IN. 1. Radia#ia ORV@ Bid. Phys.. Vol. 9. p. 21 I Priad in the USA. All *bu mewed.

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SELECITON OF APPROPRIATE SKJMES FOR PHME III TRIAIS OF RADIOSENSITIZERS

To the Ediror: We would like LO commend the Journal on the prompt publication of the papers presented Scptembcr I98 I in the conference on Chemical Modification et Key Biyne.

Unfortunately, several of the Phase 111 clinical trials of misonidazolc sponsored by the RTGG and reviewed in the Key Note Address’ have design features that make negative results almost inevitable. While it is true that it is still not known in which human tumors rcoxygcnation is least cRcctivc. WC have to disagree with the prectia of using misonida- zolc indiscriminately in Phase III curative end palliative radiotherapy studia, sina to do so greatly increases the probability of negative results. Thcauntiel requirement for rational application of hypoxic cell sensitizers is to identify predictively those tumors whose control is limited by failure of rcoxygenatlon. But even in the absence of this specific radiobiologic information, one can still k guhkd by clinical upcrience end general biologic considerations, so es to avoid trials with little pmapcct of success.

Hypoxic all sensitizers could thwretically improve the therapeutic ratio between cancer and normal tissues in two ways: (a) by improving local control without incrcaaing complications when the sensitizer is added to a known acceptable regimen of radiotherapy, or (b) by reducing the. number of compliations while maintaining the same local control rate when addition of the sensitizer permits a reduction in radiation dose. However, when the aim of radiation therapy can be achid with a moderate dae that is well below the tolerance of the doac-limiting normal tissue. there is no place for a radiosensitizer.

This principle applies particularly to palliative therapy. Because of the limitations on incremental end total doses of misonidazolc imposed by its nutrotoxicity. en enhancement ratio of -I .2 is the highest one can reasonably hope for.’ Therefore. an increase of the radiation dose by 20% would achieve et least the same cffst as the addition of misonida- zolc. However, in the treatment of brain metasta.ua, for example. no improvement in the rate or length of palliation with en increased radiation dose has ever been shown. The RTGG itself has conducted studies comparing various radiation schedules ranging up to 5000 rad in 20 fractions over 4 weeks. ” No significant dilTcrcncc was shown between any of tbeac schedulea end the standard regimen of 3000 rad in 10 fractions. It is thus futile to exp~ that 3000 rad plus misonidazole will do any better than the higher dose schcdula already teated.

With regard to curative therapy. to have any realistic hope of demonstrating a clinical benefit in Phase III trials of misonidazolc, one

should concentrate on tumors where at least some local control can be achieved with conventional high-dose radiotherapy. If the baseline control rate is essentially Zen. as in glioblastoma. a significant degree of sensitization could go undetected. sina the threshold of a steep increase in tumor control with increasing dose will not have been reacbcd.~ Selecting patients who have a modcat expectation of cure for Phase III studies is also important, so that one can observe the long-term cITccts of radiation end misonidazole on normal tissues.

Similar logic dictates that if sensitizers are tested on tumor popula- tions so heterogeneous that no dose-response relationship can be demon- strated with irradiation alone, it is very unlikely that any improvement in owzqll tumor control ntcx would result from addition of a scnsitiz- ct.’

Because several ongoing trials are subject to one or another of these limitations, we believe that premature disappointment with sensitizers may ensue as the studies mature over the next few years. We would urge that more selective rather than more wide-ranging Phase III stud& be planned for new radiostnsitizers to maximize the probability of dcmon- strating a clinical advantage from their use.

bbHE H. MAOR. M.D. Associitc Radiotherapist and Assistant Professor of Radiotherapy

LESER J. PETERS, M.D. Profmsor and Head Division of Radiotherapy

The University of Texas M. D. Anderson Hospital end Tumor Institute 6723 Bcrtncr Ave. Houston, Texas 77030

I. Borgelt. B.. Gclbcr, R., Kramer. S., Brady. L.W.. Chang, C.H.. David, L.W.. Perez, C.A.. Hendrickson. F.R.: The palliation of brain metastascs: Final rcaults of the first two studies by the Radiation Therapy Oncology Group. IIU. J. Radial. 0~01. Biol. Phys. Q l-9, 1980.

2. Kurtz, J.M.. Gclbcr. R., Brady, L.W.. Carella. R.J.. Cooper, J.S.: The palliation of brain metastascs in a favorable patient popultion: A randomized clinical trial by the Radiation Therapy Oncology Group. Inr. 1. Radiat. Cmcol. Biol. Phys. 7: 891-895. 1981.

3. Peters, L.J.. Withers, H.R.. Thamcs, H.D.. Jr.. Fletcher, G.H.: Keynote Addrcas: The problem: Tumor radioresistance in clinical radiotherapy. Inr. 1. Radial. &col. Biol. Phys. 8: 101-108, 1982.

4. Phillips, T.L.. W assetman, T.H.. Stctz. J., Brady, L.W.: Clinical trials of hypoxic cell sensitizers. I~I. J. Radial. Oncol. Biol. Phys. %: 327-334.1982.

5. Withers, H.R.. Peters, L.J.: Biologic aapccta of radiation therapy. In Texrbodc of Radiotherapy, 3rd edition, Fletcher, G.H. (Rd.). Phila- delphia, Lea & Febigcr. 1980. pp. 103-l 80.

This investigation was supported in part by Grant CA 06294, awarded by the National Cancer Institute, Department of Health and Human Services.

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