XELIRI (Capecitabine and Irinotecan): A Novel Combination Under Development
XELIRI (Capecitabine and Irinotecan): A Novel Combination Under Development
Abstract & Commentary
William B. Ershler, MD, INOVA Fairfax Hospital Cancer Center, Fairfax, VA; Director, Institute for Advanced Studies in Aging, Washington, DC, is Editor for Clinical Oncology Alert.
Synopsis: In a phase I trial, the combination of capecitabine and irinotecan was explored in patients with upper and lower gastrointestinal cancers. Irinotecan was administered on day 1 by 90 minute intravenous infusion and capecitabine given orally twice a day on days 2-15 on a 21-day cycle. Important clinical responses were observed in several heavily pretreated patients. Dose limiting toxicities included diarrhea and neutropenia. The recommended doses for future investigation were irinotecan 250 mg/m2 and capecitabine 1000 mg/m2 twice daily.
Source: Delord JP, et al. Br J Cancer. 2005;92:820-826.
Capecitabine is becoming increasingly used in a number of clinical settings because of its demonstrable efficacy, ease of administration, and acceptable toxicity profile. It is a fluoropyrimidine carbonate, a pro-drug of 5-fluorouracil. It is rapidly and almost completely absorbed in the upper intestinal tract1 and metabolized to 5-FU in a 3-step enzymatic cascade.2 Capecitabine is frequently used instead of 5-FU in the treatment of colorectal cancer. Two large phase III trials including more than 1200 patients have demonstrated that, as first-line therapy for metastatic disease, capecitabine achieves significantly superior response rates with at least equivalent time to progression and survival when compared with 5-FU/leukovorin.3,4 Furthermore, capecitabine demonstrated an improved safety profile when compared to 5-FU and is associated with a very low incidence of alopecia and myelosuppression.5 Phase II studies of capecitabine in gastric and pancreatic cancer have also shown promising activity and a favorable safety profile.6-8
The combination of capecitabine with irinotecan is supported by their different mechanisms of action and a demonstrated synergistic antitumor activity in animal models. Furthermore, capecitabine and irinotecan show only partial overlap of key toxicities. The predominant adverse events associated with irinotecan are neutropenia and diarrhea. Capecitabine is also associated with diarrhea, but only minimal myelosuppression.
Delord and colleagues performed a phase I trial in 27 patients with gastrointestinal tumors aimed to assess the toxicity and potential for significant pharmacokinetic interactions using a regimen of irinotecan (200 and 250 mg/m2) administered every 3 weeks by a 90-minute infusion in combination with capecitabine doses (700-1250/m2 twice daily) on days 2 through 15 of the 21-day cycle.
A total of 103 treatment cycles were administered to 27 patients. The principal dose limiting toxicities were diarrhea and neutropenia. Capecitabine 1150/m2 twice daily with irinotecan 250/m2 was identified as the maximum tolerated dose and capecitabine 1000 mg/m2 twice daily with irinotecan 250 mg/m2 was identified as the recommended dose for further study. The combination was clinically active, with objective responses achieved in heavily pretreated patients.
Comment by William B. Ershler, MD
The combination of 5-FU and Irinotecan has demonstrable activity for the treatment of colorectal cancer, greater than either agent administered alone. However, in the commonly used Saltz regimen9 toxicity has been substantial and treatment related deaths have been reported. It has been suggested that continuous infusion 5-FU would be safer for combinations with irinotecan.10 With this and the preclinical data mentioned above, the XEXLIRI (capecitabine, irinotecan) regimen makes sense. The French group is to be commended for conducting and presenting an excellent phase I analysis of this combination. A rationale can be forwarded to examine this combination for gastric, pancreatic and colorectal cancers.
References
1. Reigher B, et al. Clin Pharmacokinet. 2001;40:85-104.
2. Miwa M, et al. Eur J Cancer. 1998;34:1274-1281.
3. Hoff PM, et al. J Clin Oncol. 2001;19:2282-2292.
4. Van Custem, et al. J Clin Oncol. 2001;19:4097-4106.
5. Cassidy J, et al. J Clin Oncol. 2004;22:2084-2091.
6. Cartwright TH, et al. J Clin Oncol. 2002;20:160-164.
7. Hong YS, et al. Proc Am Soc Clin Oncol. 2002;21: 156a.
8. Koizumi W, et al. Oncology. 2003;64:232-236.
9. Saltz LB, et al. N Engl J Med. 2000;343:905-911.
10. Rothenberg ML, et al. J Clin Oncol. 2001;19: 3801-3807.
In a phase I trial, the combination of capecitabine and irinotecan was explored in patients with upper and lower gastrointestinal cancers. Irinotecan was administered on day 1 by 90 minute intravenous infusion and capecitabine given orally twice a day on days 2-15 on a 21-day cycle. Important clinical responses were observed in several heavily pretreated patients. Dose limiting toxicities included diarrhea and neutropenia. The recommended doses for future investigation were irinotecan 250 mg/m2 and capecitabine 1000 mg/m2 twice daily.Subscribe Now for Access
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