With respect to Dr. D'Angio's presentation on second malignancies, some discussion on the overall frequency of second cancers in all sites of patients included in his survey would be helpful. One must not only be interested in the second cancers within irradiated areas, but additionally the total incidence in all sites. Needless to say, even a modestly increased incidence of second malignancies would not detract from marked improvements in survival resulting from combined therapy. A second point relates to the case-control method, where the potential always exists for unwitting bias in terms of selecting the control population. Such can be illustrated by the data shown for antifolates, for example. Deletion of the pilot study cases treated with antifolates reversed the relative risk ratio seemingly present in the larger total study. When removal of a fraction of cases serves to reverse completely an initial set of findings, the question of statistical manipulation cannot help but be raised. Finally, the apparently lower incidence of "in-field" malignancies is a fascinating observation. T h e explanation proposed by Dr. D'Angio certainly is viable; namely, that of not permitting the survival of mutant cells when chemotherapy and irradiation are concurrently employed.
Dr. Phillips' presentation relates to an area of sore neglect. T h e emphasis today on combination approaches has as much, if not more, potential than any other in clinical cancer therapeutics. Furthermore, we are witnessing many examples of substantial improvement in survival and cure rates. It must be emphasized, however, that we have been rather cavalier in administering potent chemical agents to patients receiving concurrent radiotherapy. Generally this is done without any preclinical evaluation of toxicity, an approach which would be soundly condemned if a new drug were introduced into clinical trial without