Phase I Targeting Dominant Intraprostatic Lesion Using MR Spectroscopy and HDR Brachytherapy

1.1 The goal of radiotherapy is to deliver a high dose of radiation to the target volume while minimizing the dose to the surrounding normal tissue. Using CT based three-dimensional treatment planning system and multiple field technique, the three dimensional conformal radiotherapy (CRT) has become the standard of care for external beam radiotherapy for prostate cancer. Multiple institutional studies and prospective randomized trials have been done documenting the safety and efficacy of this modality. Brachytherapy is an alternative method of delivering conformal radiotherapy for treatment of prostate cancer. The technique of HDR prostate brachytherapy has been in clinical practice since the 1980's \[1-13\]. Kovacs et al reported one of the earliest experiences using HDR brachytherapy boost at University of Kiel.\[10, 11, 13\] Patients treated were mostly T2b-T3, G3. They used a combination of split course external beam radiotherapy and two 15 Gy HDR treatments. They reported 18% positive biopsy rate 18 months post treatment. The result was updated at 10 years and 78 percent of 171 patients remained free of disease at median follow-up of 55 months. Mate et al at Swedish Medical Center reported their experience with HDR brachytherapy \[9\]. They used a more moderated hypofractionated schema with four treatments of 3-4 Gy fractions of HDR treatments combined with 45-50 Gy of external beam radiotherapy. They recommended routine cystoscopy at the end of the implant procedure to ensure the catheters are placed at the proper depth and to avoid injuring the urethra. Pretreatment patient characteristics were stage T1b to T3c, mean initial PSA was 12.9 and Gleason grade ranges 3 to 9. They reported 84% 5-year biochemical disease free survival. Martinez et al at the William Beaumont Hospital reported the only on-going prospective dose escalation trial using HDR brachytherapy as a boost. There have been multiple updates of their results.\[5-7, 12\] They have continued to dose escalate using increasingly larger fractions of HDR treatment range from 5.5-6.5 Gy x 3 to 8.25-11.5 Gy x 2 combined with 46 Gy of external beam radiotherapy. As of their most recent update, they have shown acceptable toxicity level using 9.5 Gy x 2 treatments. Patients with PSA ≥ 10, T ≥ T2b, and Gleason score ≥ 7 were selected for the trial. Despite a high frequency of poor prognostic factors, the actuarial biochemical control rate was 89% at 2 years and 63% at 5 years. The 5-year actuarial rates of local failure and distant metastasis were 16% and 14%, respectively. Borghede et al. at Goteborg University in Sweden reported their experience using 50 Gy of external beam radiotherapy combined with 2 fractions of 10 Gy HDR boost.\[1, 2\] They used ultrasound to target tumor nodules within the prostate and gave an additional 5 Gy boost during each HDR treatment. Patients included in the study were T1-3, and grade 1-3. They report a 4% positive biopsy rate at 18-months post treatment. This is a remarkably low positive biopsy rate considering no hormonal therapy was used in the study. The results from these clinical trials and others have shown the technique of HDR brachytherapy for prostate cancer is feasible with minimal morbidity. Other institutional trials have suggested HDR boost may be more efficacious compared to external beam radiotherapy alone or external beam radiotherapy with short term hormonal therapy. Results of these studies need to be confirmed in large multi-institutional trials.