Oral Therapy for Colorectal Cancer: How to Choose

Heidelberger and associates[1] synthesized fluorouracil (5-FU) in 1957 after observing that rat hepatomas utilized radiolabeled uracil more avidly than malignant tissues. For the past 40 years, 5-FU has been extensively investigated in various schedules, in combination with biochemical modulators, and for a variety of malignancies.[2]

Early in the clinical development of 5-FU, investigators noted erratic bioavailability (0% to 80%) and unpredictable exposure and toxicity associated with oral administration.[3] Hence, the oral administration of 5-FU was abandoned and clinical development focused on intravenous schedules, including weekly bolus regimens, daily for 5 consecutive days, and protracted intravenous schedules.

Intravenous 5-FU schedules have been investigated primarily in advanced colorectal cancer. Clinical research over the past 2 decades has emphasized the use of 5-FU with the biochemical modulator, leucovorin calcium. Unfortunately, trials in advanced colorectal cancer reported modest gains in survival—which were not readily reproducible—and poorly described effects on palliation and quality of life.

These trials, however, have provided insight into the schedule-dependent toxicities of 5-FU. Myelosuppression and oral mucositis have been the consistent dose-limiting toxicities associated with daily × 5 schedules, while diarrhea has been the predominant serious toxicity associated with weekly schedules. Hand-foot syndrome has been the dose-limiting toxicity of prolonged infusion schedules.

Oral Fluorinated Pyrimidines

The review by Damjanov and Meropol highlights the clinical development of oral fluorinated pyrimidines—capecitabine (Xeloda), UFT (uracil and tegafur), S-1, and eniluracil plus oral 5-FU. These agents were developed to allow convenient prolonged oral dosing of fluorinated pyrimdines while reducing toxicities such as neutropenia and oral mucositis. Of these oral agents, capecitabine is the only oral fluorinated pyrimidine approved by the Food and Drug Administration (FDA). These agent received accelerated approval for the treatment of refractory breast cancer patients. Subsequent comments will focus on the three agents (capecitabine, UFT plus oral leucovorin, eniluracil plus oral 5-FU) whose clinical development is most mature.

The oral fluorinated pyrimidines provide insights in the clinical importance of dihydropyrimidine dehydrogenase (DPD), the initial and rate-limiting catabolic enzyme of 5-FU. Eniluracil is an irreversible inactivator of DPD; uracil (in UFT) provides competitive inhibition of the enzyme, whereas capecitabine does not affect the enzyme.

Many oncologists are aware of this enzyme because of the clinical condition associated with DPD deficiency that results in life-threatening toxicity following treatment with conventional doses of 5-FU.[3,4] In addition, variable DPD levels—the result of considerable interpatient differences in enzyme activity in the liver and gastrointestinal (GI) tract—may be responsible for the unpredictability of exposure to both oral and intravenous 5-FU. Rapid intracellular catabolism of 5-FU by DPD has been suggested as a mechanism of 5-FU resistance.[5]

Catabolic end products of 5-FU have been implicated in the pathogenesis of certain fluorinated pyrimidine toxicities. For example, alpha-fluoro-beta-alanine (FBAL) has been found to be neurotoxic in animal models and may have a role in producing the neurotoxicity associated with fluorinated pyrimidines.[6] In addition, the poorly understood toxicity of hand-foot syndrome associated with protracted 5-FU infusions and capecitabine is not commonly observed in the fluorinated pyrimidines that inhibit or inactivate DPD (ie, UFT and eniluracil). This contrasting profile of toxicities has led to the speculation that the 5-FU catabolites may be implicated in the pathogenesis of hand-foot syndrome.

Circumventing Erratic Absorption

Attempts to circumvent the erratic absorption of oral 5-FU have focused on two different approaches. The first approach is to inactivate DPD—coadministration of 5-FU with eniluracil increases the bioavailability of 5-FU and provides greater consistency in exposure. Eniluracil dramatically alters the systemic disposition of 5-FU. In combination with eniluracil, the average terminal half-life of 5-FU, which has been conventionally reported to be 8 to 20 minutes, ranges from 4 to 6 hours.[7]

The second method is to administer prodrugs of 5-FU, which are converted to 5-FU after GI absorption. Both capecitabine and tegafur (in UFT) are absorbed as prodrugs from the GI tract. Capecitabine undergoes a three-step enzymatic conversion to 5-FU with the final conversion being mediated by thymidine phosphorylase. Limited data suggest that higher levels of this enzyme may be found in colorectal tumors than in normal tissue.[8]

Phase II trials of each of the fluorinated pyrimdines have demonstrated a favorable toxicity profile and comparable efficacy to reported data for intravenous 5-FU/leucovorin schedules. Each of these three oral agents have been compared to standard 5-FU/leucovorin schedules in large phase III trials. End points have included survival, response rates, time to progression, palliation of prespecified symptoms, and quality of life. The trials have been completed, and published results should be available in the near future.

