Editorial
NEJM
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Robert E. Wittes, M.D.
Of the many things that physicians do, participating in cooperative clinical trials is among the strangest. Relatively undervalued in the typical academic promotion-and-tenure process, often inadequately reimbursed by government funding agencies, faced with informed-consent regulations that vastly exceed in degree of disclosure what is required for routine care, and confronting progressively greater degrees of regulation with each passing year, the clinical trialist may be forgiven for occasionally wondering whether society really wants this kind of work to go forward.
In the end, however, it does go forward. Some of the fuel for the engine is a stream of products from the drug and device industries, often accompanied by industrial-strength incentives. A large number of trials, however, are divorced from the bottom-line needs of companies and are carried out with public dollars and in the public interest. The oldest and largest coordinated effort of this kind is the cooperative-trials program funded by the National Cancer Institute (NCI). About 50 years old now, the program comprises 10 major networks and several smaller ones, involving thousands of oncologists in academic centers and community sites throughout North America and countries overseas. Physicians participate in this work for the best possible reason: they wish to be personally involved in the process of making medical interventions better.
This issue of the Journal contains an example of the yield.1 The trial by Grier et al. comparing two strategies of multidrug treatment for certain highly malignant bone tumors of childhood, each combined with appropriate local therapy to the primary site, shows that sequential alternation of two drug combinations is significantly superior to the use of one combination alone. The degree of superiority is substantial: a 28 percent improvement in five-year event-free survival and an 18 percent improvement in five-year overall survival among patients with nonmetastatic disease. This improvement is achieved at the expense of some increase in the incidence of infection and the number of days in the hospital, but overall, any differences in toxic effects and convenience do not begin to attenuate the overall improvement in outcome. The preferential suppression of local, as opposed to distant, recurrence suggests that the augmentation of the anticancer effect may result from improved interaction between chemotherapy and the local treatments.
Two additional features are sobering. The 14-year interval between the beginning of this study and the publication of the final report seems longer than what would be required for reliable ascertainment of major events. Also, this trial was based on drugs and methods that had all been available for many years before the study began. Nevertheless, the results are medically important and have already altered the standard of care.
Adequate accrual rates are the lifeblood of clinical trials. Without them, studies wither, and the delivery of new information to improve medical practice is delayed, sometimes past the point of interest and relevance, or studies may be aborted altogether. In the case of the present study, however, the surprisingly rapid rate of accrual early in the trial allowed something even more important than mere speed of execution. It permitted an interim increase in the size of the study so that definitive results could be obtained for the major subgroup of interest � patients with nonmetastatic disease. Obtaining these results was a major achievement, since the findings now permit decisions about treatment and planning of subsequent studies to proceed on much firmer ground.
Among oncologic specialists, pediatric oncologists are in an enviable position. Because childhood cancer is rare, pediatricians long ago accepted the need for extensive multicenter cooperation to determine the value of new therapies reliably. Pediatric oncologists are concentrated in academic health centers, and it is there that most children with newly diagnosed cancer are referred for treatment. Finally, for reasons that are still obscure, many childhood cancers are very responsive to treatment, and cure has long been both a feasible objective for treatment and a powerful motivator of physicians' behavior. As a consequence of this alignment of favorable tumor biology with a culture oriented toward cooperative clinical research, the majority of children with cancer in the United States receive definitive treatment for cancer while enrolled in clinical trials. The benefits have been monumental; the curability of most cancer in childhood stands as one of the great success stories of modern medicine.
By contrast, many adult cancers are quite common, and most of the common ones are relatively refractory to treatment once they have spread beyond the primary site. Most adult patients are treated in the community, rather than in academic centers. The strength of the commitment to clinical trials on the part of many community oncologists is shown by performance: about one third of the accrual for cooperative-group trials sponsored by the NCI comes from community practices. Even so, in sharp contrast to the case for children, the number of adults with cancer who enter clinical trials appears to be a very small percentage of the total,2 so there is plenty of untapped reserve with which to bolster the accrual rates of key cancer studies. In order to do so, funding organizations must find the resources to support the increased participation of highly motivated physicians.
For the past several years, the NCI, its clinical-trials groups, and outside advisors have been engaged in a substantial restructuring of its programs3; one important goal is to improve the access of patients and physicians to NCI-funded trials. Current evidence suggests that there has been substantial improvement during the past three to four years in the speed of completion of major NCI-sponsored randomized clinical trials involving adults (Christian M: personal communication).
The molecular basis of much childhood cancer is increasingly well defined. As new drugs are developed that target pathogenetic or phenotypic molecular lesions, the eligibility of patients for trials will depend in part on the expression of the target. Analysis of tumor tissue will also permit prospective stratification and retrospective analysis of the relation of therapeutic response and other outcome measures to molecular phenotype. The oncology community is currently grappling with the difficult and expensive challenge of providing adequate and meaningfully annotated tissue resources as an indispensable tool for the next generation of clinical trials. To the extent that a particular disease becomes increasingly subdivided according to patterns of molecular expression, trials of new therapies may actually evolve into several separate studies of molecularly defined subgroups. In this scenario, patients' access to trials and their willingness to participate in them are likely to become, even more than they are now, the rate-limiting factors.
But if accrual is the lifeblood of a clinical-trials program, the actual interventions to be tested � the drugs, the diagnostics, and other innovative devices � are its heart. Currently, there is reason to wonder whether the progressive subdivision of even common adult tumors into a large number of molecularly specific subgroups will remove the large-market incentive that drives decision making in the pharmaceutical industry. However one regards this threat, it pales in comparison with the prospects for the discovery of drugs for pediatric cancers, an arena in which a market incentive has never existed. Pediatric cancer is a success story today because the chemotherapeutic agents of the past 50 years, brought to the clinic for testing mainly in adults, happened to work even better in children. Since the relevant molecular targets of the future are likely to differ between adult and childhood tumors, there is no reason to expect a similar "success by accident."
Pediatric oncologists of the future will not have much to work with unless the leaders of drug-discovery programs regard the molecular lesions of pediatric tumors as worth their time and effort. The pharmaceutical industry currently has no incentive to think this way. The National Cancer Policy Board is currently sponsoring working groups about this and other barriers to the timely development of anticancer drugs. It seems likely that novel models for discovery and development will be necessary in order to create the tools on which further progress against childhood cancer will depend.
Source Information
From the Memorial Sloan-Kettering Cancer Center, New York.
References
- Grier HE, Krailo MD, Tarbell NJ, et al. Addition of ifosfamide
and etoposide to standard chemotherapy for Ewing's sarcoma and primitive
neuroectodermal tumor of bone. N Engl J Med 2003;348:694-701.
[Abstract/Full Text] - Facts and figures about cancer clinical trials. Bethesda, Md.: National Cancer Institute, 2002. (Accessed January 30, 2003, at http://cancer.gov/clinicaltrials/facts-and-figures.)
- Cancer clinical trials: a new national system. Bethesda, Md.: National Cancer Institute, 2003. (Accessed January 30, 2003, at http://cancer.gov/common/popups/popNationalSystem.htm.)