Duration of androgen deprivation therapy with postoperative radiotherapy for prostate cancer: a comparison of long-course versus short-course androgen deprivation therapy in the RADICALS-HD randomised trial.

BACKGROUND: Previous evidence supports androgen deprivation therapy (ADT) with primary radiotherapy as initial treatment for intermediate-risk and high-risk localised prostate cancer. However, the use and optimal duration of ADT with postoperative radiotherapy after radical prostatectomy remains uncertain. METHODS: RADICALS-HD was a randomised controlled trial of ADT duration within the RADICALS protocol. Here, we report on the comparison of short-course versus long-course ADT. Key eligibility criteria were indication for radiotherapy after previous radical prostatectomy for prostate cancer, prostate-specific antigen less than 5 ng/mL, absence of metastatic disease, and written consent. Participants were randomly assigned (1:1) to add 6 months of ADT (short-course ADT) or 24 months of ADT (long-course ADT) to radiotherapy, using subcutaneous gonadotrophin-releasing hormone analogue (monthly in the short-course ADT group and 3-monthly in the long-course ADT group), daily oral bicalutamide monotherapy 150 mg, or monthly subcutaneous degarelix. Randomisation was done centrally through minimisation with a random element, stratified by Gleason score, positive margins, radiotherapy timing, planned radiotherapy schedule, and planned type of ADT, in a computerised system. The allocated treatment was not masked. The primary outcome measure was metastasis-free survival, defined as metastasis arising from prostate cancer or death from any cause. The comparison had more than 80% power with two-sided α of 5% to detect an absolute increase in 10-year metastasis-free survival from 75% to 81% (hazard ratio [HR] 0·72). Standard time-to-event analyses were used. Analyses followed intention-to-treat principle. The trial is registered with the ISRCTN registry, ISRCTN40814031, and ClinicalTrials.gov, NCT00541047. FINDINGS: Between Jan 30, 2008, and July 7, 2015, 1523 patients (median age 65 years, IQR 60-69) were randomly assigned to receive short-course ADT (n=761) or long-course ADT (n=762) in addition to postoperative radiotherapy at 138 centres in Canada, Denmark, Ireland, and the UK. With a median follow-up of 8·9 years (7·0-10·0), 313 metastasis-free survival events were reported overall (174 in the short-course ADT group and 139 in the long-course ADT group; HR 0·773 [95% CI 0·612-0·975]; p=0·029). 10-year metastasis-free survival was 71·9% (95% CI 67·6-75·7) in the short-course ADT group and 78·1% (74·2-81·5) in the long-course ADT group. Toxicity of grade 3 or higher was reported for 105 (14%) of 753 participants in the short-course ADT group and 142 (19%) of 757 participants in the long-course ADT group (p=0·025), with no treatment-related deaths. INTERPRETATION: Compared with adding 6 months of ADT, adding 24 months of ADT improved metastasis-free survival in people receiving postoperative radiotherapy. For individuals who can accept the additional duration of adverse effects, long-course ADT should be offered with postoperative radiotherapy. FUNDING: Cancer Research UK, UK Research and Innovation (formerly Medical Research Council), and Canadian Cancer Society.

Adding 6 months of androgen deprivation therapy to postoperative radiotherapy for prostate cancer: a comparison of short-course versus no androgen deprivation therapy in the RADICALS-HD randomised controlled trial.

