Response evaluation

Response Criteria Evaluation of target lesions

♦ Complete Response (CR) Disappearance of all target lesions

♦ Partial Response (PR) At least a 30 per cent decrease in the sum of the longest diameter (LD) of target lesions, taking as reference the baseline sum LD

♦ Progressive Disease (PD) At least a 20 per cent increase in the sum of the

LD of target lesions, taking as reference the smallest sum LD recorded since the treatment started or the appearance of one or more new lesions

Box 3.3 (continued)

Response Criteria

* Stable Disease (SD)

* Complete Response (CR)

* Incomplete Response/ Stable Disease (SD)

* Progressive Disease (PD)

Evaluation of target lesions

Neither sufficient shrinkage to qualify for PR nor sufficient increase to qualify for PD, taking as reference the smallest sum LD since the treatment started.

Evaluation of non-target lesions

Disappearance of all non-target lesions and normalization of tumour marker level Persistence of one or more non-target lesion(s) or/and maintenance of tumour marker level above the normal limits

Appearance of one or more new lesions and/or unequivocal progression of existing non-target lesions of the form, 'what is the probability that the true response rate exceeds x per cent?' One such design, introduced by Fleming [4] takes as a starting point the assumption that for any new treatment, there will be a level of response, p1, below which - in the light of response rates for standard therapy - the treament would not be considered for further study, and a higher level, p2, above which the treatment would certainly warrant further investigation. The sample size is determined by the need to minimize the probability of concluding that the response rate is greater than p1 when that is false and to minimize the probability of concluding that the response rate is less than p2 when that too is false.

However, as in many clinical situations, summarizing the results of a study simply in terms of a p value from a hypothesis test is of limited value. Given the twin desires of treating as few patients as possible with an insufficiently active treatment, while treating enough patients to gain a reasonably precise estimate of efficacy, the first phase II trials of a new treatment may often be conducted in two stages. Gehan [5] proposed such a design where, in the first stage, the aim is to screen out insufficiently active treatments. A set number of patients are treated (the number is determined by the minimum acceptable response rate and the maximum acceptable probability of rejecting an effective treatment); if no responses are seen, the trial proceeds no further. If any responses are seen, the trial continues to the second stage in which sufficient patients are treated to estimate the response rate with a given level of precision.

An alternative two-stage design is given by Simon [6]. This takes as its premise the point of view that the aim of a phase II trial is simply to screen out inadequate treatments at as early a stage as possible, that large numbers are needed to provide reasonably precise estimates of response rates, and therefore that estimation should not be the main aim of a phase II trial. Therefore the design allows either the number of patients in the first stage, or the total number of patients to be minimized if the treatment has an inadequate response rate, subject to specification of the error rates. As for the Fleming single-stage design, this requires specification of an unacceptable level of activity (p1) and an activity level above which there would be interest in taking the treatment forward for further testing (p2).

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