HOLLYWOOD, Florida—British researchers report that a three-step strategy of neoadjuvant chemotherapy, synchronous chemoradiation, then total mesorectal excision (TME) for patients with MRI-defined poor-risk rectal cancer produced objective response rates (RRs) of 88% after chemotherapy and 97% after chemoradiation, and permitted R0 in almost all cases, with a 24% pathologic complete response (pCR) rate. Ian Chau, MD, Department of Medicine, Royal Marsden Hospital, London, reported the study results at the 2005 Gastrointestinal Cancers Symposium (abstract 163).
"TME has been adopted as the standard rectal cancer surgical technique in several European countries. Circumferential resection margin (CRM) involvement, defined as tumor observed 1 mm or less from the resection margin, results in higher rates of local recurrence and poorer survival," Dr. Chau said.
High-resolution thin-slice (3 mm) MRI can accurately stage rectal cancer and predict potential CRM (see Figure). "It provides 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," he said.
The British study included 77 patients with newly diagnosed MRI-defined, poor-risk rectal cancer. Criteria for poor risk included tumors within 1 mm of the mesorectal fascia, which threaten or involve the CRM; T3 tumors at or below the levators; T3c or T3d tumors at any other level, ie, tumors extending more than 5 mm into perirectal fat; T4 tumors; or any T stage tumor with four or more involved lymph nodes.
Of the 77 patients in this study, 52% had the CRM threatened or involved, 42% had low-lying tumors, some of which were considered to be threatening the CRM, 42% had T3c or T3d tumors, 23% had T4 tumors, and 35% had T1-4 N2 tumors.
Treatment Regimen
The treatment regimen included 12 weeks of neoadjuvant capecitabine(Drug information on capecitabine) (Xeloda), 1,000 mg/m2 twice daily orally for 14 days every 3 weeks, and oxaliplatin(Drug information on oxaliplatin) (Eloxatin), 130 mg/m2 IV every 3 weeks. Beginning at week 13, capecitabine, at 825 mg/m2 twice daily, was continued with concomitant radiotherapy, 45 Gy in 25 fractions followed by a 9-Gy boost to the primary tumor.
TME was planned for 6 weeks after completion of chemoradiation, and patients received 12 weeks of postoperative capecitabine (1,250 mg/m2 twice daily for 14 days every 3 weeks). MRI was repeated after chemotherapy and after chemoradiotherapy.
The primary study endpoint was pCR. Secondary endpoints included radiologic response rate and pathologic downstaging. Dr. Chau reported data for 68 evaluable patients.
Study Results
After chemotherapy, the overall response rate (complete and partial responses plus stable disease) by MRI was 88.2%, which increased to 97% after chemoradiation (14 complete responses, 52 partial responses, and 2 patients with stable disease).
Tumor responses were accompanied by rapid symptomatic responses, Dr. Chau said. This included complete resolution of pelvic pain in 34 of 44 patients, constipation/diarrhea in 45 of 50 patients, rectal bleeding in 27 of 27 patients, and weight loss in 13 of 14 patients.
At the time of this report, 62 patients had proceeded to resection. Compared with baseline MRI, 49 patients (79%) had primary tumors downstaged (13 patients in tumor only, 13 in nodes only, and 23 in both tumor and nodes). All but one patient (98%) who had TME had an R0 resection with clear CRM. There were 15 pCRs (24.2%), and only microscopic tumor foci were found in a further 26 patients (42%).
Cardiac and thromboembolic toxicities during neoadjuvant chemotherapy included one fatal and one nonfatal myocardial infarction, two nonfatal arrhythmias, two nonfatal anginas, one fatal cardiac failure, one nonfatal stroke, and one fatal pulmonary embolism. Dr. Chau said that due to these toxicities, the protocol was amended in January 2004 to exclude patients with active cardiac disease or myocardial infarction within the last 12 months.
Dr. Chau said that 1-year failure-free survival and overall survival rates in all patients at a median follow-up of 15.9 months are 86% and 94.8%, respectively.
"Capecitabine and oxaliplatin prior to synchronous chemoradiotherapy and TME results in substantial tumor regression and achievement of R0 resection," Dr. Chau concluded.
