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© 2000 American Society for Clinical Oncology
High-Time Chemotherapy or High Time for Low DoseCancer Institute of New Jersey Robert Wood Johnson Medical School New Brunswick, NJ
University of Pennsylvania School Medical Center Philadelphia, PA WE ARE APPARENTLY in the midst of a shift in the paradigms for the treatment of many cancers. The two prior decades brought us a focus on an ever-escalating dosing approach, based on the simple precept that if a little is good, then more is better. This escalation of dose-intensity was made possible by the rapid advancements in the technology of supportive care, including empirical antibiotics, blood cell replacement therapies (RBCs, platelets), and cytokines. The apex of this technology to support high-dose chemotherapy is the use of autologous blood progenitor stem cells in combination with all of the above. The addition of the autologous stem cells permitted the escalation of the chemotherapy doses beyond myelotoxicity to find other dose-limiting end-organ toxicities. Although such dose escalation may show some benefit for lymphomas, myeloma, leukemias, and neuroblastoma,1,2 its effect on other diseases has not been substantiated. In particular, high-dose chemotherapy (with stem-cell support) for breast cancer is not more efficacious than standard-dose therapy.3,4 Several recent publications concerned with high-dose chemotherapy and stem-cell support, the identification of the target cell, and the scheduling of drugs such as cyclophosphamide and vinca alkaloids present us with substrate to examine many of the concepts and approaches used for different dosing algorithms.5-8 A "new" paradigm for dosing of chemotherapy5-8 is theoretically based on targeting the vascular system of the tumor rather than the tumor itself by using low-dose continuous chemotherapy. Some of these issues were previously discussed in the Journal of Clinical Oncology by us and others over the years.9-11 The recent simultaneous publication of a number of articles and a critical review of some past successes of low-dose chemotherapy suggest that this an appropriate time to revisit time and dose. The idea of a log-dose survival curve (ie, the more you give the more you kill) was developed as consequence of in vitro models to study the biology of chemotherapy cell kill. Skipper et al12 stated that the dose effect is only valid for log-phase, nonmutagenic cells when non–cell-cycle–specific agents are applied. They and others also noted that the model would not hold for antimetabolites, and the model would be of limited usefulness in vivo.10-12 Despite these predictions, the oncology community rapidly embraced the concept of dose-response cell kill. The true surprise in the studies of single, pulsed, high-dose chemotherapy (with stem-cell support) is not the lack of effectiveness in diseases such as breast cancer, but rather its limited success in lymphomas, leukemias, myeloma, and neuroblastoma. In contrast, the appropriate application of dose-intensity to genetically heterogeneous tumors with heterogeneous growth characteristics and altered or deleted suppressor genes or mutant and activated oncogenes to maximize tumor kill and minimize normal tissue toxicity remains a persisting challenge. The often-cited formula for cell kill, ie, e-ket, has both a concentration (c) and a time (t) component in the exponent. One can hypothesize a maximal dose, ie, a concentration of drug, that kills cells above which there is no further efficacy (ie, a plateau). This effect can be a product of either saturable metabolism, saturation of a known target, or the achievement of dose-limiting toxicities (DLTs). In this circumstance, the only variable in cell kill at any given dose is time. The importance of scheduling has been long known12 (see review in 9-11). The empirically successful chemotherapy regimens actually serve to illustrate this point. Multiple repetitive chemotherapy cycles for the treatment of acute lymphoblastic leukemia, the combination of cyclophosphamide, methotrexate, and fluorouracil for breast cancer, daily cyclophosphamide for neuroblastoma, and therapy with mechlorethamine, vincristine, procarbazine, and prednisone Hodgkin’s disease are each therapeutic regimens that demonstrate the principle. These examples are even more striking because they each use drugs well below the maximum-tolerated dose (MTD) for each agent. Methotrexate at 25 to 40 mg/m2 weekly is well below the 12 to 20 g/m2 doses used in high-dose methotrexate (plus leucovorin) regimens, and 50 to 100 mg of daily oral cyclophosphamide is well below the 2 to 3 g/m2 that can be given every 3 to 4 weeks. Using repetitive doses below the MTD of the agents not only proved successful for several tumors, but also withstood the test of time and challenges from other (more aggressive) regimens. Do repetitive lower doses of such agents work because the target is not exclusively the tumor cell?5-8 Recent publications suggest that such an approach with low-dose repetitive therapy produces an antiangiogenic effect. Are such antiangiogenic properties of 6-mercaptopurine metabolites and methotrexate important for the success of treatment with these agents?13,14 The answer is not completely known, but only a few drugs developed before 1960 were ever used consistently at doses well below single MTDs over protracted periods of time, and these offer some of the most notable successes in chemotherapy of patients with cancer. The realization that drug schedule is a critical determinant of success preceded any notion that the target of such therapy may be the tumor vasculature.12,15 That the schedule may improve the therapeutic efficacy of conventional drugs because of cytocidal action against tumor vasculature is another important justification for a reappraisal of our dosing and scheduling of conventional chemotherapeutic agents. Although this is an intriguing concept, there is already a suggestion that vascular parameters alone may not be predictive of survival or local or distant recurrences in neuroblastoma.16 New drug discovery continues, and one current approach is to seek agents with high specificity for unique cancer targets while minimizing normal organ toxicity.17 The identification of such targets and their respective agents will very likely accelerate as a direct consequence of the new