XELOX Prior to Chemoradiation and Total Mesorectal Excision Produces Almost Universal Tumor Regression

LONDON-Capecitabine (Xeloda) and oxaliplatin(Drug information on oxaliplatin) (Eloxatin), in combination (XELOX), prior to synchronous chemoradiation and total mesorectal excision (TME), produces almost universal tumor regression, rapid symptomatic response, and allows R0 resection in patients with poor risk/locally advanced rectal cancer. These results were reported by Ian Chau, MRCP, of the Royal Marsden Hospital, London and Surrey, United Kingdom (ASCO abstract 1087). "After neoadjuvant treatment with capecitabine(Drug information on capecitabine)/oxaliplatin followed by chemoradiation, tumor response was achieved in all patients, "Dr. Chau reported. "All patients then had R0 resection with tumor regression away from the circumferential resection margin (CRM), except for one inoperable patient." TME has been adopted as the standard technique in rectal cancer by surgeons in several European countries. CRM involvement, defined as tumor observed in less than or equal to 1 mm from the resection margin, is an important prognostic factor resulting in higher rates of local recurrence and poorer survival in rectal cancer surgery. High-resolution, thin-slice magnetic resonance imaging (MRI) has been shown to accurately stage rectal cancer and predict potential CRM. MRI can provide an objective method to define poor risk rectal cancer, identify patients most likely to benefit from a preoperative treatment strategy, and assess primary tumor response. Poor Risk Factors In this study, patients were judged to have poor risk rectal cancer if there were: tumors within 1 mm of mesorectal fascia, T3 tumors at/below levators, tumors extending greater than or equal to 5 mm into perirectal fat, T4 tumors, and T1-4N2 tumors. All patients on the study had tumor threatening CRM. "In our previous study, neoadjuvant protracted venous infusion fluorouracil(Drug information on fluorouracil) (5-FU) and mitomycin(Drug information on mitomycin) (Mutamycin) as a prelude to synchronous chemoradiation was administered with negligible risk of progression in the primary tumor and evolution of metastatic disease. This approach produced considerable symptomatic response with associated tumor regression as neoadjuvant treatment," Dr. Chau said. "Oxaliplatin and capecitabine has been shown to have promising activity as first-line treatment in metastatic colorectal cancer and may provide better efficacy than 5-FU and mitomycin as a neoadjuvant treatment." Treatment and Response Patients received 12 weeks of neoadjuvant capecitabine 1,000 mg/m² bid po for 14 days and oxaliplatin 130 mg/m² IV every 3 weeks. Starting on week 13, capecitabine was continued at 825 mg/m² bid continuously with concomitant radiotherapy 45Gy in 25 fractions followed by a 5.4- 9 Gy boost to the primary tumor. TME was planned 6 weeks after chemoradiation. Postoperatively, patients received 12 weeks of capecitabine at 1,250 mg/m² bid. MRI was repeated after chemotherapy and chemoradiation. From November 2001 to November 2002, 22 patients were recruited. Patients had a median age of 62 years (range 38- 80), and a Eastern Cooperative Oncology Group (ECOG) performance status of 0 (27.3%) or 1 (72.7%). Following neoadjuvant capecitabine/ oxaliplatin, the objective response rate was 94.7%. In addition, 93% of patients had symptomatic responses in a median of 23 days including reduced rectal bleeding (100%), improvement in diarrhea/ constipation (75%), diminished pelvic pain/tenesmus (93%), and weight gain/ stabilization (100%). Following chemoradiation, tumor response was achieved in all patients (see Table 1). Pathologic complete response was found in five patients (28%), and in an additional nine patients (47%), only microscopic tumor foci were found in surgical specimens. Thirteen patients (68.4%) had downstaging of their primary tumor either in T (n = 3) or N (n = 3) or both (n = 7) staging. "No patients developed progressive disease after neoadjuvant chemotherapy or chemoradiation," Dr. Chau said. One patient died from myocardial infarction and one from pulmonary embolism. No grade 4 toxicity occurred during chemotherapy or chemoradiation. Significance of Findings In discussing the significance of these findings, Dr. Chau noted, "Despite the most optimal surgical approach in the form of total mesorectal excision and highquality preoperative radiotherapy, recent studies have reported an unacceptably high-15% to 20% rate of R1 resection- microscopic incomplete resection at the margin. Clearly, a more effective preoperative treatment strategy needs to be implemented in order to improve both local control and survival. Our study reports, for the first time, the implementation of a preoperative treatment strategy based on imaging assessment on the resection margin. Moreover, all patients with threatened and involved circumferential resection margin based on preoperative MRI were rendered margin negative on histology after treatment."