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In Reply

Department of Medical Oncology, Gastrointestinal Cancer Center, Dana-Farber Cancer Institute, Boston, MA

John Marshall

Division of Hematology/Oncology, Georgetown University Lombardi Cancer Center, Washington, DC

José Barrueco

Pfizer Global Pharmaceuticals, New York, NY

As Drs Punt and Koopman discuss, both the Bolus, Infusional, or Capecitabine with Camptosar-Celecoxib (BICC-C) trial¹ and European Organisation for Research and Treatment of Cancer (EORTC) 40015² trials reported greater toxicity for irinotecan plus oral capecitabine (CapeIRI) among patients with previously untreated metastatic colorectal cancer. Phase II studies of that schedule of oral capecitabine with irinotecan had suggested acceptable response rates and tolerability.^3-6 However, in the BICC-C trial, CapeIRI was less effective and more toxic than irinotecan plus infusional fluorouracil (FU) and leucovorin (LV; FOLFIRI). Although we considered the possibility that the inferior efficacy results for CapeIRI may have reflected early treatment discontinuation due to toxicity, the superior progression-free survival for FOLFIRI (v CapeIRI) remained unchanged after excluding those patients who discontinued chemotherapy early due to unacceptable toxicity.

As we previously reported,⁷ chemotherapy toxicities in BICC-C did not differ among patients randomly assigned to receive celecoxib or placebo; as such, the increased toxicity associated with CapeIRI could not be explained by use or avoidance of concurrent celecoxib. In addition, we did not observe any material differences in baseline characteristics among patients randomly assigned to receive CapeIRI when compared with FOLFIRI or irinotecan plus bolus FU/LV (mIFL). The median number of measurable target metastatic lesions was 3.2 for FOLFIRI, 3.1 for mIFL, and 3.1 for CapeIRI. Moreover, differences in dose intensity did not seem to explain the greater toxicity or inferior efficacy associated with CapeIRI. Among patients randomly assigned to receive CapeIRI, the mean relative dose intensity was 91.9% for capecitabine and 93.8% for irinotecan across all cycles of therapy. For comparison, the mean relative dose intensity for irinotecan was 93.9% for FOLFIRI and 94.9% for mIFL.

When compared with the Combination Chemotherapy with Capecitabine, Irinotecan, and Oxaliplatin in Advanced Colorectal Cancer study,⁸ the greater toxicity for CapeIRI in BICC-C may have reflected the greater propensity for capecitabine-related toxicity among US and other non-European patients relative to European populations.⁹ However, the greater toxicity for CapeIRI in EORTC 40015 suggests that CapeIRI may not be well tolerated even among selected European populations.

Conceivably, alternative doses and schedules of the combination of capecitabine and irinotecan could provide a superior efficacy and tolerability profile than the regimen utilized in BICC-C. Nonetheless, in BICC-C, both FOLFIRI and FOLFIRI plus bevacizumab offered superior activity to their comparators and were comparably safe. The results from BICC-C suggest that, when using an irinotecan-based regimen in the treatment of first-line metastatic colorectal cancer, an infusional schedule of FU should be the preferred approach.

AUTHORS' DISCLOSURES OF POTENTIAL CONFLICTS OF INTEREST

Although all authors completed the disclosure declaration, the following author(s) indicated a financial or other interest that is relevant to the subject matter under consideration in this article. Certain relationships marked with a "U" are those for which no compensation was received; those relationships marked with a "C" were compensated. For a detailed description of the disclosure categories, or for more information about ASCO's conflict of interest policy, please refer to the Author Disclosure Declaration and the Disclosures of Potential Conflicts of Interest section in Information for Contributors.

Employment or Leadership Position: José Barrueco, Pfizer Inc (C) Consultant or Advisory Role: None Stock Ownership: None Honoraria: Charles S. Fuchs, Pfizer Oncology, Sanofi-aventis, Genentech, AstraZeneca, Bristol-Myers Squibb Co, Amgen, ImClone Systems Inc, Roche; John Marshall, Pfizer Inc, Genentech, Bristol-Myers Squibb Co, Sanofi-aventis, Roche, Amgen, Boerhinger Ingelheim Research Funding: Charles S. Fuchs, Pfizer Expert Testimony: None Other Remuneration: None

REFERENCES

1. Fuchs CS, Marshall J, Mitchell E, et al: Randomized, controlled trial of irinotecan plus infusional, bolus, or oral fluoropyrimidines in first-line treatment of metastatic colorectal cancer: Results from the BICC-C study. J Clin Oncol 25:4779-4786, 2007[Abstract/Free Full Text]

2. Kohne CH, De Greve J, Hartmann JT, et al: Irinotecan combined with infusional 5-fluorouracil/folinic acid or capecitabine plus celecoxib or placebo in the first-line treatment of patients with metastatic colorectal cancer. EORTC study 40015. Ann Oncol doi:10.1093/annonc/mdm544 [epub ahead of print on December 6, 2007][Abstract/Free Full Text]

3. Bajetta E, Di Bartolomeo M, Mariani L, et al: Randomized multicenter Phase II trial of two different schedules of irinotecan combined with capecitabine as first-line treatment in metastatic colorectal carcinoma. Cancer 100:279-287, 2004[CrossRef][Medline]

4. Borner MM, Bernhard J, Dietrich D, et al: A randomized phase II trial of capecitabine and two different schedules of irinotecan in first-line treatment of metastatic colorectal cancer: Efficacy, quality-of-life and toxicity. Ann Oncol 16:282-288, 2005[Abstract/Free Full Text]

5. Patt Y, Liebmann T, Diamandidis D, et al: Final efficacy and safety findings from a phase II trial of capecitabine (X) plus irinotecan (XELIRI) as first-line treatment for metastatic colorectal cancer (MCRC): Proc ESMO. Ann Oncol 15:iii88, 2004 (abstr 328P)

6. Rea DW, Nortier JWR, Ten Bokkel Huinink WW, et al: A phase I/II and pharmacokinetic study of irinotecan in combination with capecitabine as first-line therapy for advanced colorectal cancer. Ann Oncol 16:1123-1132, 2005[Abstract/Free Full Text]

7. Fuchs C, Marshall J, Mitchell E, et al: A randomized trial of first-line irinotecan/fluoropymidine combinations with or without celecoxib in metastatic colorectal cancer (BICC-C). J Clin Oncol 24:146s, 2006 (suppl; abstr 3506)

8. Koopman M, Antonini NF, Douma J, et al: Sequential versus combination chemotherapy with capecitabine, irinotecan, and oxaliplatin in advanced colorectal cancer (CAIRO): A phase III randomised controlled trial. Lancet 370:135-142, 2007[CrossRef][Medline]

9. Haller DG, Cassidy J, Clarke S, et al: Tolerability of fluoropyrimidines appears to differ by region. J Clin Oncol 24:149s, 2006 (suppl; abstr 3514)

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Related Correspondence

• Capecitabine and Irinotecan As First-Line Treatment of Advanced Colorectal Cancer
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