Defining Biochemical Cure After Low Dose Rate Prostate Brachytherapy: External Validation of 4-year Prostate-specific Antigen Nadir as a Predictor of 10- and 15-year Disease-free Survival.

AIMS: To externally validate a proposed biochemical definition of cure following low dose rate (LDR) brachytherapy for prostate cancer - 4-year post-implant prostate-specific antigen (PSA) ≤0.2 ng/ml - in a UK population, and report the long-term (10- and 15-year) outcomes for patients stratified by National Comprehensive Cancer Network (NCCN) risk groups, through analysis of a large, prospectively collected, single-centre database. MATERIALS AND METHODS: All patients treated with LDR brachytherapy for prostate cancer at a single UK centre between 2001 and November 2020 (n = 1142) were eligible; 632 patients met the inclusion criteria for the analysis. The primary end point was disease-free survival (DFS), defined as freedom from clinical, radiological or PSA progression requiring androgen deprivation therapy. Four-year PSA was categorised as ≤0.2, >0.2 to ≤0.5, >0.5 to ≤1.0 and >1.0 ng/ml. Kaplan-Meier analysis to 15 years was undertaken for each group, and sensitivity and specificity of 4-year PSA as a surrogate for long-term cure were calculated. Kaplan-Meier analysis to 15 years was repeated, stratifying patients by NCCN risk groups. RESULTS: The median cohort age was 63 years; the median follow-up was 9.1 years (range 3.5-18.7). In total, 248 patients were available for analysis at year 10, 46 at year 15. Sixty-four patients (10.1%) relapsed during the study period. The 10-year DFS for 4-year PSA categories ≤0.2, >0.2 to ≤0.5, >0.5 to ≤1.0 and >1.0 ng/ml (95% confidence intervals) were 97.5% (95.4-99.6), 89.0% (82.4-96.1), 81.5% (70.5-94.2) and 41.8% (29.7-58.9), respectively. The 10-year DFS results for NCCN low, favourable-intermediate and unfavourable-intermediate risk disease were 93.1% (89.6-96.7), 92.1% (87.6-96.9) and 75.9% (67.8-84.9), respectively. CONCLUSIONS: Patients with 4-year PSA ≤0.2 ng/ml may be considered cured, and could be discharged to general practitioner follow-up. LDR brachytherapy is an excellent treatment option for patients with low and favourable-intermediate risk prostate cancer, but those with unfavourable-intermediate risk disease should be considered for treatment intensification strategies.

Impact of nicotinamide on human tumour hypoxic fraction measured using the comet assay.

BACKGROUND AND PURPOSE: Nicotinamide has been shown to reduce hypoxia in experimental tumours, but there are no data that measure the hypoxic fraction at the time of irradiation in humans. This study investigates whether nicotinamide with radiation can reduce human tumour hypoxia. MATERIALS AND METHODS: Twenty-two patients undergoing palliative radiotherapy for treatment of accessible metastatic tumours were exposed to two doses of radiation (3.5-8 Gy, median 6 Gy) separated by 1-6 days. Directly on completion of the first dose, two fine needle aspirate biopsies (FNAB) were taken and analyzed for hypoxic fraction using the alkaline comet assay. On the second day of radiation, 13 patients were given 80 mg/kg nicotinamide post-operatively on an empty stomach 2 h before treatment; the remaining nine patients acted as controls. A second comparative pair of aspirates were obtained immediately on completion of the second fraction. RESULTS: Sixteen tumours were suitable for analysis (nine nicotinamide and seven controls). Marked inter-tumour variations in hypoxic fraction were noted (0-67%). Both nicotinamide treated tumours and controls demonstrated a significant increase in the percentage of cells containing heavily damaged DNA following the second dose of radiation (P = 0.01). A significant reduction in mean hypoxic fraction after the second radiation treatment was noted (22 to 13%, P = 0.04). This reduction was predominantly due to the nicotinamide treated group, where mean hypoxic fraction fell from 25 to 11% (P = 0.08) compared to the much smaller change in the radiation only control group, 18 to 15% (P = 0.3). CONCLUSIONS: The decrease in hypoxic fraction suggests that nicotinamide can improve tumour hypoxia measured at the time of irradiation. Exposure to the first dose of radiation, or an effect of the first FNAB on microregional tumour blood flow may also contribute.