Oral cancer chemotherapy: the promise and the pitfalls.

The future for oral cancer chemotherapy has never been brighter. The need to move cancer treatment from a predominantly hospital-based, inpatient system into the ambulatory setting has joined with the growing body of information demonstrating higher antitumor activity, lower systemic toxicity, or both with dosing regimens that produce prolonged exposure to some cancer chemotherapy. This has led to further exploration of oral administration of anticancer drugs that have been available for many years (i.e., etoposide, cyclophosphamide, and idarubicin) and novel strategies for oral use of anticancer drugs traditionally administered by the i.v. route (paclitaxel plus cyclosporin, 5-flurouracil plus eniluracil), leading to a new era in the administration of cancer chemotherapy (1). The promise for oral chemotherapy is well illustrated by the use of mercaptopurine in maintenance therapy for childhood acute lymphoblastic leukemia. The daily administration of oral mercaptopurine during many weeks of continuation therapy is an important component of most treatment protocols for childhood acute lymphoblastic leukemia (2, 3), and this schedule could not be conveniently achieved with i.v. therapy. Oral cyclophosphamide has been an important component of adjuvant therapy for breast cancer for over a decade, permitting self administration in a convenient setting and allowing patients to have a greater role in their therapy. With the development of oral anthracyclines (such as idarubicin) and less variable approaches for oral 5-fluorouracil administration (such as coadministration with eniluracil), treatment regimens with only oral chemotherapy are now under clinical evaluation for adjuvant breast cancer (4). The significant schedule dependency of etoposide, 5-fluorouracil, topoisomerase I inhibitors, and other classes of chemotherapy represent areas in which chronic oral administration of chemotherapy may make a significant difference for patients with cancer. Many of the pitfalls of oral chemotherapy can be anticipated from well-documented experiences with other therapeutic agents, including variable absorption, unpredictable and incomplete bioavailability, and uncertainty about patient compliance. Nearly all medications demonstrate a high degree of variation in oral bioavailability among patients. The report by Hande et al. (5) in this issue of Clinical Cancer Research highlights this problem. Interand intrapatient variability in etoposide area under the curve were evaluated using an elegant stable isotope dilution method that allowed simultaneous administration of i.v. and oral medication. The investigators were able to demonstrate that intrapatient variation in i.v. etoposide (,10%), was much less than the 22.2% intrapatient coefficient of variation observed after oral etoposide administration. The large intrapatient variability observed with oral administration is similar to that seen with other medications that undergo a significant amount of metabolism by small bowel and/or hepatic P-450 enzymes. Not surprisingly, a greater degree of interpatient variability (2–3fold), compared with intrapatient variability, was observed after both i.v. and oral administration of etoposide. The report makes two points with broad implications for the development of oral chemotherapy: (a) The administration of repeated doses of a drug to the same patient will have less pharmacokinetic variation than that observed in the overall patient population. This is not unanticipated, because genetic sources of variability are eliminated when comparisons are made within the same individual. The lower intrapatient variability suggests that approaches such as individualized therapy based on measurement of drug concentrations in blood (therapeutic drug monitoring) or titration of the dose based on toxicity may be achievable within patients by measuring concentrations early in therapy and using this information to determine future doses. However, the assumption that less variability in pharmacokinetics will lead to less variation in toxicity is not supported by the literature for all drugs (6). (b) A second point from the paper by Hande et al. (5) is that greater variability in plasma pharmacokinetics should be expected with oral administration when compared with i.v. administration of cancer chemotherapy, as is widely recognized for other classes of medication. This has important implications for therapeutic drug monitoring approaches, because measurement of systemic exposure after an initial oral dose will be less predictive of concentrations achieved with the next cycle of therapy. Nonlinear drug absorption is another pharmacokinetic variable that has the potential to significantly influence oral chemotherapy, and apparent saturation of drug absorption has been observed for oral methotrexate, etoposide, and leucovorin and may also exist for other anticancer agents (7–9). This has led to hyperfractionation approaches, whereby oral drug is administered multiple times a day rather than as one large daily dose, to achieve a greater overall daily systemic exposure. These factors do not preclude oral therapy, however, because oral mercaptopurine is a successful therapy, even with low bioavailability (;6%) and high interpatient pharmacokinetic variability (10, 11). Received 7/21/99; revised 7/28/99; accepted 7/28/99. The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked advertisement in accordance with 18 U.S.C. Section 1734 solely to indicate this fact. 1 To whom requests for reprints should be addressed, at University of Aberdeen, Institute of Medical Sciences, Department of Medicine and Therapeutics, Foresterhill, Aberdeen AB25 2ZD, United Kingdom. Phone: 44-1224-681818, extension 52730; Fax: 44-1224-273066; Email: [email protected]. 2669 Vol. 5, 2669–2671, October 1999 Clinical Cancer Research