Clinical trials of radiosensitizers: What should we expect?

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The lack of positive results from the clinical trials undertaken so far with misonidazole (MISO) are widely considered as disappointing. This is leading to a growing sentiment that bypoxic cells may not be a significant limitation to local control of human tumors. To examine whether this is a reasonable conclusion, the relevant in vitro and in vivo data have been summarized so that predictions of the extent of radiosensitization of the hypoxic cells can be made from a knowledge of the clinically achievable levels of MISO. This analysis shows the following: First, the original curve of Adams with V-79 cells is probably over-optimistic in predicting sensitizer enhancement ratios (SERs). A new curve based on the available in vivo data predicts lower sensitization so that even at the highest MISO doses used clinically, SERs for the hypoxic cells to large single X-ray doses of only 1.45 would be expected. In a clinical trial, reoxygenation of the bypoxic cells is likely to occur, thereby considerably reducing the SER for the total tumor cell population. This, together with the problems of heterogeneous tumors and insufficient patient numbers, could well have been responsible for the negative clinical results. Second, even if tumor levels of the new radiosensitizer SR-2508 10 times those of MISO can be achieved clinically, this will still not lead to full radiosensitization of the hypoxic cells (although an SER in excess of 2.0 should be attainable). In conclusion the in vitro and in vivo data with radiosensitizers suggest that only a small effect, if any, is likely to be demonstrated in the clinical trials with MISO, even for those tumors the control of which is limited by hypoxic cells. Thus the question of whether hypoxic cells may or may not limit the local control of tumors by radiotherapy has not been addressed adequately by the presently available radiosensitizing drugs.