BACKGROUND: Previous evidence indicates that adjuvant, short-course androgen deprivation therapy (ADT) improves metastasis-free survival when given with primary radiotherapy for intermediate-risk and high-risk localised prostate cancer. However, the value of ADT with postoperative radiotherapy after radical prostatectomy is unclear. METHODS: RADICALS-HD was an international randomised controlled trial to test the efficacy of ADT used in combination with postoperative radiotherapy for prostate cancer. Key eligibility criteria were indication for radiotherapy after radical prostatectomy for prostate cancer, prostate-specific antigen less than 5 ng/mL, absence of metastatic disease, and written consent. Participants were randomly assigned (1:1) to radiotherapy alone (no ADT) or radiotherapy with 6 months of ADT (short-course ADT), using monthly subcutaneous gonadotropin-releasing hormone analogue injections, daily oral bicalutamide monotherapy 150 mg, or monthly subcutaneous degarelix. Randomisation was done centrally through minimisation with a random element, stratified by Gleason score, positive margins, radiotherapy timing, planned radiotherapy schedule, and planned type of ADT, in a computerised system. The allocated treatment was not masked. The primary outcome measure was metastasis-free survival, defined as distant metastasis arising from prostate cancer or death from any cause. Standard survival analysis methods were used, accounting for randomisation stratification factors. The trial had 80% power with two-sided α of 5% to detect an absolute increase in 10-year metastasis-free survival from 80% to 86% (hazard ratio [HR] 0·67). Analyses followed the intention-to-treat principle. The trial is registered with the ISRCTN registry, ISRCTN40814031, and ClinicalTrials.gov, NCT00541047. FINDINGS: Between Nov 22, 2007, and June 29, 2015, 1480 patients (median age 66 years [IQR 61-69]) were randomly assigned to receive no ADT (n=737) or short-course ADT (n=743) in addition to postoperative radiotherapy at 121 centres in Canada, Denmark, Ireland, and the UK. With a median follow-up of 9·0 years (IQR 7·1-10·1), metastasis-free survival events were reported for 268 participants (142 in the no ADT group and 126 in the short-course ADT group; HR 0·886 [95% CI 0·688-1·140], p=0·35). 10-year metastasis-free survival was 79·2% (95% CI 75·4-82·5) in the no ADT group and 80·4% (76·6-83·6) in the short-course ADT group. Toxicity of grade 3 or higher was reported for 121 (17%) of 737 participants in the no ADT group and 100 (14%) of 743 in the short-course ADT group (p=0·15), with no treatment-related deaths. INTERPRETATION: Metastatic disease is uncommon following postoperative bed radiotherapy after radical prostatectomy. Adding 6 months of ADT to this radiotherapy did not improve metastasis-free survival compared with no ADT. These findings do not support the use of short-course ADT with postoperative radiotherapy in this patient population. FUNDING: Cancer Research UK, UK Research and Innovation (formerly Medical Research Council), and Canadian Cancer Society.

Factors Associated with Long-Term Prostate Cancer Survival after Palliative Radiotherapy to a Bone Metastasis and Contemporary Palliative Systemic Therapy: A Retrospective, Population-Based Study.

BACKGROUND: Radiation therapy (RT) is an established palliative treatment for bone metastases; however, little is known about post-radiation survival and factors which impact it. The aim of this study was to assess a population-based sample of metastatic prostate cancer patients receiving palliative radiation therapy to bone metastases and contemporary palliative systemic therapy and identify factors that impact long-term survival. MATERIALS/METHODS: This retrospective, population-based, cohort study assessed all prostate cancer patients receiving palliative RT for bone metastases at a Canadian provincial Cancer program during a contemporary time period. Baseline patient, disease, and treatment characteristics were extracted from the provincial medical physics databases and the electronic medical record. Post-RT Survival intervals were defined as the time interval from the first fraction of palliative RT to death from any cause or date of the last known follow-up. The median survival of the cohort was used to dichotomize the cohort into short- and long-term survivors following RT. Univariable and multivariable hazard regression analyses were performed to identify variables associated with post-RT survival. RESULTS: From 1 January 2018 until 31 December 2019, 545 palliative RT courses for bone metastases were delivered to n = 274 metastatic prostate cancer patients with a median age of 76 yrs (Interquartile range (IQR) 39-83) and a median follow-up of 10.6 months (range 0.2 to 47.9). The median survival of the cohort was 10.6 months (IQR 3.5-25 months). The ECOG performance status of the whole cohort was ≤2 in n = 200 (73%) and 3-4 in n = 67 (24.5%). The most commonly treated sites of bone metastasis were the pelvis and lower extremities n = 130 (47.4%), skull and spine n = 114 (41.6%), and chest and upper extremities n = 30 (10.9%). Most patients had CHAARTED high volume disease n = 239 (87.2%). On multivariable hazard regression analysis, an ECOG performance status of 3-4 (p = 0.02), CHAARTED high volume disease burden (p = 0.023), and non-receipt of systemic therapy (p = 0.006) were significantly associated with worse post-RT survival. CONCLUSION: Amongst metastatic prostate cancer patients treated with palliative radiotherapy to bone metastases and modern palliative systemic therapies, ECOG performance status, CHAARTED metastatic disease burden, and type of first-line palliative systemic therapy were significantly associated with post-RT survival durations.

