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Clinical Research Saves Money: Reflections on High-Dose Therapy of Breast Cancer

THE CONTROVERSY GENERATED by the recent presentations at the plenary session of the 35th annual meeting of American Society of Clinical Oncology (ASCO) regarding the merits of high-dose therapy in the treatment of breast cancer from four randomized trials again highlights the social and economic importance of clinical cancer research in our society. The growth of high-dose therapy for breast cancer and other solid tumors has its origins in the demonstration that markedly increased doses of active cytotoxic agents or high-dose chemoradiotherapy plus autologous bone marrow or peripheral stem-cell reinfusion could salvage some patients with relapsed or refractory hematologic cancers. The higher order of resistance of epithelial cancers to conventional-dose chemotherapy was well appreciated, but some experimental evidence in human tumor cell lines suggested that there was a lack of cross-resistance among different alkylating agents—a concept that was not demonstrated in patients with solid tumors.^1-3 Nonetheless, it was unknown whether combined high-dose alkylating agent therapy could significantly impact the outcome of high-risk adjuvant or metastatic disease in a positive way.

The giant leap from developmental therapeutics and early clinical trials to community-wide applications of high-dose therapy circumvented essential scientific scrutiny. The forces that propelled this approach into widespread use without definite scientific validation are numerous and reflect a disordered (and by definition expensive) approach to the introduction of new treatments, some of which can be costly in morbidity as well as dollars. Because not all cases are submitted to a central registry, it is impossible to assess the total cost of the widespread application of high-dose therapy of breast cancer. The well-intentioned but premature enthusiasm of patients and advocates was adapted to the "medical industry" at a time when physicians knew it was toxic, expensive, and experimental.

Commentaries from some investigators presenting data at the plenary session supported the theme that high-dose therapy needed further investigation in the setting of a clinical trial. Given the questions raised as to the value of high-dose therapy, what happens to the reimbursement policy of third parties? Are the results of courtroom decisions and legislative actions to be questioned and possibly reassessed? Do they recant their previous policies? Should they confine their support to trials that ask important questions? It is obvious to this writer that not all that passes for a "clinical trial" is indeed one designed to gain meaningful information.

There are many examples in oncology where controlled clinical trials have definitively changed medical practice with considerable savings in unnecessary and excessive treatment, such as the demonstration that prolonged chemotherapy in adjuvant breast treatment was no better than shorter duration; that 12 months of alternating MOPP with ABVD was no better than 6 months of ABVD alone in the treatment of advanced Hodgkin's disease; the replacement of surgical hormonal ablation by medical substitutes, to name a few.

How can the process be improved? The public interest is best served by insisting on a peer-reviewed system through a "fair broker" (the National Cancer Institute [NCI] or other impartial public bodies, such as the United States Department of Defense) working in concert with investigators and the representatives of the third-party payers. A uniformity of opinion that a new treatment is expensive and unproven should be the starting point. Next would be the implementation of trials that are beyond the developmental phase I/II stage and designed to study the efficacy of the new treatment in broader patient groups. The clinical costs for participation in these approved trials should be paid for by third parties. The latter are justified in re-examining the policy of indiscriminate reimbursement and focusing their financial efforts on supporting the clinical research because, in some ways, they are the potential beneficiaries of this process. A concerted effort must be made to reform the implementation of clinical trials designed to define the most effective, least morbid, and/or least expensive treatment. The payers must be brought initially into the process to fund the appropriate trials rather than be forced by legislation or court action to pay for the unproven, perhaps well-intentioned, treatments.⁴ The currently contemplated reforms by the NCI will not correct this deficiency unless the scientific importance of "approved clinical trials" is accepted by patients, physicians, and the payers. It must be agreed that new treatments are unproven and therefore must be a subject for clinical investigation. Patients who are on such approved trials may, in fact, get better care and closer observation; they should be reassured that they are not receiving a known inferior control therapy. Whether they are the beneficiaries of the experimental therapy is the goal of the trial.

If the process can be efficiently undertaken, then resources will be saved. Knowledge, negative or positive, will be accumulated in a more timely fashion. Ultimately the patient would be the beneficiary of the progress and not the victim of unproven innovation.

It is clear from the presentations at the ASCO annual meeting that the heralded results of some trials are underpowered to provide definitive answers. This gives further importance to the role of intergroup participation to maximize patient accrual. We must be prepared for the possibility of small (at best) or statistically minute differences in the continuous follow-up of these and other series. The mortality rate, although reduced to a low level, may equal the salvage value of high-dose therapy and thus obscure the differences. On the other hand, there may be a niche for this approach in certain subtypes of unfavorable breast cancer, such as some forms of locally advanced disease. Well-designed clinical trials should continue to address this question.

There have been few studies comparing the costs of a clinical trial in oncology that defines the correct approach to a particular disease with the consequence of widespread use of an unproven treatment. Perhaps high-dose therapy of breast cancer will provide such an opportunity.

REFERENCES

1. Frei E, Cucchi C, Rosowsky A, et al: Alkylating agent resistance: In vitro studies of human cell lines. Proc Natl Acad Sci U S A 82:2158-2162, 1985[Abstract/Free Full Text]

2. Teicher B, Cucci C, Lee J, et al: Alkylating agents: In vitro studies of cross-resistance patterns in human tumor cell lines. Cancer Res 46:4379-4383, 1986[Abstract/Free Full Text]

3. Scabel F: Patterns of resistance and therapeutic synergism among alkylating agents. Fundam Cancer Chemother 23:200-215, 1978

4. Canellos GP: Selection bias in trials of transplantation for metastatic breast cancer: Have we picked the apple before it was ripe? J Clin Oncol 15:3169-3170, 1997[Medline]

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