How Should Tumor Markers Be Selected for Clinical

To summarize the preceding paragraphs, a good tumor marker study should provide accurate estimate of the magnitude of difference in outcomes between subgroups of patients who are positive or negative for the marker, using a reliable, accurate, and reproducible assay. Do prognostic and predictive factors exist that permit such elegant selection of patients for treatment? Sadly, in most solid tumors, the answer is no. For patients with newly diagnosed solid malignancies, there is no example of a prognostic factor that predicts subsequent recurrence and death with absolute certainty. Therefore, when these markers are applied in the clinic, both physician and patient must accept some margin of error. These decisions involve both the tumor marker results, as already discussed, and also a careful assessment of the magnitude of effectiveness of therapy for the patient's condition (proportional reduction in risk of events), the degree of toxicity of that therapy, and the patient's willingness (as well as the caregiver's and society's) to either forgo potential benefit to avoid toxicity or to accept toxicity and cost to gain benefit.

Therefore, part of the art, and science, of medicine is to determine which markers are most reliable in separating groups of patients into those that will do well from those that will not, and into those that will benefit from therapy from those that will not. If performed appropriately, tumor marker analysis should permit delivery of therapy as efficiently as possible, providing benefit to the greatest number of patients while avoiding exposure to toxicities as much as possible.

Levels of Evidence (LOE) to evaluate tumor markers have been proposed, again by the American Society of Clinical Oncology Expert Panel on Tumor Markers (Table 7.3).4 LOE I data are generated from either a prospective, highly powered study that specifically addresses the issue of tumor marker utility or from an overview or meta-analysis of studies, each of which provides lower levels of evidence. LOE II data are derived from companion studies in which specimens are collected prospectively as part of a therapeutic clinical trial, with preestablished endpoints and statistical evaluation for the marker as well as for the therapeutic intervention.

Ideally, the estimate of the relative strength of a marker for clinical utilities should be determined within the context of LOE I (or at worse II) studies. In these studies, the marker is the primary objective of a well-designed, highly powered, hypothesis-driven prospective clinical trial, or it is the objective of a statistically rigorous overview of LOE II and/or III studies. Furthermore, the strength of new prognostic or predictive factors can only be estimated by multivariate analytical methods, including preexisting accepted factors such as TNM staging and histopathology. It is possible that a marker may be quite prognostic or predictive when considered in a univariate fashion but that it is, in fact, only reflecting information already achieved through other, established methods. In this case, acceptance of the new marker would only occur if it can be performed more easily or reliably or less expensively.

TABLE 7.3. Levels of evidence for grading clinical utility of tumor markers.

Level Type of Evidence

I Evidence from a single high-powered prospective study that is specifically designed to test marker or evidence from meta-analysis and/or overview of Level II or III studies. In the former case, the study must be designed so that therapy and follow-up are dictated by protocol. Ideally, the study is a prospective randomized trial in which diagnostic and/or therapeutic clinical decisions in one arm are determined based at least in part on marker results, and diagnostic and/or therapeutic clinical decisions in control arm are made independently of marker results. However, may also include prospective but not randomized trials with marker data and clinical outcome as primary objective.

II Evidence from study in which marker data are determined in relationship to prospective therapeutic trial that is performed to test therapeutic hypothesis but not specifically designed to test marker utility (i.e., marker study is secondary objective of protocol). However, specimen collection for marker study and statistical analysis are prospectively determined in protocol as secondary objectives.

III Evidence from large but retrospective studies from which variable numbers of samples are available or selected. Therapeutic aspects and follow-up of patient population may or may not have been prospectively dictated. Statistical analysis for tumor marker was not dictated prospectively at time of therapeutic trial design.

IV Evidence from small retrospective studies which do not have prospectively dictated therapy, follow-up, specimen selection, or statistical analysis. May be matched case controls, etc.

V Evidence from small pilot studies designed to determine or estimate distribution of marker levels in sample population. May include "correlation" with other known or investigational markers of outcome, but not designed to determine clinical utility.

Source: From Hayes et al.,4 by permission of Journal of the National Cancer Institute.

A Disquistion On The Evils Of Using Tobacco

A Disquistion On The Evils Of Using Tobacco

Among the evils which a vitiated appetite has fastened upon mankind, those that arise from the use of Tobacco hold a prominent place, and call loudly for reform. We pity the poor Chinese, who stupifies body and mind with opium, and the wretched Hindoo, who is under a similar slavery to his favorite plant, the Betel but we present the humiliating spectacle of an enlightened and christian nation, wasting annually more than twenty-five millions of dollars, and destroying the health and the lives of thousands, by a practice not at all less degrading than that of the Chinese or Hindoo.

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