Minimizing Chemo Toxicities for Patients with Metastatic Colon Cancer

SALT LAKE CITY—Reliable tests are sorely needed to help determine the best dose regimen before chemotherapy to minimize toxicities for patients with metastatic colon cancer, according to a talk given at the annual meeting of the Hematology/Oncology Pharmacy Association.

Marlo Blazer, PharmD, BCOP, outpatient oncology pharmacist at the Arthur G. James Cancer Hospital and Richard J. Solove Research Institute at the Ohio State University Medical Center in Columbus, explained that dihydropyrimidine dehydrogenase deficiency (DPD) is responsible for the breakdown of the chemotherapy drug 5-fluorouracil (5FU). “The cytotoxic effects of capecitabine and 5FU can only occur after conversion into the active nucleotides—and the amount of 5FU available for conversion is determined by the extent of its breakdown.”

Unfortunately, 3% to 5% of these patients have a partial DPD and 0.2% have a complete loss. “The central assumption to existing studies is that the degree of deficiency is proportionally related to severity of 5FU toxicity,” said Blazer. “For patients who are admitted for what we suspect is DPD, we see the classic triad of toxicities: febrile neutropenia, mucositis, and diarrhea. And we often see dehydration because of the mucositis and diarrhea.”

There are currently several ways to test for DPD. However, a recent study from France of 252 white colon cancer patients found that these assays on their own did not correlate with 5FU toxicity (Boisdron-Celle M, et al. Cancer Lett. 2007;249:271-282). In fact, “no single test had sufficient sensitivity and specificity to detect true [DPD] deficiency.” Using a 2-step, 2-test approach (first testing for DPD single-nucleotide polymorphism and plasma uracil, then conducting another test) did increase the values, and provided 83% sensitivity and 84% specificity. In other words, “98.8% of those with a grade 3 or 4 toxicity would have had their 5FU dose initially reduced. But 8% of the patients would have had an unnecessary dose reduction,” said Blazer.

In addition, past research has not looked at the costs of these tests and few studies have assessed whether initial dose reductions were necessary—“only that incidence of toxicity was reduced,” explained Blazer. “So should you test for DPD prior to beginning treatment? And what if the test came back negative? To reduce risk of toxicity, we usually reduce 75% to 80% upfront in these patients and step them up slowly based on tolerance. But there are no guidelines as far as dose reduction.”

A polymorphism of the UGT1A1 gene also can lead to increased irinotecan-associated toxicity. A recent review of 9 studies, however, had several limitations, including that the tumor type was not restricted to just colon cancer and the doses and frequency of the medication varied widely.

Overall, the investigators found that the polymorphism did not put patients at a significantly increased risk of severe diarrhea. Patients with the homozygous type of the polymorphism (UGT1A28*28), however, were 3.5 times more likely to have a severe neutropenia event compared with those with the wild type (UGT1A1*1).

“At this point and time, this is the incidence that we see. Should we be worried about giving the population at large irinotecan without testing first for the UGT1A1 polymorphism? We just don’t have a silver bullet for testing, where if we test them for UGT1A1 and they’re homozygous then we can prevent neutropenia,” said Blazer.