Teniposide. A review of 12 years of experience

Evidence from the studies reviewed here suggests that tenisposide is an active antitumor agent, with particular efficacy in ALL and neuroblastoma in children, and in NHL and brain tumors in adults. The data are flawed by the absence of conclusive trials in these malignancies. For example, it has not been established that a teniposide/ara-C combination is better than ara-C alone in ALL, nor that a teniposide/cisplatin combination is better than cisplatin alone in neuroblastoma. With a single exception, the role of tenisposide in the many combinations being used for NHL and Hodgkin's disease remains conjectural. Until this role has been reliably defined in the relevant tumor types, progress in the development of teniposide will be slow. It is of little value to look back and criticize per se the inadequacies of the clinical evaluation of teniposide. Besides the influences of investigator bias and the concurrent introduction of its analog, etoposide, the period spanned by these clinical trials encompasses that in which the principles for the development of new anticancer drugs have been laid down. In attempting prospectively to design trials which would resolve these issues, one is hampered by these inadequacies. How much enthusiasm could be generated for a randomized trial of teniposide/ara-C versus are ara-C alone in relapsed childhood ALL? Notwithstanding these difficulties, we believe that the results of trials to data argue strongly for a renewed development effort for this drug. In tumors other than ALL, the appropriate trials should be feasible. These trials should not, however, address teniposide in isolation. It is equally important to describe its activity relative to etoposide, and, on this basis, to determine in several tumors if teniposide is a useful epipodophyllotoxin in its own right. In this way, one could avoid a profusion of analogs of undertermined value, such as has occurred with the nitrosoureas. Several questions have to be asked of the epipodophyllotoxin analogs: are they indeed different in their activity in specific tumors? does one have a biochemical or pharmacologic advantage? are they totally cross-resistant? Trials in NHL, small cell lung cancer, and acute myeloblastic leukemia could best address these topics. Loike (98) has discussed the structure-activity relationships of the podophyllotoxin derivatives. It is certain that 'second generation' compounds will be developed for clinical testing. This evaluation would be greatly facilitated, and many unnecesary trials avoided, should the relative merits of the original drugs be clearly defined.