Metformin for Prevention of Anthropometric and Metabolic Complications of Androgen Deprivation Therapy in Prostate Cancer Patients Receiving Radical Radiotherapy: A Phase II Randomized Controlled Trial.

BACKGROUND: Patients with prostate cancer undergoing treatment with radical radiation therapy (RT) plus androgen deprivation therapy (ADT) experience a constellation of deleterious metabolic and anthropometric changes related to hypogonadism that are associated with increased morbidity and mortality. We assessed the effect of metformin versus placebo to blunt the adverse effects of ADT on body weight, waist circumference, and other metabolic parameters. METHODS AND MATERIALS: This phase 2, multicenter, randomized controlled trial (RCT) randomized normoglycemic men with locally advanced prostate cancer receiving radical RT and ADT (18-36 months) in a 1:1 ratio to receive metformin 500 mg by mouth 3 times a day (for 30-36 months) versus identical placebo. RESULTS: From December 2015 to October 2019, 83 men were randomized with median follow-up of 23 months. Baseline mean body mass Index (BMI) of the cohort was 30.2 (range 22.2-52.5). Change in mean weight relative to baseline was lower among men who received metformin compared with placebo at 5 months (-1.80 kg, P = .038), but was not significant with longer follow-up (1 year: +0.16 kg, P = .874). Although participants on ADT had increases in waist circumference in both study arms, metformin did not significantly reduce these changes (1 year: +2.79 cm (placebo) versus +1.46 cm (metformin), P = .336). Low-density lipoprotein (LDL) cholesterol was lower in the metformin arm (-0.32 mmol/L) compared with the placebo arm (-0.03 mmol/L) at 5 months (P = .022), but these differences were not significant with longer follow-up (1 year: -0.17 mmol/L vs -0.19 mmol/L, P = .896). There were no differences in HbA1C, triglyceride, high-density lipoprotein (HDL) cholesterol, and total cholesterol by study arm. CONCLUSIONS: Men receiving radical RT and ADT gained weight and had increases in waist circumference over time that metformin did not significantly mitigate. Although this study did not observe any preventive effect of metformin on the anthropometric and metabolic complications of ADT, metformin continues to be studied in phase 3 RCTs in this patient population to assess its potential antineoplastic effects.

Do Sustainable Palliative Single Fraction Radiotherapy Practices Proliferate or Perish 2 Years after a Knowledge Translation Campaign?

In early 2017, the Canadian Partnership Against Cancer and CancerCare Manitoba undertook a comprehensive knowledge translation (KT) campaign to improve the utilization of single fraction radiotherapy (SFRT) over multiple fraction radiotherapy (MFRT) for palliative management of bone metastases. The campaign significantly increased short-term SFRT utilization. We assess the time-dependent effects of KT-derived SFRT utilization 12-24 months removed from the KT campaign in a Provincial Cancer Program. This study identified patients receiving palliative radiotherapy for bone metastases in Manitoba in the 2018 calendar year using the provincial radiotherapy database. The proportion of patients treated with SFRT in 2018 was compared to 2017. Logistic regression analyses identified risk factors associated with MFRT receipt. In 2018, 1008 patients received palliative radiotherapy for bone metastasis, of which 63.3% received SFRT, a small overall increase in SFRT use over 2017 (59.1%). However, 41.1% of ROs demonstrated year-over-year decreases in SFRT utilization, indicative of a time-dependent loss of SFRT prescription habits derived from KT. Although SFRT use increased slightly overall in 2018, evidence of compliance fatigue was observed, suggestive of a time-perishing property of RO prescription behaviours derived from KT methodologies. Verification of the study's findings in larger cohorts would be beneficial. These findings highlight the need for additional longitudinal KT reinforcement practices in the years following KT campaigns.

A population-based study of outcomes in adjuvant radiotherapy for stage II endometrial carcinoma.