Capecitabine, UFT, and eniluracil were developed when intravenous 5-FU/leucovorin was considered “standard” first-line treatment of metastatic colorectal cancer. However, data from two phase III randomized, controlled, multinational trials of irinotecan (Camptosar) combined with 5-FU/leucovorin challenge 5-FU/leucovorin alone as the preferred first-line treatment.

In both studies, the triple drug therapy of irinotecan and 5-FU/leucovorin resulted in statistically significant improvements in survival, objective tumor response rates, and time-to-tumor progression, as compared to results seen with 5-FU/leucovorin. These differences in survival were maintained despite the fact that approximately 30% to 40% of patients on the 5-FU/leucovorin arm crossed over to irinotecan at the time of disease progression.[9,10]

The most clinically significant toxicities for patients receiving the irinotecan-containing combinations were diarrhea, nausea, vomiting, neutropenia, and alopecia. In one trial, grade 4 neutropenia, neutropenic fever, and mucosititis were observed less frequently with a weekly irinotecan combination than with monthly administration of 5-FU/leucovorin.[9,10]

Future Role of Fluoropyrimidines

The article reviewed—“Oral Therapy for Colorectal Cancer: How to Choose”—questions the selection of an oral fluorinated pyrimidine as the initial treatment of metastatic colorectal cancer. However, the selection of first-line colorectal cancer treatment has become more complicated in light of the survival advantage associated with the triple-drug treatment of irinotecan plus 5-FU/leucovorin.

If the oral fluorinated pyrimdines demonstrate survival data comparable to intravenous 5-FU/leucovorin, their optimal use in colorectal cancer may need to be revisited. Future trials may investigate combinations with irinotecan or other promising agents. Their use in special patient populations—such as elderly patients or those with poor performance status—who may not tolerate ggressive therapies should be explored, focusing on palliative benefits.

References:

1. Heidelberger C, Chaudhuari NK, Daneberg P, et al: Fluorinated pyrimidines. A new class of tumor inhibitory compounds. Nature 179:663-666, 1957.

2. Grem JL: 5-Fluorinated pyrimidines, in: Chabner BA, Longo DL (eds): Cancer Chemotherapy and Biotherapy: Principles and Practice, pp 149-210. Philadelphia, Lippincott-Raven, 1996.

3. Diasio RB, Harris BE: Clinical pharmacology of 5-fluorouracil. Clin Pharm 16:215-237, 1989.

4. Houyau P, Gay C, Chatelut E, et al: Severe fluorouracil toxicity in a patient with dihyropyrimidine dehyrogenase deficiency. J Natl Cancer Inst 85:1602-1603, 1993.

5. Etienne MC, Cheradame S, Fischel JL, et al: Response to fluorouracil therapy in cancer patients: The role of tumoral dihydropyrimidine dehydrogenase activity. J Clin Oncol 13:1663-1670, 1995.

6. Zhang RWQ, Soong SJ, Liu TP, et al: Pharmacokinetics and tissue distribution of 2-fluoro-beta-alanine in rats: Potential relevance to toxicity pattern of 5-fluorouracil. Drug Metab Dispos 20:113-119, 1992.

7. Schilsky RL, Hohneker J, Ratain MJ, et al: Phase I clinical and pharmacological study of eniluracil plus fluorouracil in patients with advanced cancer. J Clin Oncol 49:1450-1457, 1998.

8. Schuller J, Cassidy J, Reigner B, et al: Tumor selectivity of Xeloda in colorectal cancer patients (abstract). Proc Am Soc Clin Oncol 16:227a, 1997.

9. Douillard JY, Cunningham D, Roth AD, et al: A randomized phase III trial comparing irinotecan + 5FU/folinic acid to the same schedule of 5-FU/FA in patients with metastatic colorectal cancer as front-line chemotherapy (abstract). Proc Am Soc Clin Oncol 18:899, 1999.

10. Saltz LB, Locker PK, Elfring GL, et al: Weekly irinotecan, leucovorin, and fluorouracil is superior to daily ´ 5 LV/FU in patients with previously untreated colorectal cancer (abstract). Pro Am Soc Clin Oncol 18:898, 1999.