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Journal of Clinical Oncology, Vol 23, No 12 (April 20), 2005: pp. 2868-2869 © 2005 American Society of Clinical Oncology. DOI: 10.1200/JCO.2005.05.300
In Reply:Department of Breast Medical Oncology, The University of Texas M.D. Anderson Cancer Center, Houston, TX Montemurro et al add to the existing controversy about optimal duration of trastuzumab administration. Why is this a controversy in the first place? In oncology it is standard practice to discontinue the administration of an antitumor agent, whether cytotoxic, endocrine, or biologic, once disease progression occurs during the administration of that agent. It appears evident that if such an agent is unable to stop the growth of the tumor being treated, continued administration might add toxicity but not therapeutic benefit. Over the years, this assumption has been challenged several times without success. In the 1970s, some oncologists would administer a single agent or a combination of two drugs, and on documentation of disease progression, would continue the drugs but would also add one or two more agents; the underlying assumption was that the first drug could still be effective with some clones of cells while the second drug would attack others.1 Eventually this practice disappeared for lack of supportive evidence. A somewhat different reasoning drove the indefinite administration of tamoxifen. On development of progressive disease while receiving tamoxifen, some oncologists continued giving this drug while adding a second endocrine intervention, a progestin for instance. It was hypothesized that chronic competition for the estrogen receptor would suppress estrogen action by one mechanism, while the progestin would suppress tumor growth by another. There was no experimental evidence for either of these hypotheses, but that did not dissuade believers from following this practice. Eventually a prospective randomized trial established that there was no benefit in continuing tamoxifen beyond disease progression, and a clean change in therapy was the optimal strategy.2,3 Trastuzumab has multiple proposed mechanisms of action, including antibody-dependent cellular cytotoxicity, cell cycle arrest, downregulation of HER2 signaling, potentiation of chemotherapy effect, and so on.4 Many investigators assumed that the predominant mechanism of action was downregulation of the growth-factor–signaling pathway, and this led to the hypothesis that chronic suppression of HER2 signaling would be beneficial by interrupting the continued growth stimulation constitutive HER2 activation exerted over the cell. Although this is a reasonable hypothesis, there is little preclinical evidence in support. Moreover, the clinical data in support of this practice are even weaker. Practice pattern surveys suggest that approximately 50% of oncologists continue to administer trastuzumab beyond disease progression on a trastuzumab-containing regimen. The clinical data available in the literature or presented at meetings are all based on retrospective analyses of subsets of patients who participated in a clinical trial or in single institution experiences.5,6 Montemurro et al made a valiant attempt at analyzing retrospectively their own experience with continuation of trastuzumab beyond disease progression. However, none of these two approaches accounts for the selection bias that goes into ad hoc therapeutic decisions. Therefore, the only way to generate reliable data is by performing the appropriate controlled clinical trial. However, this has proven easier said than done. My group at the M.D. Anderson Cancer Center proposed such a trial in 1999; a protocol was developed, was vetted by the appropriate internal committees, and was approved by the sponsor for activation as a multicenter trial. The design was simple: on documentation of progressive metastatic breast cancer while receiving a taxane plus trastuzumab-containing regimen, chemotherapy would be changed from the taxane to vinorelbine, and based on a randomization, trastuzumab would be stopped or continued until progressive disease was documented again. After 18 months and the contribution of more than 30 centers, 17 patients had been registered onto this trial, most of them from a single institution. Every investigator with whom we discussed the trial was enthusiastic about it, but accrual lagged. It was eventually closed 2 years ago, and is currently being recast as an Intergroup trial, sponsored and led by the Southwest Oncology Group. Although the long terminal half-life of trastuzumab will complicate interpretation of the data, this is clearly the best opportunity to determine whether continuation of trastuzumab beyond disease progression is useful or not. Although modern medicine is largely evidence-driven, there are specific examples where enthusiasm overtook reason: the broad adoption of high-dose chemotherapy as the leading standard before any evidence supporting it was generated was one example, and the routine, long-term administration of postmenopausal hormone-replacement therapy without even assessing its safety was another.7,8 These experiences were sobering because it is likely that more patients were hurt than benefited by these practices. Trastuzumab is largely well tolerated. However, cardiac toxicity has been documented, especially in combination with anthracyclines, and the drug is very expensive. Treating patients unlikely to benefit from the drug exposes them to potentially serious toxicity, and wastes resources. Conversely, not confirming the hypothesis under discussion, should it be true, would deprive thousands of women of a potentially beneficial therapeutic intervention. Neither option is attractive, therefore, we must succeed with the proposed clinical trial. Author's Disclosures of Potential Conflicts of Interest The author indicated no potential conflicts of interest. Acknowledgment The authors whish to acknowledge Dr Gabriel N. Hortobagyi for reviewing this letter. REFERENCES 1. Rosner D, Nemoto T, Lane WW: A randomized study of intensive versus moderate chemotherapy programs in metastatic breast cancer. Cancer 59:874-883, 1987[CrossRef][Medline] 2. Pronzato P, Rubagotti A, Amoroso D, et al: Second-line hormonotherapy for breast cancer: Uselessness of first-line continuation. Am J Clin Oncol 16:522-525, 1993[Medline] 3. Byrne MJ, Gebski V, Forbes J, et al: Medroxyprogesterone acetate addition or substitution for tamoxifen in advanced tamoxifen-resistant breast cancer: A phase III randomized trial—Australian-New Zealand Breast Cancer Trials Group. J Clin Oncol 15:3141-3148, 1997[Abstract] 4. Rubin I, Yarden Y: The basic biology of HER2. Ann Oncol 12:S3-S8, 2001 (suppl 1)
5. Tripathy D, Slamon DJ, Cobleigh M, et al: Safety of treatment of metastatic breast cancer with trastuzumab beyond disease progression. J Clin Oncol 22:1063-1070, 2004 6. Gelmon KA, Mackey J, Verma S, et al: Use of trastuzumab beyond disease progression: Observations from a retrospective review of case histories. Clin Breast Cancer 5:52-58, 2004 [Discussion: Clin Breast Cancer 5:59-62, 2004][Medline]
7. Hortobagyi GN: High-dose chemotherapy for primary breast cancer: Facts versus anecdotes. J Clin Oncol 17:25-29, 1999 8. Beral V, Banks E, Reeves G: Evidence from randomised trials on the long-term effects of hormone replacement therapy. Lancet 360:942-944, 2002[CrossRef][Medline]
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Copyright © 2005 by the American Society of Clinical Oncology, Online ISSN: 1527-7755. Print ISSN: 0732-183X
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