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Journal of Clinical Oncology, Vol 23, No 15 (May 20), 2005: pp. 3645-3646 © 2005 American Society of Clinical Oncology. DOI: 10.1200/JCO.2005.05.270
Resisting a Fundamentalist PolicySaratoga Springs, NY To the Editor: In the September 1, 2004, issue of the Journal of Clinical Oncology, two sets of authors reviewed the experience to date with in vitro chemosensitivity testing (IVCT).1,2 Schrag et al2 also developed an American Society of Clinical Oncology (ASCO) policy statement for practitioners. While IVCT still waits for validation in prospective randomized trials, there are provocative reports that consistently show higher response rates for assay-directed therapy. These data are largely exploratory or descriptive, and none of these reports has yet addressed classical regulatory end points such as time to progression, survival, or quality of life in a convincing manner. As a matter that perhaps should bother our clinical consciences, pivotal randomized trials of IVCT have yet to be undertaken. But given the positive and intriguing nature of the published results, both sets of authors call for randomized trials to be pursued. On the other hand, the ASCO committee goes one step further, admonishing the use of IVCT outside of a clinical trial setting. Is such an admonition justified, especially when there are no such clinical trials available? In my opinion, proscription against this approach is an excessively conservative conclusion. Certainly, we are nowhere near creating a standard of care to either support or deny this approach, meaning that in general it cannot be routinely recommended for clinical decision making. But should it be denied to patients, including those who walk in the door asking for it? Such an extreme proscription against testing outside a clinical trial makes it sound as if the existing data on the subject are largely negative. Yet, the review by both sets of authors hardly establishes such grounds for a summary admonition. Thus, we should reject their extreme proscription. Paradoxically, as the number of possible treatments options supported by completed randomized trials increases, the scientific literature becomes increasingly vague for guiding physicians. For example, almost any doublet that incorporates a taxane or gemcitabine is acceptable in the treatment of non–small-cell lung cancer these days, but this does not mean that generalizations about equivalence establish equal efficacy for all approaches in an individual patient. Moreover, clinicians are confronted on nearly a daily basis by decisions that have not been addressed by randomized trial evaluation. Indeed, a great many promising observations will never make it to prospective controlled evaluations because of scarce resources. Nevertheless, clinical decisions are made according to experience, new basic science insights, bias or personal preference, philosophical beliefs, and so on—in short, the so-called art of medicine. With these uncertainties, would it be wrong to make a clinical decision based on IVCT? Where the certainty of clinical science fails, leaving only marginal treatment options and a certain unsatisfactory outcome, other questions become highlighted for patient care: (1) Is there any new insight about cancer biology that would enable us to do better for a particular patient? (2) Is there any technology or methodology available that might generate an outcome superior to what has been historically possible? (3) Is there anything about this patient’s particular malignancy that could be exploited for a superior outcome? For a given patient, IVCT could have bearing on each of these points. Beyond the scientific proof afforded by definitive trials, there is sure to be controversy and risk for patients. Nevertheless, policy-level circumscription of clinical initiative to help patients outside of what is established by randomized trial results or participation advances a naive conservatism without due credit to responsibly made observations (ie, the early or maturing science) that awaits organized prospective evaluations. For those who espouse this approach, I don’t argue with it as a chosen practice style. But as ASCO policy, we should resist the deterioration of conservatism into an intolerant view about clinical practice that constrains autonomy and discourages what may be a highly justifiable initiative. To my knowledge, ASCO has not been knighted a regulatory agency. With the absence of effective laboratory tests to guide practice, many patients do not get even a second chance at treatment when their disease progresses. On the other hand, the clinical necessity of spending 6 to 8 weeks to diagnose treatment failure often consumes a substantial portion of a patient’s remaining survival, and not infrequently with profound toxicity. Therefore, the call to quash the use of a laboratory test that might avoid a useless intervention makes an uncalled-for, if not irrational, orthodoxy bordering on fundamentalism. In most cases what we have achieved for patients through the randomized trial mechanism is still far too little to circumscribe the initiative of individual practitioners, particularly in a field growing as rapidly as cancer medicine. Until the trialist approach has delivered curative results with a high success rate, the clinical autonomy to integrate promising insights and methods, including IVCT, remains an essential component of patient advocacy. No doubt, beyond scientific consensus is a wilderness of potential clinical pitfalls that require specialized consent for patients and shrewd judgment on behalf of their oncologists. In the area of in vitro testing, it would be difficult to justify an effort to surpass randomized trials-based approach in most adjuvant settings. Additionally, the risks and discomfort associated with the procurement of fresh, live tissue when there is a highly effective treatment at hand has generally mitigated the use of IVCT on a consistent basis in my practice. But there are many worthy exceptions. Patients who want testing after a thorough discussion about the limited experience that supports it are not being outrageous, and should not be summarily hindered by a restrictive ASCO policy. At its inception approximately two decades ago, the results of a chemosensitivity test might have meant the difference between receiving treatment and not receiving any treatment at all. Since then, the proliferation of treatment options should encourage us to foster any methodology that can prioritize these options to enhance efficacy and spare toxicity. While the pharmacogenomic revolution appears to be having growing pains that could take quite a long time to sort out, IVCT is an immediately available method for distinguishing between marginal choices. Let’s not take it away prematurely. Author's Disclosure of Potential Conflicts of Interest The author or his immediate family members have indicated a financial interest. No conflict exists for drugs or devices used in a study if they are not being evaluated as part of the investigation. Consultant: Michael Castro, Sanofi-Synthelabo, Genomic Health. For a detailed description of these categories, or for more information about ASCO’s conflict of interest policy, please refer to the Author Disclosure Declaration and the Disclosures of Potential Conflicts of Interest section of Information for Contributors found in the front of every issue. REFERENCES
1. Samson DJ, Seidenfeld J, Ziegler K, et al: Chemotherapy sensitivity and resistance assays: A systematic review. J Clin Oncol 22
: 3618
-3630, 2004
2. Schrag D, Garewal HR, Burstein HJ, et al: American Society of Clinical Oncology technology assessment: Chemotherapy sensitivity and resistance assays. J Clin Oncol 22
: 3631
-3638, 2004
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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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