Trial Design Types

The first issue to clarify is what, specifically, is meant by the MTD, for as Storer9 points out, "a strict quantitative definition of the MTD is rarely acknowledged in clinical protocols." As discussed previously, a dose given to an individual patient is deemed "tolerable" in that patient if he/she does not experience a DLT, but in statistical terms the MTD must be defined with reference to the patient population. By virtue of the traditional and still frequently used "3 + 3" design, described below, the MTD is usually defined as the highest dose level for which the incidence of DLT is less than 33%. Thus, when employing this design, we are saying that we want to determine the dose that will be tolerable in at least 2/3 of the patients, and therefore are accepting that serious toxicity will be produced in up to 1/3 of the patients. Given that most cancers carry an appreciable risk of mortality, this seems an appropriate percentile to target, but it should not be used unthinkingly. There may be some patient populations, for example, in whom a lower percentile would be more appropriate; conversely, patients at a very high risk of mortality or morbidity may be willing to accept a greater chance of serious side effects for potential therapeutic benefits.

In the traditional "3 + 3" design11 (Table 8.1), groups of three patients are treated. If none experiences a DLT, the dose is escalated, whereas if two or more experience a DLT, dose escalation is terminated and the previous dose level is provisionally defined as the MTD. If one of three has a DLT, three more patients are added at the same dose level, and if none of these has dose-limiting toxicity, dose escalation continues; otherwise, the previous dose level is considered the MTD. Once a presumed MTD is reached, however, if only three patients have been studied at that dose, three more are added and if two or more of these patients experience a DLT (yielding greater than one of six), further dose reduction occurs. Thus, it is intuitive that this design is targeting a dose that is close to but less than the 33rd percentile. Simulations conducted by Storer9 and others indicate that it is nearer to the 25th percentile.

Accelerated Titration

One criticism of the traditional design, particularly when accompanied by a conservative starting dose, is that too many patients are treated at subtherapeutic levels. Simon et al.12 have therefore proposed a variant of the "3 + 3" algorithm, known as the accelerated titration design, to overcome this problem. Essentially, only one patient is treated at each dose level, and the dose is doubled for each subsequent patient until either a DLT is observed or two patients experience grade 2 or higher toxicity. At this point the design reverts to the traditional "3 + 3" with subsequent dose increments of 40%. Intrapatient dose escalation is also permitted if the patient had no worse than grade 1 toxicity at the previous

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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