array of technologies (eg, DNA chips and other emerging advances). Aiming at unique cancer targets may also allow dosing without end-organ toxicities. Another focus of new drug development is the application of the array technologies to help individualize the therapies to a given tumor by assessing the presence of the genotypically derived targets. Regardless of the approach, each of the therapeutic approaches must first be developed by using well-established pharmacologic principles to define the optimal dose (not necessarily a single dose or short-course MTD) and schedule.18,19 In addition, the recent publications should also remind us that we need to scientifically re-evaluate our existing armamentarium to define whether they might be used in more optimal ways.5-8,13,20 One such approach requires that we apply the traditional pharmacologic principle of concentration x time. How can we use this principle to improve efficacy? Perhaps a theoretical example would serve to illustrate the issues. High-dose chemotherapy delivered as a single (or closely spaced) dose may not make sense for a solid tumor with a long doubling time relative to the presence of the active drugs. In this circumstance, only a small proportion of the tumor cells will be susceptible. If 2 to 3 g/m2 of cyclophosphamide in 2 to 3 days does not eliminate a breast cancer, then it is highly unlikely that 4 to 5 g/m2 given over a similar time period will be any more effective. First, much of the parent drug will be eliminated in the urine, and second, increasing the dose over the same time period will not likely expose a greater number of cancer cells. Because time may be a more critical variable (ie, prolonged exposure at a minimally effective concentration is more likely to expose a greater number of cancer cells), an approach to define time would be very helpful. If we define a desired drug concentration, then a median effective concentration (EC50) for 30 days may be better than an EC1500 for 1 day, even though the calculated drug exposure is the same. Are there any data to substantiate this concept? When etoposide was given as a daily dose for 21 days, it demonstrated less toxicity and paradoxically greater efficacy than a similar total dose administered as a 24-hour infusion (see review in Hainsworth and Greco20). Thus the smaller, more frequent dose was more effective than the larger bolus dose even though the area under the curve was the same. Whether the improved efficacy and reduced toxicities were related to the actions of the agent on other targets such as the vasculature now becomes an area of intense interest and an area ripe for translational research. When we use time as a variable we may need to define new end points. MTDs and DLTs that are classically defined for only a few closely spaced doses may totally miss the optimal dosing approach. The MTDs and DLTs of longer-exposure, lower-dose schedules may be entirely different from the classic toxicities associated with intermittent higher doses. Weekly taxanes clearly illustrate these points. Weekly paclitaxel at 80 mg/m2 generates less neurotoxicity and count suppression than 225 mg/m2 every 3 weeks, but other toxicities such as weakening of the nails are seen. If, for example, we wished to push drugs to their time limits, we would take advantage of the t variable in the e-ket relationship and continue the treatment for longer periods. Instead of using cyclophosphamide as part of the cyclophosphamide, methotrexate, and fluorouracil combination for 14 days for patients with breast cancer, we might extend it to 21 or more days and then add the supportive care technologies, if needed. The radiation oncology community has long understood that frequent low doses offer better therapeutic ratio over less frequent higher doses. On the basis of these concepts, we propose a new old concept for cancer therapy designed to eradicate a greater percentage of cancer cells: namely, high-time chemotherapy. High-time therapy would seek the longest time for drug exposure at a given desired drug concentration. When an effective dose of a drug can be maintained for 14 days with little, but reversible, marrow (or other) toxicity, then we could either increase the daily dose during these 14 days or extend the same dose to 21 or more days until the greatest time can be achieved that results in a DLT. Other areas of interest would be whether supportive care technologies can be used to further the time exposure. The correlation of clinical outcome with inhibition or stimulation of a specific biochemical parameter (target) would further enhance rational schedule design. Oncology has entered a new and very exciting era. The investments that were made into our understanding of the basic mechanism of cancer biology and the technologies spawned from these studies are now on the verge of paying off in terms of new highly specific and selective therapies. We are at a crossroads in the development of our therapies. Some of our most effective regimens were developed in part through careful clinical trials and built on empiric successes. These can undoubtedly be improved through application of new techniques and knowledge. For example, analysis of successes and failures can lead to risk-based therapy. Newer therapies can now be more rationally designed from a base of genomics, proteomics, and informatics. Although these newer approaches to therapy offer exciting possibilities, they all must undergo a careful evaluation for defining optimal dosing.21,22 Concurrent with the evaluations of these newer approaches, we must re-examine our existing and extant therapies as potential high-time therapies. Important principles of drug dose and schedule, regardless of the target cells, need to be incorporated into protocols with intermediate end points or surrogate markers of treatment success or failure. Public or underwriter pressure, allure of high-dose therapy, and technical capabilities for the sake of the technology (eg, supportive care) should not drive the treatment algorithms unless they are based on sound scientific data.23 More is not always better, and this is a high time for low dose. REFERENCES
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Copyright © 2000 by the American Society of Clinical Oncology, Online ISSN: 1527-7755. Print ISSN: 0732-183X
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