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Are Dose-Finding Studies Still Necessary When Targeted Therapy Is Associated With Chemotherapy?

Department of Medical Oncology, Regina Elena National Cancer Institute, Rome, Italy

Sara Lonardi

Department of Medical Oncology, Padova University Hospital, Padova, Italy

Susanna Di Segni

Pharmacokinetic Unit, Regina Elena National Cancer Institute, Rome, Italy

Andrea Fontana, Fotios Loupakis

Department of Oncology, Livorno, Italy

Francesco Cognetti

Department of Medical Oncology, Regina Elena National Cancer Institute, Rome, Italy

Roberto Labianca

Oncology Unit Ospedali Riuniti, Bergamo, Italy

To the Editor:

We read with great interest the article by Meyerhardt et al¹ reporting the results of a phase II study of capecitabine, oxaliplatin, and erlotinib in pretreated patients with metastatic colorectal cancer, published in the April 20, 2006, issue of the Journal of Clinical Oncology.

Thirty-two patients were globally accrued to receive daily oral erlotinib at 150 mg, oral capecitabine at 1,000 mg/m² twice a day on days 1 to 14, and intravenous oxaliplatin at 130 mg/m² on day 1.

The authors showed data on this interesting schedule giving particular emphasis on toxicities developed during the first 13 patients. In fact, an unexpected number of patients presented with grade 3 to 4 toxicities with such a schedule were recorded.

Before the dose reduction of capecitabine from 1,000 mg/m² twice a day for 14 days (cohort 1) to 750 mg/m² (cohort 2), 92% of patients experienced at least one grade 3 or 4 toxicity, principally diarrhea (38%), followed by nausea/emesis (31%), dehydration (23%), and fatigue (23%).

After the capecitabine reduction, grade 3 to 4 toxicities decreased to 68% (anyway high), and as written in the text, "therapy appeared better tolerated," ¹ but diarrhea, despite capecitabine reduction, did not improve at all in the cohort 2, changing from 38% to 37%.

Although patients accrued in the study were pretreated, young (median age, 56 years), and with good performance status (patients with a performance status of 2 were not included in the trial), the percentage of grade 3 to 4 diarrhea is quite different from previous studies that used capecitabine and oxaliplatin at the same doses,^2-5 which led us to believe that such a statement is imputable to the maintained dose of erlotinib to 150 mg.

Probably in the absence of a well conducted dose-finding trial with erlotinib in association with capecitabine and oxaliplatin, investigators reasonably associated a high proportion of patients presenting severe diarrhea, to the dose of capecitabine, exposing patients in cohort 2 to the same gastrointestinal toxicity. An indirect proof of this hypothesis is the significant reduction of emesis (31% to 16%), dehydration (23% to 11%), and fatigue (23% to 11%)—symptoms probably not related to erlotinib assumption dose.

In conclusion, we believe that the dose-finding study always has to precede phase II trial in order to avoid unexpected toxicity and to give all of the cohorts the same dose, even when an harmless biologic drug is added to proven chemotherapeutic regimen.

Authors' Disclosures of Potential Conflicts of Interest

The authors indicated no potential conflicts of interest.

REFERENCES

1. Meyerhardt JA, Zhu AX, Enzinger PC, et al: Phase II study of capecitabine, oxaliplatin, and erlotinib in previously treated patients with metastastic colorectal cancer. J Clin Oncol 24:1892-1897, 2006[Abstract/Free Full Text]

2. Makatsoris T, Kalofonos HP, Aravantinos G, et al: A phase II study of capecitabine plus oxaliplatin (XELOX): A new first-line option in metastatic colorectal cancer. Int J Gastrointest Cancer 35:103-109, 2005[CrossRef][Medline]

3. Cassidy J, Tabernero J, Twelves C, et al: XELOX (capecitabine plus oxaliplatin): Active first-line therapy for patients with metastatic colorectal cancer. J Clin Oncol 22:2084-2091, 2004[Abstract/Free Full Text]

4. Scheithauer W, Kornek GV, Raderer M, et al: Randomized multicenter phase II trial of two different schedules of capecitabine plus oxaliplatin as first-line treatment in advanced colorectal cancer. J Clin Oncol 21:1307-1312, 2003[Abstract/Free Full Text]

5. Borner MM, Dietrich D, Stupp R, et al: Phase II study of capecitabine and oxaliplatin in first- and second-line treatment of advanced or metastatic colorectal cancer. J Clin Oncol 20:1759-1766, 2002[Abstract/Free Full Text]

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  Jeffrey A. Meyerhardt and Charles S. Fuchs
  JCO 2006 24: 4669 [Full Text]

This Article Full Text (PDF) Purchase Article View Shopping Cart Alert me when this article is cited Alert me if a correction is posted Services Email this article to a colleague Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Save to my personal folders Download to citation manager Rights & Permissions Citing Articles Citing Articles via Google Scholar Google Scholar Articles by Gelibter, A. J. Articles by Labianca, R. Search for Related Content PubMed PubMed Citation Articles by Gelibter, A. J. Articles by Labianca, R. Related Articles Related Reply Social Bookmarking                            What's this?