Preoperative chemoradiotherapy using concurrent capecitabine and irinotecan in magnetic resonance imaging-defined locally advanced rectal cancer: impact on long-term clinical outcomes.
OBJECTIVE
To assess long-term clinical outcomes of preoperative chemoradiotherapy of magnetic resonance imaging (MRI)-defined locally advanced rectal adenocarcinoma using concurrent irinotecan and capecitabine.


METHODS
One hundred ten patients without distant metastases entered this phase II trial North West/North Wales Clinical Oncology Group (NWCOG) -2 after MRI demonstration of tumor threatening (≤ 2 mm) or involving mesorectal fascia. Pelvic radiotherapy was given to 45 Gy in 25 fractions over 5 weeks with concurrent oral capecitabine at 650 mg/m(2) twice per day continuously days 1 through 35 and intravenous irinotecan at 60 mg/m(2) once weekly weeks 1 to 4. One hundred seven patients subsequently underwent surgical resection.


RESULTS
Comparing prechemoradiotherapy MRI scans with histology of the resected specimen, 72 patients (67%) had their initial MRI T stage downstaged and 64 patients (80%) had their N stage downstaged. Twenty-four patients (22%) demonstrated a pathologic complete response (ypCR) and 98 patients (92%) demonstrated a negative circumferential resection margin (> 1 mm). Three-year local recurrence-free survival was 96.9%, metastasis-free survival (MFS) was 71.1%, disease-free survival was (DFS) 63.5%, and overall survival (OS) was 88.2%. By univariate analysis, lower histologic stage was significantly associated with superior MFS, DFS, and OS, whether expressed as ypT0-2 versus ypT3-4, ypN0 versus ypN1-2, or ypCR/microfoci (near-ypCR) versus other patients. By multivariate analysis both ypN stage (P = .048) and ypCR/microfoci/others (P = .013) remained significant predictors of DFS but only ypCR/microfoci/others for OS (P = .005) with no difference in outcome between ypCR compared to microfoci.


CONCLUSIONS
This regimen demonstrates high response rates and promising long-term survival. Downstaging to ypCR/microfoci may be a useful short-term surrogate for long-term survival but needs validation in large phase III trials powered for survival outcomes.
Department of Clinical Oncology, North Wales Cancer Treatment Centre, Rhyl, LL18 5UJ United Kingdom. simon.gollins@wales.nhs.uk
Simon
S
Gollins
Arthur
A
Sun Myint
Brian
B
Haylock
Marcus
M
Wise
Mark
M
Saunders
Rekha
R
Neupane
Sharadah
S
Essapen
Les
L
Samuel
Mark
M
Dougal
Arwel
A
Lloyd
Jackie
J
Morris
Clare
C
Topham
Shabbir
S
Susnerwala
D000230:Adenocarcinoma / Q000188:drug therapy / Q000401:mortality / Q000532:radiotherapy / Q000556:secondary / Q000601:surgery / Q000628:therapy*; D000328:Adult; D000368:Aged; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000008:administration & dosage* / Q000009:adverse effects; D002166:Camptothecin / Q000008:administration & dosage / Q000009:adverse effects / Q000031:analogs & derivatives; D017024:Chemotherapy, Adjuvant; D016009:Chi-Square Distribution; D003841:Deoxycytidine / Q000008:administration & dosage / Q000009:adverse effects / Q000031:analogs & derivatives; D018572:Disease-Free Survival; D005260:Female; D005472:Fluorouracil / Q000008:administration & dosage / Q000009:adverse effects / Q000031:analogs & derivatives; D006801:Humans; D053208:Kaplan-Meier Estimate; D008279:Magnetic Resonance Imaging; D008297:Male; D008875:Middle Aged; D020360:Neoadjuvant Therapy; D009361:Neoplasm Invasiveness; D009364:Neoplasm Recurrence, Local; D016016:Proportional Hazards Models; D011829:Radiation Dosage; D018714:Radiotherapy, Adjuvant; D012004:Rectal Neoplasms / Q000188:drug therapy / Q000401:mortality / Q000473:pathology / Q000532:radiotherapy / Q000601:surgery / Q000628:therapy*; D018570:Risk Assessment; D012307:Risk Factors; D013997:Time Factors; D016896:Treatment Outcome; D006113:United Kingdom
D003841:Deoxycytidine; D005472:Fluorouracil; D002166:Camptothecin