OBJECTIVE: Our study aimed to analyze recurrence and survival outcomes in stage II endometrial cancer patients treated with adjuvant radiotherapy at CancerCare Manitoba, a Canadian provincial cancer program. METHODS: This retrospective population-based cohort study identified all International Federation of Gynecology and Obstetrics (FIGO) 2009 stage II endometrioid type endometrial carcinoma diagnosed between January 1995 and December 2019. All patients underwent surgery followed by vaginal vault brachytherapy alone or external beam pelvic radiotherapy plus vaginal vault brachytherapy. We used Kaplan-Meier curves to describe overall survival and recurrence-free survival, and cumulative incidence to describe recurrence. Cox regression was used to predict overall survival and recurrence-free survival competing risk regression to predict recurrence. RESULTS: A total of 121 patients were included (78 vaginal brachytherapy alone and 43 external beam pelvic radiotherapy plus vaginal brachytherapy) with a median age of 62 (range 24-85). The median follow-up was 55.2 months (range 7.1-147.9) in the vaginal brachytherapy group and 41.9 months (range 7.4-127.0) in the pelvic radiotherapy group. Lymph node dissection was performed in 79 (65.3%) patients. There were 14 (17.9%) recurrences (8 vaginal vault, 3 pelvic, 3 distant) with vaginal brachytherapy and 7 (16.3%) recurrences (3 vaginal vault, 2 pelvic, 2 distant) with external beam pelvic radiotherapy. The 5 year overall survival was 73.1% with vaginal vault brachytherapy vs 73.7% with external beam pelvic radiotherapy plus vaginal brachytherapy (p=0.31), the 5 year recurrence-free survival was 65.0% vs 68.2% (p=0.61), and the 5 year recurrence risk was 20.3% vs 19.4% (p=0.94). On univariable and multivariable analysis, only age was a statistically significant predictor for overall survival and recurrence-free survival (p<0.05), but not lymphovascular space invasion (HR, 2.97; 95% CI, 0.99 to 8.93 for overall survival, p=0.15). The type of adjuvant radiotherapy did not predict for recurrence (p=0.94). CONCLUSIONS: There was no significant difference in overall survival, recurrence-free survival, and recurrence risk between vaginal vault brachytherapy vs external beam pelvic radiotherapy plus vaginal vault brachytherapy in patients with stage II endometrial cancer.

Gastrointestinal and genitourinary toxicity profiles of metformin versus placebo in men with prostate cancer receiving prostate radiotherapy: interim toxicity results of a double-blinded, multicenter, phase II randomized controlled trial.

Androgen deprivation therapy (ADT) used for prostate cancer (PCa) management is associated with metabolic and anthropometric toxicity. Metformin given concurrent to ADT is hypothesized to counteract these changes. This planned interim analysis reports the gastrointestinal and genitourinary toxicity profiles of PCa patients receiving ADT and prostate/pelvic radiotherapy plus metformin versus placebo as part of a phase 2 randomized controlled trial. Men with intermediate or high-risk PCa were randomized 1:1 to metformin versus placebo. Both groups were given ADT for 18-36 months with minimum 2-month neoadjuvant phase prior to radiotherapy. Acute gastrointestinal and genitourinary toxicities were quantified using CTCAE v4.0. Differences in ≥ grade 2 toxicities by treatment were assessed by chi-squared test. 83 patients were enrolled with 44 patients randomized to placebo and 39 randomized to metformin. There were no significant differences at any time point in ≥ grade 2 gastrointestinal toxicities or overall gastrointestinal toxicity. Overall ≥ grade 2 gastrointestinal toxicity was low prior to radiotherapy (7.9% (placebo) vs. 3.1% (metformin), p = 0.39) and at the end of radiotherapy (2.8% (placebo) vs 3.1% (metformin), p = 0.64). There were no differences in overall ≥ grade 2 genitourinary toxicity between treatment arms (19.0% (placebo) vs. 9.4% (metformin), p = 0.30). Metformin added to radiotherapy and ADT did not increase rates of ≥ grade 2 gastrointestinal or genitourinary toxicity and is generally safe and well-tolerated.

Do Coordinated Knowledge Translation Campaigns Persuade Radiation Oncologists to Use Single-Fraction Radiation Therapy Compared With Multiple-Fraction Radiation Therapy for Bone Metastases?

