NEW HAVEN, Connecticut-Capecitabine (Xeloda) was developed as an oral tumor-activated alternative to fluorouracil (5-FU) and now appears set to replace that agent in some combination regimens for colorectal cancer according to Edward Chu, MD. Dr. Chu reported that phase II trials suggest that either capecitabine/oxaliplatin (Eloxatin) or capecitabine/irinotecan (CPT-11, Camptosar) might be effective replacements for 5-FU-based regimens. Dr. Chu is professor of medicine and pharmacology at Yale University School of Medicine and associate director of the Yale Cancer Center, New Haven, Connecticut.
NEW HAVEN, ConnecticutCapecitabine (Xeloda) was developed as an oral tumor-activated alternative to fluorouracil (5-FU) and now appears set to replace that agent in some combination regimens for colorectal cancer according to Edward Chu, MD. Dr. Chu reported that phase II trials suggest that either capecitabine/oxaliplatin (Eloxatin) or capecitabine/irinotecan (CPT-11, Camptosar) might be effective replacements for 5-FU-based regimens. Dr. Chu is professor of medicine and pharmacology at Yale University School of Medicine and associate director of the Yale Cancer Center, New Haven, Connecticut.
"Capecitabine should replace infusional 5-FU/leucovorin as the combination partner for oxaliplatin. It offers improved convenience over regimens incorporating infusional 5-FU, and the combination requires only one clinic visit for oxaliplatin administration every 3 weeks," Dr. Chu said.
"Phase II trials data show that capecitabine/oxaliplatin (Xelox) is a highly active first-line therapy for metastatic colorectal cancer," he continued. "It produced a 55% response rate with consistently high response rates, over 50%, in all patient subgroups. Thirty-two percent of patients had disease stabilization, and this lasted more than 3 months in all patients. Median time to progression was 7.6 months, and median survival was 19 months. Toxicity is manageable and is similar to that of the FOLFOX4 (fluorouracil, leucovorin, oxaliplatin) regimen."
Capecitabine/oxaliplatin would be an attractive option because oral capecitabine is metabolized to 5-FU by thymidine phosphorylase, an enzyme found in higher concentrations in tumors than in normal tissue. The result is preferential production at the tumor site. "Oral administration of capecitabine mimics the mechanism of action of continuous infusion 5-FU but without the complications and inconvenience associated with continuous infusion," Dr. Chu said.
The capecitabine/oxaliplatin combination is theoretically appealing because the two drugs have different molecular mechanisms of action and no overlap of key toxicities. Previous studies have also shown improved clinical efficacy when oxaliplatin was added to 5-FU/leucovorin.
The main grade 3 or 4 toxicity with capecitabine/oxaliplatin is diarrhea, which afflicted 35% of patients treated with a higher-dose regimen (capecitabine 1,250 mg/m2 bid and oxaliplatin 130 mg/m2) as first-line therapy and 50% of those treated with a higher-dose regimen as second-line therapy. Three percent of patients suffered grade 3 hand-foot syndrome in an international phase II trial of capecitabine/oxaliplatin as first-line treatment for metastatic colorectal cancer. There were no grade 4 hematologic toxicities, and 60-day all-cause mortality was 2%, according to Dr. Chu. The US gastrointestinal intergroup is planning a phase III trial of capecitabine/oxaliplatin vs FOLFOX.
Teamed With Irinotecan
Similar results were reported in phase I/II trials of capecitabine/irinotecan (Xeliri), although toxicity was more of a problem and more dosage adjustments were required. Dr. Chu said that British, German, and Italian researchers have reported overall response rates of 50% to 65% and that planned phase III trials will define the role of this combination in advanced disease and in the adjuvant setting.
"There is a potential for capecitabine to replace intravenous 5-FU/leucovorin as a combination partner with irinotecan," Dr. Chu said. He emphasized that irinotecan should be given 24 hours before capecitabine, based on animal studies of most effective sequencing.
Diarrhea and neutropenia were the most common dose-limiting toxicities with capecitabine/irinotecan. Other grade 3 toxicities included hand-foot syndrome and nausea/vomiting.
XELIRI vs XELOX
Finally, Dr. Chu reviewed the results of an interesting randomized phase II trial comparing the combination of capecitabine/irinotecan vs capecitabine/oxaliplatin (XELOX) as first-line treatment of patients with advanced colorectal cancer. The trial was presented by Dr. Axel Grothey at the European Society of Medical Oncology (ESMO) meeting held recently in Nice, France.
The capecitabine dose was the same in both arms, 1,000 mg/m2 orally, bid for 14 days with a 1 week rest period. Irinotecan was initially administered at a dose of 100 mg/m2 IV on days 1 and 8 on an every-3-week schedule, but because of a nonsignificantly higher rate of early toxic deaths, the dose of irinotecan was reduced to 80 mg/m2. Oxaliplatin was administered at a dose of 70 mg/m2 IV on days 1 and 8 on an every-3-week schedule. Once the dose of irinotecan was reduced, both treatment arms were relatively well tolerated with the toxicity profile being equivalent.
The clinical activity of the two arms was also equivalent, with response rates of 37.1% and 43.1% being observed for capecitabine/irinotecan and capecitabine/oxaliplatin regimens, respectively. Progression-free and overall survival have not yet been determined given the relatively short follow-up period. However, these results provide further evidence that capecitabine can be effectively combined with either irinotecan or oxaliplatin.
"Capecitabine may be as effective as 5-FU/leucovorin in serving as a backbone for combination regimens with oxaliplatin and/or irinotecan," Dr Chu stated. "An every-3-week schedule seems to be better tolerated than a day 1, day 8 schedule and further studies are in progress to confirm which one has the best therapeutic activity combined with a tolerable safety profile."