Thymidine phosphorylase expression is associated with response to capecitabine plus irinotecan in patients with metastatic colorectal cancer.
OBJECTIVE
To evaluate the clinical activity and toxicity of capecitabine plus irinotecan as first-line therapy for patients with metastatic colorectal cancer (mCRC), and to describe the association of expression of thymidine phosphorylase (TP), thymidylate synthase (TS), and dihydropyrimidine dehydrogenase (DPD) with antitumor activity.


METHODS
Patients with previously untreated mCRC received irinotecan days 1 and 8 intravenously, and capecitabine days 2 to 15 orally in 21-day cycles. Doses were irinotecan 125 mg/m2 and capecitabine 1,000 mg/m2 bid (n = 15; cohort 1), or irinotecan 100 mg/m2 and capecitabine 900 mg/m2 bid (n = 52; cohort 2). Tissues from primary and metastatic sites were assessed for TP, TS, and DPD gene and protein expression.


RESULTS
An unacceptable level of GI toxicity in the first 15 patients led to a protocol modification in starting doses. The response rate was 45% (30 of 67 patients). Overall survival was associated with TP expression assessed by immunohistochemistry in both primary tumors (P = .045) and metastases (P = .001). Objective tumor response was associated with TP expression in primary tumors (odds ratio, 4.77; 95% CI, 1.25 to 18.18), with a similar trend in metastases (odds ratio, 8.67; 95% CI, 0.95 to 79.1). TP gene expression in primary tumors was also associated with response.


CONCLUSIONS
These data indicate that capecitabine plus irinotecan is an active regimen against mCRC. The biomarker analysis (including metastatic tissue) was feasible in a multicenter setting, and provides preliminary evidence that TP expression may be a predictive marker for response.
Meropol
Neal J
NJ
Fox Chase Cancer Center, Philadelphia, PA 19111, USA. Neal.Meropol@fccc.edu
Gold
Philip J
PJ
Diasio
Robert B
RB
Andria
Michael
M
Dhami
Mandeep
M
Godfrey
Thomas
T
Kovatich
Albert J
AJ
Lund
Kirk A
KA
Mitchell
Edith
E
Schwarting
Roland
R
D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000009:adverse effects / Q000627:therapeutic use*; D014408:Biomarkers, Tumor / Q000378:metabolism*; D002166:Camptothecin / Q000008:administration & dosage / Q000031:analogs & derivatives; D000069287:Capecitabine; D015179:Colorectal Neoplasms / Q000188:drug therapy* / Q000201:enzymology* / Q000473:pathology; D003841:Deoxycytidine / Q000008:administration & dosage / Q000031:analogs & derivatives; D042943:Dihydrouracil Dehydrogenase (NADP) / Q000378:metabolism; D018572:Disease-Free Survival; D005240:Feasibility Studies; D005260:Female; D005472:Fluorouracil / Q000008:administration & dosage; D015971:Gene Expression Regulation, Enzymologic; D015972:Gene Expression Regulation, Neoplastic; D006801:Humans; D007150:Immunohistochemistry; D000077146:Irinotecan; D016015:Logistic Models; D008297:Male; D008875:Middle Aged; D009367:Neoplasm Staging; D011237:Predictive Value of Tests; D016016:Proportional Hazards Models; D020133:Reverse Transcriptase Polymerase Chain Reaction; D016019:Survival Analysis; D013939:Thymidine Phosphorylase / Q000378:metabolism*; D013940:Thymidylate Synthase / Q000378:metabolism; D016896:Treatment Outcome
D014408:Biomarkers, Tumor; D003841:Deoxycytidine; D000069287:Capecitabine; D000077146:Irinotecan; D042943:Dihydrouracil Dehydrogenase (NADP); D013940:Thymidylate Synthase; D013939:Thymidine Phosphorylase; D005472:Fluorouracil; D002166:Camptothecin