LONDON, Ontario-A Canadian study is evaluating the safety and efficacy of single-agent capecitabine(Xeloda) among patients with advanced colorectal cancer deemed unsuitable for more aggressive treatment with bolus fluorouracil (5-FU)/leucovorin/irinotecan (also known as CPT-11, Camptosar).
LONDON, OntarioA Canadian study is evaluating the safety and efficacy of single-agent capecitabine
(Xeloda) among patients with advanced colorectal cancer deemed unsuitable for more aggressive treatment with bolus fluorouracil (5-FU)/leucovorin/irinotecan (also known as CPT-11, Camptosar).
The nonrandomized, multicenter phase I/II trial is based on concerns about the potential toxicity of the widely used bolus combination among patients who are elderly or unfit, according to lead investigator Mark Vincent, MD, associate professor of oncology, University of Western Ontario, and staff oncologist, London Regional Cancer Center. He discussed his ASCO paper (abstract 2366) in an interview with ONI.
The investigators chose to study patients who fit into three broad categories: Those who were too ill or too old to be considered for aggressive therapy, those who would have been specifically excluded from the original trial of the IV bolus 5-FU/irinotecan regimen, and patient groups that had not seemed to experience a survival benefit from the addition of
These broad criteria translated into five patient subgroups:
Patients in these groups are being offered capecitabine at a dose of 1,000 mg/m² bid, Dr. Vincent said. However, trial investigators are not required to enroll everyone over age 65 into the trial. A fit and otherwise healthy 66-year-old, for example, would not be a candidate for the study. Furthermore, the patient’s preferences are followed whenever possible, and some prefer to defer use of irinotecan until second-line therapy.
Patients with an impaired performance status and those with an elevated LDH level were selected because neither group seemed to reap the added survival benefits of the irinotecan in the original 5-FU/irinotecan study, Dr. Vincent said.
"There was a huge benefit to CPT-11 in fit people and in fit people with a normal LDH, but less survival benefit for anybody else," he noted. "It seemed reasonable to offer people with an elevated LDH a more gentle treatment because a more aggressive treatment might not add much."
The fourth and fifth subgroupsprior pelvic irradiation or abnormal liver function testswere chosen because these patient groups were not included in the original 5-FU/irinotecan trial. The investigators in the current study have placed no limit on the severity of liver function impairment, but these patients do have to be performance status 1 or 2.
Dr. Vincent acknowledged the challenge of studying such a varied group of patients. "If you’re fit, you’re fit, but people can be unfit in multiple different ways and for many different reasons," he said. "The challenge is: How do you study a heterogeneous group of people? And I think we’re still on the learning curve a little bit as far as that is concerned. We’ve elected to enroll patients based on at least one of these criteria, but they can have three, four, or all five of the criteria."
So far, the trial has accrued 43 patients, not enough for efficacy data but enough to form some initial impressions. "Groups 1 to 3 are tolerating the 2,000 mg/m² [1,000 mg/m² bid] dose very well," Dr. Vincent said. "We seem to have substantially gotten rid of the grade 3-4 diarrhea but are still getting a bit of hand-foot syndrome."
In the group with prior pelvic irradiation, he said, "we’ve had to take the Xeloda dose down to 1,500 mg/m² [750 mg/m² bid] because some patients experienced diarrhea. As for patients with abnormal liver function tests, we haven’t accrued enough to be able to make an informative statement."
Although efficacy data will not be available for some time, Dr. Vincent said that his impression is that many patients are staying on the treatment regimen for prolonged periods of time, probably because the therapy is both well tolerated and effective at preventing the progression of disease.
"We don’t really have any benchmark study to compare ours with because no other study has been designed like this-to specifically beat the bushes for the elderly and infirm," Dr. Vincent said. "The number of people who could potentially fall into one of these categories is huge."
The researchers hope to enroll 120 to 170 patients in the study . "Through regression analysis, we might be able to identify which subgroups are associated with particular outcomes. We’ve already been able to say that if you’ve had prior irradiation, you probably will need a dose reduction," Dr. Vincent said.