Prostate cancer: Hot, but hot enough?

Abstract

In this issue Fosmire and colleagues (3) report early results of testing a transrectal ultrasound applicator for hyperthermia treatment of prostate cancer. The growing number of reports on the incidence and significance of positive prostatic biopsies 18-24 months after radiotherapy (2, 6, 8, 9) has motivated investigation of hyperthermia as one means of improving upon results with radiotherapy alone. Trials of interstitial radiation plus interstitial hyperthermia for prostate cancer are in progress at a few institutions, but there are no detailed reports yet on temperature distributions and treatment results. Transrectal microwave applicators have been proposed but have disadvantageous physical characteristics; external microwave or radiofrequency applicators produce poorly localized power deposition that does not result in significant prostate temperature elevation (7). External focused ultrasound theoretically could be useful for prostate treatment (4), and the results of Fosmire et al. (3) show promise for the transrectal ultrasound approach. These investigators use various ways to report prostate and normal tissue temperature elevations. The temperature of all prostate thermometry sensors (average of eight per patient) over the 30-min treatment period in 22 treatments in 14 patients was 4 1.9 + 1.3”C. Because the minimum tumor temperature or T90 (temperature exceeded by 90% of measured temperatures) probably has the greatest prognostic significance (5, 7) however, analysis of these latter temperatures may yield a better assessment of this heating technique. There is no detailed information about the location of sensors relative to tumor/normal tissue interfaces, so it is not clear that the eight stationery sensors per prostate yield an accurate estimate of minimum temperature or TgO. If the average minimum temperature of 40.4 + 1.5”C reported is used as an estimate of T9,, over a 30-min treatment, we calculate that the thermal isoeffective dose would be EQ MIN T9043 = 0.82 (+5.7 1, -0.71) min (7). This falls short of our estimate of the median thermal dose of 10 min needed in a patient population to show efficacy of hyperthermia plus radiotherapy relative to radiotherapy alone, based upon a complete response endpoint. This endpoint may underestimate the thermal dose required for improved freedom from relapse. In the past there have not been clearly defined thermal goals of treatment, so Phase I/feasibility trials of hyperthermia have usually left us ignorant about the potential usefulness of a hyperthermia device. Ultimate tests of efficacy of new treatment modalities for prostate cancer will require many years of follow-up of patients: there does not appear to be a short-cut to determination of treatment efficacy in this frequently indolent disease. Improvements in the transrectal applicator described by the authors may allow safe temperature elevation and thermal dose delivery to the levels we have estimated: I urge the University of Arizona investigators to continue improving their novel applicator and the approach to temperature measurement prior to launching a Phase III trial. The time investment and determination of investigators seeking improvement in prostate cancer treatment will be considerable before answers emerge, and we need to be confident the efforts are structured for success. We do not need another negative Phase III trial of hyperthermia.