Thymidine phosphorylase expression is associated with response to capecitabine plus irinotecan in patients with metastatic colorectal cancer

Neal J. Meropol, Philip J. Gold, Robert B Diasio, Michael Andria, Mandeep Dhami, Thomas Godfrey, Albert J. Kovatich, Kirk A. Lund, Edith Mitchell, Roland Schwarting

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Abstract

Purpose: 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. Patients and 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. Conclusion: 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.

Original languageEnglish (US)
Pages (from-to)4069-4077
Number of pages9
JournalJournal of Clinical Oncology
Volume24
Issue number25
DOIs
StatePublished - Sep 1 2006
Externally publishedYes

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irinotecan
Thymidine Phosphorylase
Colorectal Neoplasms
Dihydrouracil Dehydrogenase (NADP)
Thymidylate Synthase
Neoplasms
Odds Ratio
Neoplasm Metastasis
Gene Expression
Capecitabine
Biomarkers
Immunohistochemistry

ASJC Scopus subject areas

  • Cancer Research
  • Oncology

Cite this

Thymidine phosphorylase expression is associated with response to capecitabine plus irinotecan in patients with metastatic colorectal cancer. / Meropol, Neal J.; Gold, Philip J.; Diasio, Robert B; Andria, Michael; Dhami, Mandeep; Godfrey, Thomas; Kovatich, Albert J.; Lund, Kirk A.; Mitchell, Edith; Schwarting, Roland.

In: Journal of Clinical Oncology, Vol. 24, No. 25, 01.09.2006, p. 4069-4077.

Research output: Contribution to journalArticle

Meropol, NJ, Gold, PJ, Diasio, RB, Andria, M, Dhami, M, Godfrey, T, Kovatich, AJ, Lund, KA, Mitchell, E & Schwarting, R 2006, 'Thymidine phosphorylase expression is associated with response to capecitabine plus irinotecan in patients with metastatic colorectal cancer', Journal of Clinical Oncology, vol. 24, no. 25, pp. 4069-4077. https://doi.org/10.1200/JCO.2005.05.2084
Meropol, Neal J. ; Gold, Philip J. ; Diasio, Robert B ; Andria, Michael ; Dhami, Mandeep ; Godfrey, Thomas ; Kovatich, Albert J. ; Lund, Kirk A. ; Mitchell, Edith ; Schwarting, Roland. / Thymidine phosphorylase expression is associated with response to capecitabine plus irinotecan in patients with metastatic colorectal cancer. In: Journal of Clinical Oncology. 2006 ; Vol. 24, No. 25. pp. 4069-4077.
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abstract = "Purpose: 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. Patients and 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. Conclusion: 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.",
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T1 - Thymidine phosphorylase expression is associated with response to capecitabine plus irinotecan in patients with metastatic colorectal cancer

AU - Meropol, Neal J.

AU - Gold, Philip J.

AU - Diasio, Robert B

AU - Andria, Michael

AU - Dhami, Mandeep

AU - Godfrey, Thomas

AU - Kovatich, Albert J.

AU - Lund, Kirk A.

AU - Mitchell, Edith

AU - Schwarting, Roland

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Y1 - 2006/9/1

N2 - Purpose: 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. Patients and 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. Conclusion: 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.

AB - Purpose: 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. Patients and 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. Conclusion: 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.

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