Keeping an Open Mind About the Doses of Chemotherapy
Authors: R. S. Gelman
Journal: JNCI Journal of the National Cancer Institute (1990)

Historically, the drugs used in combination chemotherapy have been justified on the basis of single-agent activity against the cancer of interest, different mechanisms of action, and nonoverlapping toxic effects. The actual doses in the combination have usually been the result of well-informed guesses or of phase I studies in which the doses of all drugs are held constant with the exception of one drug whose dose is increased until a maximum tolerated dose (MTD) for this drug within the combination is reached. Carter et al. (/) have described several experimental designs that involve varying the doses of two or more drugs and choosing the best combination on the basis of benefit and toxicity. However, because of the large number of treatment groups required (e.g., 2* + 2k + 1 for a fc-drug combination using the central composite design), these designs have been used more often in animal experiments than in clinical trials. Once a regimen has been deemed useful in a phase III trial (which may or may not involve testing the combination against a subset of its drugs), it is difficult to generate enthusiasm for further tinkering with the doses involved. This resistance to change has sometimes resulted in certain combinations (e.g., the combination of cyclophosphamide, methotrexate, fluorouracil, vincristine, and prednisone) becoming popular decades before it is accepted that one of the component drugs (e.g., vincristine) adds no benefit, but only toxicity to the regimen (2). One of the weaknesses of retrospective meta-analyses of dose intensity (3,4) has been that regimens become standard so quickly that large differences in dose intensity are found only when some of the regimens being compared omit some drug completely. Perhaps the same drugs used in different amounts would result in better therapeutic results than the standard combination; however, the possible variations are endless and not considered as likely to lead to a home run as discovering a new drug or figuring out how to increase the doses of all the drugs. The development of hematopoietic growth factors has provided a reason to re-evaluate the doses in current combination regimens and to combine some drugs previously thought to be incompatible. Yet many of the ongoing phase I studies of combination chemotherapies and growth factors are simply increasing the doses of the most marrow-toxic drug in the combination. Not much explanation has been given as to why the resultant ratios of drug doses are expected to be more beneficial; not much thought has been given to whether it would be better to lower the doses of some non-marrow-toxic drugs because toxic effects to other organs will now become dose limiting. In this issue of the Journal, Simon and Korn (5) present a logical method for balancing the single-agent toxicity and the effectiveness of various drugs when one is choosing a new combination of drugs worthy of evaluation in phase III trials. If enough is already known about the nonhematologic dose-limiting toxic effects of the drugs, this method can be used to suggest which regimens should have priority in prospective studies of hematopoietic growth factors. Simon and Korn's approach requires two simplifying assumptions: (a) the MTD of any drug combination in any organ is a linear function of the drug doses involved, and (b) tumor response is a function of a linear combination of the drug doses. Any method of integrating data from only «/ig/e-agent studies would require some assumptions about additivity of effects, and linear functions are standard, and usually adequate, approximations for more complicated curves. Nonetheless, we need to evaluate how close to truth these assumptions are likely to be and how much difference to the conclusions an incorrect assumption could make. Simon and Korn are correct that the determination of MTDs is so imprecise that it would be difficult to assess the adequacy of the first assumption above. In addition, if there were only one type of overlapping toxicity in the tolerable region and if the relationship of toxicity to drug doses differed from linearity by being convex (i.e., bent closer to the origin than expected from additivity), the best regimen would be the same as the one chosen using the linearity assumption. The only real worry is that the toxicity of a combination might be less severe than predicted from additivity. If the bone marrow curve in Simon and Korn's figure 3B were very concave (e.g., if a moderate amount of cisplatin did not much worsen the neutropenia associated with nearly full dose cyclophosphamide), it might well be that the optimum regimen would have 15% less cisplatin but nearly full dose cyclophosphamide, for a total dose intensity of 2.64 (a 50% improvement over cisplatin alone), rather than consisting of nearly full dose cisplatin and a minimal amount of cyclophosphamide. Perhaps such concavity is unreasonable with these particular drugs, but it would still seem safer to try to obtain at least two points on the MTD curve.