PURPOSE: Although level 1 evidence supports the use of single-fraction radiation therapy (SFRT) compared with multiple-fraction radiation therapy (MFRT) for the palliative management of bone metastases, SFRT is underused. In early 2017, the Canadian Partnership Against Cancer and CancerCare Manitoba undertook a comprehensive knowledge translation campaign in Manitoba, Canada featuring educational outreach visits, local consensus meetings, and audit and feedback interventions to encourage greater use of SFRT. This study assessed the impact of this campaign on SFRT use and identified variables associated with MFRT usage. METHODS AND MATERIALS: This retrospective, population-based cohort study identified all patients treated with palliative radiation therapy for bone metastases in Manitoba, Canada, from January 1, 2017, to December 31, 2017, using the provincial radiation therapy database. Baseline characteristics were extracted and tabulated by fractionation schedule. The proportion of patients treated with SFRT in 2017 (postintervention) was compared with the 2016 (preintervention) levels. Univariable and multivariable logistic regression analyses were performed to identify risk factors associated with MFRT use. RESULTS: In 2017, 927 patients received palliative radiation therapy for bone metastasis, of which 548 (59.1%) received SFRT, a 21.1% absolute increase in SFRT use compared with 2016 levels (38.0%). With use of multivariable analysis, variables associated with receipt of MFRT included: complicated bone metastasis, soft tissue extension, hematological primary malignancy, and treatment at a subsidiary center. CONCLUSION: The comprehensive knowledge translation campaign carried out in Manitoba resulted in a significant increase in SFRT use for bone metastases. Continued audit/feedback strategies are recommended to further reinforce knowledge translation efforts supporting SFRT use in the future.

Impact of spironolactone exposure on prostate cancer incidence amongst men with heart failure: A Pharmacoepidemiological study.

AIMS: Aldosterone has been found to influence cancer cell growth, cell cycle regulation and cell migration, including in prostate cancer cells. Spironolactone is an aldosterone antagonist used for managing chronic heart failure (HF) with known antiandrogenic effects. We examined the effect of spironolactone exposure amongst men with HF on the incidence of prostate cancer. METHODS: This retrospective cohort study utilized provincial clinical and administrative databases from the Manitoba Centre for Health Policy. Incident cases of prostate cancer were identified from the provincial cancer registry, and spironolactone exposure was quantified from pharmacare databases. A multivariable proportional hazards model was used to assess the time-dependent impact of spironolactone exposure on prostate cancer incidence. RESULTS: A total of 18 562 men with newly diagnosed HF from 2007 to 2015 with a median age of 72 years (interquartile range: 61-81) and a median follow-up from HF diagnosis to prostate cancer incidence of 2.7 years (interquartile range: 1.1-4.9) were included. A time-dependent multivariable analysis of spironolactone exposure following HF diagnosis found a reduced the risk of prostate cancer hazard ratio 0.55 (95% confidence interval 0.31-0.98, P = .043). CONCLUSION: Spironolactone exposure significantly reduced the incidence of prostate cancer amongst men with HF. These findings support the plausibility of aldosterone as a promoter of prostate cancer growth and development. Prospective clinical trials are warranted to further assess the role of spironolactone or other mineralocorticoid receptor antagonists as a means to prevent prostate cancer development or as an adjunctive measure to prostate cancer treatments.

Population-based Assessment of Intermittent Androgen Deprivation Therapy Utilization for Relapsed, Nonmetastatic, Hormone-sensitive Adenocarcinoma of the Prostate.

OBJECTIVES: Androgen deprivation therapy (ADT) is the standard of care for men with nonmetastatic hormone-sensitive prostate cancer (nmHSPC) after treatment failure. Although intermittent ADT (iADT) is noninferior to continuous ADT for prostate cancer outcomes, with superior quality of life and cost-to-benefit ratio, little is known regarding its real-world utilization. The authors aimed to determine the utilization of iADT in a Canadian Provincial Cancer Program for relapsed nmHSPC and identified risk factors associated with the nonreceipt of iADT. MATERIALS AND METHODS: This retrospective population-based cohort study used linked administrative databases to identify all patients with relapsed nmHSPC from 2012 to 2016 and quantified ADT prescription history. Patients were defined as iADT eligible if prostate-specific antigen (PSA) was <4 ng/mL and trending downwards on ≥2 sequential PSAs after ≥6 months of ADT. Univariable and multivariable logistic regression analyses were performed to determine factors associated with nonreceipt of iADT. RESULTS: A total of 601 men with relapsed, nmHSPC were included with a median age at relapse of 73 (range, 46 to 96), pre-ADT PSA of 12.2 ng/mL, and a median pre-ADT PSA doubling time of 7.8 months. 80.9% of the cohort were eligible to receive iADT and 74.4% were treated with iADT. On multivariable analysis, patients originally treated with surgery (odds ratio [OR], 0.19; 95% confidence interval [CI], 0.08-0.46) or having a Gleason Score ≥8 (OR, 0.30; 95% CI, 0.12-0.78) had decreased odds of receipt of iADT. Patients with longer PSA doubling times were more likely to receive iADT (OR, 2.71; 95% CI, 1.17-6.31). CONCLUSIONS: The utilization of iADT was relatively common for men in Manitoba during the study period, however, the uptake of iADT can be improved among identified subgroups.

