaliplatin (ELOXATIN®) 50mg/m2 /wk x 5 weeks (N=329), Capecitabine (XELODA®) 825 mg/m2 PO BID 5 days/wk x 5 weeks (N=472) or XELODA® with ELOXATIN®, x 5 weeks (N=330). Radiation therapy consisted of 4,500cGy in 25 fractions over 5 wks plus a boost. The primary goals of this study were to compare preoperative XELODA® and CI 5-FU given along with concurrent pelvic RT and also determine whether ELOXATIN® would be of additional benefit. The primary endpoint of local-regional tumor control included locoregional tumor recurrence, less than complete surgical resection and no surgery. When combined with RT, this study showed no significant differences in local-regional tumor control, Disease Free Survival or Overall Survival between infusional 5-FU and XELODA® given alone or in combination with ELOXATIN®. The addition of ELOXATIN® was however associated with significantly more grade 3-4 diarrhea (P<0.0001). The authors concluded that outcomes and toxicities are similar with CI 5-FU or oral XELODA® when combined with RT. The addition of ELOXATIN® did not improve outcomes but resulted in significant toxicity. Oral XELODA® therefore obviates the need for central venous access and ambulatory infusion pumps and makes it more convenient for the patients without compromising efficacy. Allegra CJ, Yothers G, O'Connell MJ, et al. J Clin Oncol 32, 2014 (suppl 3; abstr 390)