PSA outcomes and late toxicity of single-fraction HDR brachytherapy and LDR brachytherapy as monotherapy in localized prostate cancer: A phase 2 randomized pilot study.

PURPOSE: To evaluate the PSA outcomes and the late patient's reported health related quality of life (HRQOL) and toxicity after single-fraction High-Dose-Rate brachytherapy (HDRB) and Low-Dose-Rate brachytherapy (LDRB) for prostate cancer. METHODS: Men with low and favorable intermediate-risk prostate cancer across 3 centres were randomized between monotherapy brachytherapy with either Iodine-125 LDRB or 19 Gy single-fraction HDRB. Biochemical outcomes were evaluated using the Phoenix definition, PSA nadir and absolute PSA value <0.4 ng/mL. Toxicities and HRQOL were recorded at 24 and 36 months. RESULTS: A total of 31 patients were randomized, 15 in the LDRB arm and 16 patients in the HDRB arm. After a median follow-up of 45(36-53) months, 3 patients in the HDRB arm experienced biochemical failure (p = 0.092). Nineteen Gy single-fraction HDRB was associated with significantly higher PSA nadir compared to LDRB (1.02 ± 0.66vs 0.25 ± 0.39, p < 0.0001). Moreover, a significantly larger proportion of patients in the LDRB group had a PSA <0.4 ng/mL (13/15 vs 2/16, p < 0.0001). For late Genito-Urinary, Gastro-Intestinal, and sexual toxicities at 24 and 36 months, no significant differences were found between the 2 arms. As for HRQOL, the IPSS and EPIC-26 urinary irritative score were significantly better for patients treated with HDRB over the first 36 months post-treatment (p = 0.001 and p = 0.01, respectively), reflecting superior HRQOL. CONCLUSION: HDRB resulted in superior HRQOL in the irritative urinary domain compared to LDRB. PSA nadir was significantly lower in the LDRB group and a higher proportion of patients in the LDRB group reached PSA <0.4 ng/mL.

The Clinical Significance of Bone Mineral Density Changes Following Long-Term Androgen Deprivation Therapy in Localized Prostate Cancer Patients.

PURPOSE: Long-term androgen deprivation therapy has been associated with decreased bone mineral density in men with prostate cancer. Some evidence suggests that there is no impact on fracture risk despite this bone mineral density loss. Our study aimed to quantify changes in bone mineral density in men with high risk prostate cancer on long-term androgen deprivation therapy and calcium and vitamin D supplementation. MATERIALS AND METHODS: Bone mineral density analysis was conducted for localized high risk prostate cancer patients enrolled in the phase III randomized trial PCS-V (Prostate Cancer Study 5), comparing conventional and hypofractionated radiation therapy. Patients received 28 months of luteinizing hormone-releasing hormone agonist and calcium and vitamin D supplementation (500 mg calcium BID+400 IU vitamin D3 BID). The areal density and T-scores (spine, femoral neck and total femur) at baseline and 30 months of followup were extracted, and the absolute change was calculated. Clinical bone density status (normal, osteopenia, osteoporosis) was monitored. RESULTS: The lumbar spine, femoral neck and total femoral bone mineral density were measured for 226, 231, and 173 patients, respectively. The mean percent change in bone mineral density was -2.65%, -2.76% and -4.27% for these respective sites (p <0.001 for all). The average decrease in bone mineral density across all sites was -3.2%, with no decline in bone mineral density category in most patients (83%). Eight patients (4%) became osteoporotic. CONCLUSIONS: Despite a mild decline in bone mineral density, the change in clinical bone mineral density category remained low with long-term androgen deprivation therapy. Consequently, calcium and vitamin D supplementation alone may suffice for most localized prostate cancer patients on long-term androgen deprivation therapy.

Optimizing treatment sequencing of chemotherapy for patients with rectal cancer: The KIR randomized phase II trial.

