A multicenter phase II study of "adjuvant" irinotecan following resection of colorectal hepatic metastases.
OBJECTIVE
This study evaluates the efficacy and toxicity of single-agent irinotecan following hepatectomy for metachronous colorectal metastases, and examines the predictive value of p27 and p53 expression and of microsatellite instability (MSI) status.


METHODS
Twenty-nine patients, previously treated with 5-fluorouracil, with operable hepatic colorectal metastases underwent hepatectomy and received adjuvant irinotecan (thrice weekly) for 6 planned cycles. Metastases were examined for p53 and p27 expression by immunohistochemistry and for MSI using mono- and dinucleotide markers.


RESULTS
The starting dose of irinotecan was 350 mg/m2 (in 3 patients), 300 mg/m2 (n = 14), and 250 mg/m2 (n = 12). Four patients failed to complete 6 cycles (2 progressive disease and 2 toxicity). Grade > or =3 toxicity was experienced in 8% of cycles (13 of 165). The estimated median relapse-free survival (RFS) was 45.2 months. RFS at 18 months was estimated to be 59% (95% confidence interval [CI], 43-80), 2-year overall survival (OS) was 85% (95% CI, 72-99.8), and the median follow-up was 27.9 months. Six patients (21%) have died; median OS has not been reached. In univariate analyses, p27 and MSI status were not predictive for RFS while p53 approached statistical significance (P = 0.051). Duration of chemotherapy was the only significant predictive factor (P = 0.006).


CONCLUSIONS
The tolerability of this regimen after major liver resection supports further evaluation of irinotecan-based adjuvant chemotherapy in this group of patients.
Mackay
Helen J
HJ
Princess Margaret Hospital, Toronto, Canada.
Billingsley
Kevin
K
Gallinger
Steven
S
Berry
Scott
S
Smith
Andrew
A
Yeung
Raymond
R
Pond
Gregory R
GR
Croitoru
Marina
M
Swanson
Paul E
PE
Krishnamurthi
Smitha
S
Siu
Lillian L
LL
D000230:Adenocarcinoma / Q000737:chemistry / Q000188:drug therapy / Q000556:secondary* / Q000601:surgery; D000328:Adult; D000368:Aged; D000964:Antimetabolites, Antineoplastic / Q000627:therapeutic use; D000972:Antineoplastic Agents, Phytogenic / Q000009:adverse effects / Q000627:therapeutic use*; D014408:Biomarkers, Tumor / Q000032:analysis; D002166:Camptothecin / Q000009:adverse effects / Q000031:analogs & derivatives* / Q000627:therapeutic use; D017024:Chemotherapy, Adjuvant; D015179:Colorectal Neoplasms / Q000473:pathology*; D003131:Combined Modality Therapy; D050760:Cyclin-Dependent Kinase Inhibitor p27 / Q000032:analysis; D004273:DNA, Neoplasm / Q000032:analysis; D018572:Disease-Free Survival; D005260:Female; D005472:Fluorouracil / Q000627:therapeutic use; D005767:Gastrointestinal Diseases / Q000139:chemically induced; D006498:Hepatectomy / Q000379:methods*; D006801:Humans; D000077146:Irinotecan; D015993:Life Tables; D008113:Liver Neoplasms / Q000737:chemistry / Q000188:drug therapy / Q000556:secondary* / Q000601:surgery; D008297:Male; D018895:Microsatellite Repeats; D008875:Middle Aged; D009363:Neoplasm Proteins / Q000032:analysis; D009503:Neutropenia / Q000139:chemically induced; D016019:Survival Analysis; D016896:Treatment Outcome; D016159:Tumor Suppressor Protein p53 / Q000032:analysis
D000964:Antimetabolites, Antineoplastic; D000972:Antineoplastic Agents, Phytogenic; D014408:Biomarkers, Tumor; D004273:DNA, Neoplasm; D009363:Neoplasm Proteins; D016159:Tumor Suppressor Protein p53; D050760:Cyclin-Dependent Kinase Inhibitor p27; D000077146:Irinotecan; D005472:Fluorouracil; D002166:Camptothecin