HOLLYWOOD, FloridaBritish 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
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.
The treatment regimen included 12 weeks of neoadjuvant
capecitabine (Xeloda), 1,000 mg/m2 twice daily orally for 14 days
every 3 weeks, and 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.
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
"Capecitabine and oxaliplatin prior to synchronous
chemoradiotherapy and TME results in substantial tumor regression and
achievement of R0 resection," Dr. Chau concluded.