Accelerating prostate stereotactic ablative body radiotherapy: Efficacy and toxicity of a randomized phase II study of 11 versus 29 days overall treatment time (PATRIOT).

BACKGROUND: Prostate stereotactic ablative radiotherapy (SABR) regimens differ in time, dose, and fractionation. We report an update of a multicentre, Canadian randomized phase II study to investigate the impact of overall treatment time on quality of life (QOL), efficacy, and toxicity. METHODS: Men with intermediate risk prostate cancer were randomized to 40 Gy in 5 fractions delivered every other day (EOD) versus once per week (QW). Primary outcome was proportion of patients experiencing a minimally clinically important change (MCIC) in acute bowel QOL using EPIC. Secondary outcomes were toxicity, biochemical failure (BF), other QOL domains, and the rate of salvage therapy. FINDINGS: 152 men from 3 centers were randomized; the median follow-up was 62 months. Results are described for EOD versus QW. Acute bowel and urinary QOL was reported previously. Late changes in QOL were not significantly different between the two arms. There were 1 (1.3%) vs 3 (2.7%) late grade 3 + GI toxicities (p = 0.36) and 5 (6.7%) vs 2 (2.7%) late grade 3 GU toxicities (p = 0.44). Two and 5 patients had BF (5-year failure rate 3.0 vs 7.2%, p = 0.22); 0 and 4 patients received salvage therapy (p = 0.04). 5-Year OS and CSS was 95.8% and 98.6% with no difference between arms (p = 0.49, p = 0.15). 3 patients in the QW arm developed metastases. INTERPRETATION: Although we previously reported that weekly prostate SABR had better bowel and urinary QOL compared to EOD, the updated results show no difference in late toxicity, QOL, BF, or PSA kinetics. Patients should be counseled that QW SABR reduces short-term toxicity compared to QW SABR.

Dosimetric predictors of toxicity and quality of life following prostate stereotactic ablative radiotherapy.

PURPOSE: SABR offers an effective treatment option for clinically localized prostate cancer. Here we report the dosimetric predictors of late toxicity and quality of life (QOL) in a pooled cohort of patients from four phase II trials. METHODS: The combined cohort included all three prostate cancer risk groups. The prescription dose was 35-40 Gy in 5 fractions. Toxicity (CTCAE) and QOL (EPIC) were collected. Multiple dosimetric parameters for the bladder, rectum and penile bulb were collected. Univariate (UVA) followed by multivariate (MVA) logistic regression analysis was conducted to search for significant dosimetric predictors of late GI/GU toxicity, or minimal clinically important change in the relevant QOL domain. RESULTS: 258 patients were included with median follow up of 6.1 years. For QOL, bladder Dmax, V38, D1cc, D2cc, D5cc and rectal V35 were predictors of urinary and bowel MCIC on UVA. On MVA, only bladder V38 remained significant. For late toxicity, various parameters were significant on UVA but only rectal Dmax, V38 and bladder D2cc were significant predictors on MVA. CONCLUSIONS: This report confirms that the high-dose regions in the bladder and rectum are more significant predictors of late toxicity and QOL after prostate SABR compared to low-dose regions. Caution must be taken to avoid high doses and hotspots in those organs.

Long-Term Dynamics of Three Dimensional Telomere Profiles in Circulating Tumor Cells in High-Risk Prostate Cancer Patients Undergoing Androgen-Deprivation and Radiation Therapy.

