Hypoxic cell radiosensitizers: illusion or elusion?

Seven years have elapsed since an editorial appeared in this Journal discussing the present and future of hypoxic cell sensitizers. l6 At that time, it was stated that “in time and with further good experimental and clinical evaluations, rational development, and critical analysis, it may be possible to relate through professional and lay publications that a hypoxic cell sensitizer has led to increased cancer cures.“16 Since that was written, further good experimental and clinical evaluations and critical analysis have occurred, and yet the ability to state that hypoxic cell sensitizers lead to increased cancer cures still remains either an illusion (a fantasy) or an elusion (an answer which is hard to identify). There is no doubt that irradiation is an important therapy in the control of cancer, and with dramatic improvements in technology, physics, tumor localization, and treatment planning, there have been net gains in tumor control rates from radiation. Ultimately, radiation acts via biochemical reactions, and it would seem necessary and desirable to alter the biochemical mechanisms of radiation effects on cells for further therapeutic gain. Such is the role of chemical modifiers, which are compounds, that do not directly kill cancer cells, but when combined with cell killing effects of radiation lead to a therapeutic gain. This gain is achieved either by increasing the cytotoxic effects of radiation or by decreasing the toxic effects of radiation on normal tissues, and increasing the therapeutic ratio (Fig. 1). Such compounds include possibilities broader than hypoxic cell sensitizers.j The hypoxic cell radiosensitizers have been the most widely studied of the chemical modifiers with 14 years of clinical evaluation to date. Unfortunately, almost all Phase III trials with misonidazole (the standard drug tested) have not led to therapeutic gain’3,17 The lack of success of these Phase III trials has been like the weight of a dead elephant in the advancement of further biological and clinical evaluations of hypoxic cell sensitizers (Fig. 2). This has handicapped the prospects of continuing support from skeptical clinicians and biologists. However, misonidazole was not thought to be the ultimate hypoxic cell radiosensitizer,‘, rather it has provided the background for the development of analogs that will hopefully be more effective clinically. 1*2 Indeed, the failure of the misonidazole clinical trials has led to further biological research with better understanding of the many variables that occur clinically and biologically within the concept of hypoxia and has led to new understanding of cell regulatory mechanisms, including the major influence of thiol modulation.3q9,‘4 There is a continuing nagging skepticism as to whether hypoxia has any importance in fractionated clinical radiotherapy.6 However, the ultimate evaluation of this issue requires a potential solution to the influence of hypoxia and then a test of the value of that solution regarding improvements in cancer cure rates. Hypoxia may simply be an indicator of other biochemical deprivations of the cell that leads to relative radioresistance. The clinical trials of chemical modifiers are complex because short-term endpoints are often not of value, and thus the trials require: careful stratification of prognostic variables; large patient numbers; randomization; and long term follow-up of patients. When one considers that radiation itself induces a cell kill effect, and that the chemical modifier does not, we are looking for an equation of 2 + 0 = 3+ effect. This is akin to testing a fifth drug in an already established (yielding a moderate complete and partial response rate) four-drug chemotherapy combination. The current state of the clinical evaluation of hypoxic cell radiosensitizers focuses on two rationally derived analogs of misonidazole, SR-2508 (etanidazole) and Ro 038799 (pimonidazole). These two compounds have different physical chemical properties and different dose limiting clinical toxicities. SR-2508 can produce a cumulative peripheral neuropathy.4 Ro 03-8799 can produce a short-lived .acute syndrome consisting of dizziness, nausea, sweating, and mental confusion.‘5