BACKGROUND: Randomized studies have shown low compliance to adjuvant chemotherapy in rectal cancer patients receiving preoperative chemotherapy and external beam radiation (CT/EBRT) with total mesorectal excision. We hypothesize that giving neoadjuvant CT before local treatment would improve CT compliance. METHODS: Between 2010-2017, 180 patients were randomized (2:1) to either Arm A (AA) with FOLFOX x6 cycles prior to high dose rate brachytherapy (HDRBT) and surgery plus adjuvant FOLFOX x6 cycles, or Arm B (AB), with neoadjuvant HDRBT with surgery and adjuvant FOLFOX x12 cycles. The primary endpoint was CT compliance to ≥85% of full-dose CT for the first six cycles. Secondary endpoints were ypT0N0, five-year disease free survival (DFS), local control and overall survival (OS). RESULTS: Patients were randomized to either AA (n = 120, median age (MA) 62 years) or AB (n = 60, MA 63 years). 175/180 patients completed HDRBT as planned (97.2%). In AA, two patients expired during CT; three patients post-randomization received short course EBRT because of progression under CT (n = 2, AA) or personal preference (n = 1, AB). ypT0N0 was 31% in AA and 28% in AB (p = 0.7). CT Compliance was 80% in AA and 53% in AB (p = 0.0002). Acute G3/G4 toxicity was 35.8% in AA and 27.6% in AB (p = 0.23). With a median follow-up of 48.5 months (IQR 33-72), the five-year DFS was 72.3% with AA and 68.3% with AB (p = 0.74), the five-year OS 83.8% for AA and 82.2% for AB (p = 0.53), and the five-year local recurrence was 6.3% for AA and 5.8% for AB (p = 0.71). CONCLUSION: We confirmed improved compliance to neoadjuvant CT in this study. Although there is no statistical difference in ypT0N0 rate, local recurrence, and DFS between the two arms, a trend towards favourable oncological outcomes is observed.

A Phase 2 Randomized Pilot Study Comparing High-Dose-Rate Brachytherapy and Low-Dose-Rate Brachytherapy as Monotherapy in Localized Prostate Cancer.

PURPOSE: To compare health-related quality of life (HRQOL) of high-dose-rate brachytherapy (HDRB) versus low dose-rate brachytherapy (LDRB) for localized prostate cancer in a multi-institutional phase 2 randomized trial. METHODS AND MATERIALS: Men with favorable-risk prostate cancer were randomized between monotherapy brachytherapy with either Iodine-125 LDRB to 144 Gy or single-fraction Iridium-192 HDRB to 19 Gy. HRQOL and urinary toxicity were recorded at baseline and at 1, 3, 6, and 12 months using the Expanded Prostate Cancer Index Composite (EPIC)-26 scoring and the International Prostate Symptom Score (IPSS). Independent samples t test and mixed effects modeling were performed for continuous variables. Time to IPSS resolution, defined as return to its baseline score ±5 points, was calculated using Kaplan-Meier estimator curves with the log-rank test. A multiple-comparison adjusted P value of ≤.05 was considered significant. RESULTS: LDRB and HDRB were performed in 15 and 16 patients, respectively, for a total of 31 patients. At 3 months, patients treated with LDRB had a higher IPSS score (mean, 15.5 vs 6.0, respectively; P = .003) and lower EPIC urinary irritative score (mean, 69.2 vs 85.3, respectively; P = .037) compared with those who received HDRB. On repeated measures at 1, 3, 6, and 12 months, the IPSS (P = .003) and EPIC urinary irritative scores (P = .019) were significantly better in the HDR arm, translating into a lower urinary toxicity profile. There were no significant differences in the EPIC urinary incontinence, sexual, or bowel habit scores between the 2 groups at any measured time point. Time to IPSS resolution was significantly shorter in the HDRB group (mean, 2.0 months) compared with the LDRB group (mean, 6.0 months; P = .028). CONCLUSIONS: HDRB monotherapy is a promising modality associated with a lower urinary toxicity profile and higher HRQOL in the first 12 months compared with LDRB.

