BERKELEY, CA (UroToday.com) - The biologic rationale for combining heat with radiation has been well recognized for decades.
In many respects hyperthermia is the ideal complementary treatment to radiation therapy. Tumor cells that are most resistant to radiation, including those that are hypoxic, at low pH, nutritionally deprived, and in S-phase, are precisely the cells that are most sensitive to hyperthermia. Hyperthermia also enhances the effect of radiation through the induction of apoptosis and other mechanisms of cell kill. It has been demonstrated that this theoretical benefit of hyperthermia has a meaningful clinical impact, including in some instances survival benefit, as evidenced by results from phase 3 trials.
A phase 2 study at the Dana-Farber Cancer Institute (DFCI study 94-153) was initiated to provide a preliminary assessment of the efficacy of trans-rectal ultrasound hyperthermia in combination with radiation and, for most patients, androgen suppression in treatment of intermediate-risk to high-risk, clinically localized prostate cancer. The use of a trans-rectal applicator allows for direct energy deposition into the prostate to enhance tumor heating while minimizing thermal dose to the surrounding normal tissues and organs, thus addressing the challenge of heating deep-seated pelvic organs. We previously reported the favorable toxicity profile of this treatment approach, and in the current paper the long-term efficacy results from this completed trial are presented.
PSA failure was defined using the American Society for Therapeutic Radiology and Oncology (ASTRO) consensus definition. The Phoenix definition of PSA failure (PSA nadir + 2 ng/mL) was developed after the current study was designed; and, although it was not part of the primary analysis, also was assessed to provide a basis for comparison with contemporary studies. In addition to the ASTRO definition of PSA failure, failure also was defined by clinical or pathologic evidence of local or distant disease recurrence or at the time of initiation of salvage androgen suppression regardless of PSA. With median follow-up of 70 months (range, 18-110 months), the overall survival rate was 94%. After 7 years of follow-up, 61% of patients were failure free according to the 1997 ASTRO consensus, and 55% were failure free when we applied the Phoenix definition of biochemical failure. It is noteworthy that the Kaplan-Meier curves for both overall survival and disease-free survival appeared to level off after 5 years. The absolute rate of disease-free survival of 84% with hyperthermia at 2 years, which was the primary study endpoint, was a significant improvement compared with the rate of 64% for similar patients on the 4-month androgen suppression arm of RTOG 92-02 who served as the comparison group for this study. Applying the Phoenix criteria (PSA nadir + 2 ng/mL) for biochemical failure, 89% of patients were progression-free at 2 years.
Since initiation of this study in the mid-1990s, much has been learned about risk stratification. More stringent eligibility criteria for identifying patients with bulky local disease, who nonetheless are at relatively low risk of harboring micrometastases, may aid in further defining the benefit of hyperthermia in prostate cancer because it is unlikely that hyperthermia ultimately will benefit patients who have pre-existing, subclinical, distant disease. The radiation doses administered (approximately 70 Gy center of prostate dose) on this trial reflect standard of care for patients treated during the period the trial was open but are considerably less than now commonly used with intensity modulated radiation therapy with use of daily image guidance. An argument can be made that, with current abilities to safely dose escalate radiation, hyperthermia is not necessary for the treatment of prostate cancer. Although this assertion may be true for many patients, the use of very tight margins required with dose escalation may not be desirable for some patients with locally advanced disease. In addition, there may be some patients who harbor relatively radioresistant tumor cells who could benefit from hyperthermia. Future developments in functional imaging and molecular profiling may lead to the targeted selection of patients for treatments that are complementary to radiation, such as hyperthermia. Likewise, patients for whom salvage radiation therapy is being considered after primary treatment may benefit from the combined use of modest radiation doses with hyperthermia. With FDA approved systems available to administer hyperthermia for prostate cancer, the lessons learned from the current study continue to be relevant and applicable to current clinical scenarios.
Apart from traditional hyperthermia geared toward radiosensitization, the use of thermal ablation for prostate cancer is gaining therapeutic momentum. There are significant challenges, however, in completely ablating the prostate without damage to the urethra, bladder, rectum, and neurovascular bundles. It is well recognized that there is a hyperthermic rim around the ablated tissue region. An attractive strategy may be to combine thermal ablation with radiation. A safe margin for ablation near critical normal structures can be maintained by taking advantage of the hyperthermic rim to sensitize tumor in these regions to eradication with radiation. The finding of an enhanced benefit of hyperthermia with the radiation doses that were used in the current study supports such an approach. Indeed, the degree to which hyperthermia improved treatment outcome is similar to that observed with radiation dose escalation and comes without any of the added risks associated with higher radiation doses. The benefit observed in this phase 2 study also supports the hypothesis that the thermal enhancement ratio is significant for prostate cancer and is worthy of further investigation. Future clinical studies will be required to assess these new therapeutic strategies.
Mark Hurwitz, MD as part of Beyond the Abstract on UroToday.com. This initiative offers a method of publishing for the professional urology community. Authors are given an opportunity to expand on the circumstances, limitations etc... of their research by referencing the published abstract.