Damjanov and Meropol review the status of several oral fluoropyrimidine drugs that are currently undergoing clinical testing for the treatment of colorectal cancer. Meta-analysis indicates an 8% improvement in the overall response rate and a survival advantage of 0.8 months with infusional vs bolus fluorouracil(Drug information on fluorouracil) (5-FU)arguably small differences. The incidence of grade 3-4 diarrhea, mucositis, and myelosuppression is < 10% with infusional 5-FU, although hand-foot syndrome is commonly associated with this therapy. The prevailing strategy for the development of oral 5-FU drugs employs multiple daily dosing for periods of 2 to 4 weeks followed by a 1- or 2-week break in order to mimic the protracted infusional schedule.
Although preclinical studies of uracil plus tegafur(Drug information on tegafur) (UFT) documented higher intratumoral 5-FU levels following administration of UFT vs ftorafur alone, UFT has not been directly compared to ftorafur in clinical trials. The benefit of combining leucovorin with UFT vs UFT alone has also not been investigated. Based on the activity seen in phase II studies, however, clinical development in Western countries has involved UFT plus oral leucovorin calcium (Orzel) on a monthly schedule.
Two large randomized trials comparing UFT/leucovorin with a monthly schedule of bolus 5-FU/leucovorin demonstrated apparent equivalence. Although patients in the UFT arms had significantly less neutropenia and infection, quality of life was similar for the two combinations. Since the Food and Drug Administration requires evidence that each component of a fixed-combination tablet must contribute to the therapeutic effect, the new drug application for Orzel was recently withdrawn.
Through inactivation of dihydropryimidine dehydrogenase, eniluracil permits complete oral bioavailability of 5-FU, markedly prolongs its half-life, prevents the formation of catabolites that might contribute to clinical toxicity or interfere with 5-FU cytotoxicity, and circumvents a potential resistance mechanism.[1,2] Initial studies indicated that single daily dosing of eniluracil (3.7 mg/m²) rendered oral 5-FU completely bioavailable, and the effect on 5-FU clearance is similar to that seen with eniluracil in an oral dosage of 20 mg bid.
Current studies employ a fixed-combination tablet of eniluracil/5-FU in a 10:1 ratio (with the 5-FU dose of 1.0 to 1.15 mg/m² bid for 28 of 35 days). Ongoing phase III trials are comparing eniluracil/5-FU with either infusional 5-FU or monthly bolus 5-FU/leucovorin.
Oral administration of doxifluridine (5 ×-deoxy-5-fluorouridine) was supplanted by the use of capecitabine(Drug information on capecitabine) (Xeloda). The currently approved schedule for this agent is 2,500 mg/m² po in two divided doses for 14 of 21 days.
Results from two large, randomized trials of capecitabine vs monthly bolus 5-FU/leucovorin were presented at the 1999 American Society of Clinical Oncology meeting. The efficacy data for the American trial pertained to a subset of 534 of 605 randomized patients. A response advantage in favor of capecitabine was reported, but no significant difference in either median time to progression or survival was seen. In the second trial, the response rates ascertained by an independent review committee were similar19% and 15%, respectively, for the capecitabine and 5-FU/leucovorin recipientsand median time to progression was comparable.
An appealing feature of capecitabine therapy is the potential for increased activation of 5-FU in tumors that contain high levels of thymidine phosphorylase (TP). Thymidine phosphorylase activity in human tumors from 11 different sites of origin showed that, in general, the tumor tissue had higher activity than the corresponding normal tissues.
In this study, intratumoral 5-FU levels were measured in 19 colorectal cancer patients who received capecitabine, 1,255 mg/m × po bid for 5 to 7 days prior to elective surgery. In 11 patients, the median 5-FU level in primary tumor tissue was 2.9-fold higher than in adjacent normal mucosa. In 10 paired metastatic and normal liver samples, the median 5-FU in tumor was 1.4-fold higher.
These two studies support the potential for selective activation of 5-FU in tumors. However, colorectal cancer patients with high TP levels were unlikely to respond to 5-FUbased therapy, suggesting that high TP expression may be a poor prognostic factor. Whether tumors with high TP expression are sensitive to capecitabine is therefore an intriguing question that is being addressed in clinical studies.
As yet, it is unclear whether any one of the oral fluoropyrimidines is superior to the others, and whether the currently employed schedules are indeed optimal. There are strong regional preferences outside the United States for a variety of infusional 5-FU regimens (eg, high-dose weekly 24- to 48-hour infusions, twice-monthly combined-bolus/infusional regimens, and chronomodulated regimens). Few clinical studies of oral fluoropyrimidine agents have tried to mimic these intermittent high-dose regimens.
The contribution of leucovorin to infusional 5-FU regimens is unclear. The results of a randomized trial by the Southwest Oncology Group suggested no advantage to the addition of low-dose leucovorin to protracted infusional 5-FU. Preliminary data from a European phase III trial suggest an advantage in median progression-free survival with the addition of high dose leucovorin to a high dose weekly 24-hour infusion, at the cost of more diarrhea.
Oral agents representing other classes of drugs that may be useful in colorectal cancer treatment are also in clinical development. These compounds include irinotecan(Drug information on irinotecan) (Camptosar), 9-nitrocamptothecin (which acts by topoisomerase-I targeting), thalidomide(Drug information on thalidomide) (an antiangiogenesis agent), and marimastat (an inhibitor of matrix metalloproteinases).
Studies seeking to draw correlations between the molecular profile of a tumor and benefit with a specific therapy are a high priority. Since resistance to many chemotherapy agents is multifactorial, prospective trials designed to evaluate the importance of a single determinant of sensitivity may not tell a complete story.
Clearly, prospective trials that investigate the value of selecting therapy on the basis of the tumors molecular profile need to be performed. Emerging technologies hold forth the promise that not just a few, but dozens, hundreds, and even thousands of molecular targets will be quantifiable. The implications for how to design clinical trials to test the utility of such complex molecular profiles is staggering.