Dietary inferences through stable isotope analysis at the Neolithic and Bronze Age in the southern Caucasus (sixth to first millenium BC, Azerbaijan): From environmental adaptation to social impacts.

OBJECTIVES: Subsistence strategies are of great interest for understanding how prehistoric societies adapted to their environment. This is particularly the case for the southern Caucasus where relationships have been shown with the northern Caucasus and Mesopotamia since the Neolithic and where societies are alternately described as sedentary and mobile. This article aims, for the first time, to characterize human diets and their evolution using biochemical markers, from the Neolithic to the Bronze Age (sixth-first millenium BC), at Mentesh Tepe, a site in the middle Kura valley in Azerbaijan. MATERIALS AND METHODS: The data set belongs to 40 humans, 32 domestic and wild animals, and 42 charred seeds discovered in situ and perfectly dated. Stable isotope analyses were performed, including (a) δ13 Cco and δ15 N for animal and human bone collagens and for seeds, and (b) δ13 Cap for human bone apatite. RESULTS: Almost all the data (25/31) suggest an increased contribution of cereals, lentils, and freshwater fish during the Neolithic, whereas afterwards, until the Late Bronze Age, all individuals consumed more animal proteins from their livestock. None of the biological criteria (age at death and sex) and burial types (mass/single graves) were found to be related to a specific diet over time. Comparisons with other isotopic data from contemporary sites in Georgia argue in favor of a wide variety of dietary sources in the vicinity of the Kura valley and for highly mobile populations. Clear evidence of millet consumption has only been found for the Late Bronze Age.

External validation of the ProCaRS nomograms and comparison of existing risk-stratification tools for localized prostate cancer.

INTRODUCTION: The purpose of this study was to perform a direct comparison of several existing risk-stratification tools for localized prostate cancer in terms of their ability to predict for biochemical failure-free survival (BFFS). Two large databases were used and an external validation of two recently developed nomograms on an independent cohort was also performed in this analysis. METHODS: Patients who were treated with external beam radiotherapy (EBRT) and/or brachytherapy for localized prostate cancer were selected from the multi-institutional Genitourinary Radiation Oncologists of Canada (GUROC) Prostate Cancer Risk Stratification (ProCaRS) database (n=7974) and the Centre Hospitalier de l'Université de Montréal (CHUM) validation database (n=2266). The primary outcome was BFFS using the Phoenix definition. Concordance index (C-index) reported from Cox proportional hazards regression using 10-fold cross validation and decision curve analysis (DCA) were used to predict BFFS. RESULTS: C-index identified Cancer of the Prostate Risk Assessment (CAPRA) score and ProCaRS as superior to the historical GUROC and National Comprehensive Cancer Network (NCCN) risk-stratification systems. CAPRA modeled as five and three categories were superior to GUROC and NCCN only for the CHUM database. C-indices for CAPRA score, ProCaRS, GUROC, and NCCN were 0.72, 0.72, 0.71, and 0.72, respectively, for the ProCaRS database, and 0.66, 0.63, 0.57, and 0.60, respectively, for the CHUM database. However, many of these comparisons did not demonstrate a clinically meaningful difference. DCA identified minimal differences across the different risk-stratification systems, with no system emerging with optimal net benefit. External validation of the ProCaRS nomograms yielded favourable calibrations of R2=0.778 (low-dose rate [LDR]-brachytherapy) and R2=0.868 (EBRT). CONCLUSIONS: This study externally validated two ProCaRS nomograms for BFFS that may help clinicians in treatment selection and outcome prediction. A direct comparison between existing risk-stratification tools demonstrated minimal clinically significant differences in discriminative ability between the systems, favouring the CAPRA and ProCaRS systems. The incorporation of novel prognostic variables, such as genomic markers, is needed.