The holy grail of radiation oncology: lessons learned from hyperthermia

In this edition of International Journal of Radiation Oncology, Biology, Physics, Shidong Li et al. (1) propose a simple dosimetric model for an adenoviral delivery technique correlated to their recently reported Phase I trial. This model takes into account such variables as the volume of injected material containing virions and target coverage to determine the biochemical response probability in patients treated by this method. This article is one of the first to introduce a set of variables into a treatment planning system to calculate dose and its distribution in the prostate. The authors glean this information from a variety of in vitro and in vivo animal experiments, on topics such as the following: ultrasonographic spread of fluid in dog prostates, fluorescent markers, and CT scanning of renograffin-injected beef. The importance of these first and simplified models in the ever-expanding field of adenoviral gene therapy cannot be overemphasized. The explosion of technology and research dollars, combined with the promise of more effective targeted therapy, has resulted in the initiation of over 600 human gene therapy protocols worldwide (2). The most promising of these treatments have used adenoviral vectors, which are effective in transduction and advantageous in their ubiquity. Replicationcompetent adenoviral therapy, such as CG7060, is yet another strategy to further increase transduction, and hence expression, in host cells. In the forerunner to their article cited here, DeWeese et al. (3) used transrectal ultrasonography guidance to place aliquots of viral particles transperineally into the prostate to diminish side effects caused by viral deposition in normal tissue. As such, the use of a reliable model for dosimetric purposes becomes invaluable, especially after a highly publicized patient death in 1999, in which a teenager’s death was attributed partly to injection of very high viral titer (4). However, in a more generalized sense, why is this work, and similar research, of importance to the radiation oncology society? This work lays the foundation for developing accurate, reproducible, usable, and everyday treatment planning for this new therapeutic modality. This is critical if, as a society, we are to rigorously test new modalities in a systematic manner to determine their utility and efficacy before their potential widespread use. This would seem necessary when considering past experience with other treatment modalities, namely hyperthermia. Theoretically and in vitro, heat kills cells reliably, predictably, and in a repeatable way (5). The fact that hyperthermia works when the cell cycle is most resistant to X-rays and its response is not a function of oxygenation status per se made this an ideal modality to combine with RT. Clinically, however, it was not very feasible to apply temperatures greater than 41°C, and despite many encouraging Phase I/II data, many Phase III multicenter trials did not show advantages in the use of hyperthermia. Much of the problem, as in gene therapy, resides in the fact that we were unable to measure effectiveness of treatment in terms of dose (degree) and distribution of dose (heat), as well as in the problem of patient and normal-tissue tolerance. Thus, it becomes important to devise methods of accounting for these important factors. Granted, this paper is only the first step in this process. The authors have acknowledged several shortcomings of their model. For example, many assumptions are made: that all delivered virions are distributed in the injected volume, that all first-generation viral particles are assumed to “work,” that there is a linear relationship between PSA and the number of surviving cells, and that prostate cell density is independent of location. Moreover, one of the authors’ experiments is based on distribution of spheres inside fresh beef, which architecturally is different than that of a human prostate. In addition, the enlargement of the prostate gland seen after completion of the procedure could seriously alter the dose of viral particles delivered to the prostate. Regardless, though, if our past experience of searching for the next new therapeutic modality is any guide, Li et al. (1) have shown us that we are at least on the right path. In conclusion, the adenovirus and delivery system, as well as the technique, are critical in the ultimate development of gene therapy protocols to be tested in the clinic.