The article by Damjanov and Meropol elegantly outlines the rationale behind the preclinical development of several potential new oral chemotherapy options for patients with advanced colorectal carcinoma and the available data from clinical trials in advanced colorectal cancer that evaluated the activity and safety of these agents. The authors relate the history of fluorinated pyrimidine therapy in colorectal cancer and the pharmacologic challenges to delivering effective oral therapy in a such a way that the chemistry behind the processes becomes readily intelligible. They note that the erratic absorption and blood levels associated with orally administered fluorouracil(Drug information on fluorouracil) (5-FU) led to the current approaches to oral therapy.
The oral formulations use either prodrugs that are reliably absorbed and then converted to 5-FU or inhibition of 5-FU catabolism such that drug levels are sustained and erratic absorption is compensated for by modulating the catabolic process. Of the four agents reviewed, only capecitabine(Drug information on capecitabine) (Xeloda) is commercially available in the United States. As noted in the package insert, this agent is indicated only for patients with refractory metastatic breast carcinoma.
Recently, data regarding the activity and toxicity of uracil/tegafur (UFT) compared to 5-FU plus leucovorin was presented to the Oncologic Drugs Advisory Committee (ODAC) of the Food and Drug Administration (FDA). The Commission unanimously recommended approval of UFT for the treatment of advanced colorectal cancer. However, the FDA required supplemental information from the sponsor on the efficacy and toxicity of uracil alone and the contribution of uracil to the activity and toxicity of the UFT combination. As a result, the new drug application for UFT was withdrawn by the sponsor.
Advantages and Disadvantages of Oral Agents
The oral agents reviewed offer unique advantages and disadvantages. Patients prefer oral agents when their activity and toxicity profiles are comparable to those of intravenous drugs. The activity profiles of the four agents discussed in the article are nearly indistinguishable from each other and from activity noted with standard intravenous 5-FU. The toxicity profiles, on the other hand, are a bit more distinctive. For example, hand-foot syndrome is commonly seen and may be the dose-limiting toxicity for some patients treated with capecitabine.
Patients receiving eniluracil and 5-FU can experience toxicitiesincluding neutropenia and diarrheathat are typical of those associated with intravenous administration of 5-FU. The authors caution against the use of conventional doses of intravenously administered 5-FU-based therapy after cessation of therapy with eniluracil and 5-FU. The diminished biological activity of dihydropyrimidine dehydrogenase (DPD) following therapy with eniluracil can turn conventional doses of intravenous 5-FU into a deadly regimen.
Furthermore, a recently completed North Central Cancer Treatment Group study reported that several patients treated with oral eniluracil and 5-FU developed reversible neurologic toxicitya phenomenon noted to occur in individuals with genetic DPD deficiency after 5-FU administration. The adverse events these patients experienced included cerebellar toxicity, visual alterations, and sensory/motor/cortical dysfunction in several patients. The overall incidence of grade 3 neurologic toxicity in this 80-patient cohort was 14%. All neurologic toxicity was reversible after therapy with oral eniluracil and 5-FU was discontinued.
Patient preference for oral therapy was also reviewed. In the study by Liu et al, patients were unwilling to sacrifice tumor response for use of oral chemotherapy. One important issue not addressed in the Liu study, however, was that of cost. The authors likely did not examine cost issues because of the limited information available on pricing. Cost may be an important determinant of patient preference, particularly if the agents in question are not reimbursed through insurance coverage. Off-label use of capecitabine in patients with advanced colorectal carcinoma, for example, can be quite costly.
Several of the agents reviewed by Damjanov and Meropol have undergone extensive clinical testing in patients newly diagnosed with advanced colorectal carcinoma. All of these studies have evaluated a new oral agent against standard intravenous 5-FU and leucovorin.
Irinotecan(Drug information on irinotecan) (Camptosar) has been used in 5-FUrefractory colorectal carcinoma patients since 1996. Two recent studies have reported survival advantages for therapy with irinotecan/5-FU/leucovorin combination regimens over standard 5-FU/leucovorin alone.[5,6] These studies may lead to a change in the standard treatment recommendation for patients with newly diagnosed advanced colorectal carcinoma, a change that ODAC supported at its March 2000 meeting.
When regimens containing 5-FU/leucovorin are no longer regarded as the best standard therapy in this patient population, phase III trials comparing newer agents to that combination will no longer be useful, and previous such comparisons may be considered obsolete. Several trials are currently evaluating combination regimens with one of the oral agents plus intravenous irinotecan or oxaliplatin(Drug information on oxaliplatin). Unfortunately, no comparative phase III study results are available at this time.
The survival advantage for cohorts of patients treated with irinotecan plus 5-FU/leucovorin over 5-FU/leucovorin alone, cost/reimbursement issues, and the FDAs concerns raise real questions regarding the future commercial availability and, therefore, the potential impact of oral chemotherapy agents in colorectal cancer.