Patient-specific assessment, disease monitoring, and the development of an accurate early surrogate of the therapeutic efficacy of locally advanced prostate cancer still remain a clinical challenge. Contrary to prostate biopsies, circulating tumor cell (CTC) collection from blood is a less-invasive method and has potential as a real-time liquid biopsy and as a surrogate marker for treatment efficacy. In this study, we used size-based filtration to isolate CTCs from the blood of 100 prostate cancer patients with high-risk localized disease. CTCs from five time points: +0, +2, +6, +12 and +24 months were analyzed. Consenting treatment-naïve patients with cT3, Gleason 8-10, or prostate-specific antigen > 20 ng/mL and non-metastatic prostate cancer were included. For all time points, we performed 3D telomere-specific quantitative fluorescence in situ hybridization on a minimum of thirty isolated CTCs. The patients were divided into five groups based on the changes of number of telomeres vs telomere lengths over time and into three clusters based on all telomere parameters found on diagnosis. Group 2 was classified as non-respondent to treatment and the Cluster 3 presented more aggressive phenotype. Additionally, we compared our telomere results with the PSA levels for each patient at 6 months of ADT, at 6 months of completed RT, and at 36 months post-initial therapy. CTCs of patients with PSA levels above or equal to 0.1 ng/mL presented significant increases of nuclear volume, number of telomeres, and telomere aggregates. The 3D telomere analysis of CTCs identified disease heterogeneity among a clinically homogeneous group of patients, which suggests differences in therapeutic responses. Our finding suggests a new opportunity for better treatment monitoring of patients with localized high-risk prostate cancer.

Two versus five stereotactic ablative radiotherapy treatments for localized prostate cancer: A quality of life analysis of two prospective clinical trials.

PURPOSE: Stereotactic ablative radiotherapy (SABR) is appealing for prostate cancer (PCa) due to low α/ß, and increasing the dose per fraction could improve the therapeutic index and lead to a better quality of life (QOL). Here we report the outcomes of a QOL comparison between two phase II clinical trials: two vs. five fraction prostate SABR. METHODS: Patients had low or intermediate risk PCa. The doses prescribed were 26 Gy/2 and 40 Gy/5. Expanded prostate cancer index composite was collected. Urinary, bowel and sexual domains were analyzed. Minimal clinically important change (MCIC) was defined as >0.5 standard deviation. RESULTS: 30 and 152 patients were treated with 2-fraction and 5-fraction SABR. Median follow-up was 55 and 62 months. Five-year biochemical failure rate was 3.3% and 4.6%. The 2-fraction cohort had a significantly better mean QOL over time in the bowel domain (p = 0.0004), without a significant difference in the urinary or sexual domains. The 2-fraction cohort had a significantly lower rate of bowel MCIC (17.8% vs 42.3%, p = 0.01), but there was no difference in urinary (24.1% vs 35.7%) or sexual (15.3% vs 29.2%) MCIC. For MCIC x2 (moderate QOL change), the 2-fraction trial had significantly lower MCIC rates in both the bowel (7.1% vs 24%, p = 0.04) and sexual (0 vs 17.6%, p = 0.01) domains. CONCLUSIONS: 2-Fraction SABR is feasible to deliver and well tolerated, with significant signals of improved bowel and sexual QOL. A randomized trial of two vs. five fractions for prostate SABR is needed to confirm the promising findings of this study.

Once-weekly versus every-other-day stereotactic body radiotherapy in patients with prostate cancer (PATRIOT): A phase 2 randomized trial.

BACKGROUND AND PURPOSE: Prostate stereotactic body radiotherapy (SBRT) regimens differ in time, dose, and fractionation. We completed a multicentre, randomized phase II study to investigate the impact of overall treatment time on quality of life (QOL). MATERIAL AND METHODS: Men with low and intermediate-risk prostate cancer were randomly assigned to 40 Gy in 5 fractions delivered once per week (QW) vs. every other day (EOD). QOL was assessed using the Expanded Prostate Cancer Index Composite. The primary endpoint was the proportion with a minimum clinically important change (MCIC) in bowel QOL during the acute (≤12 week) period, and analysis was by intention-to-treat. ClinicalTrials.gov NCT01423474. RESULTS: 152 men from 3 centres were randomized with median follow-up of 47 months. Patients treated QW had superior acute bowel QOL with 47/69 (68%) reporting a MCIC compared to 63/70 (90%) treated EOD (p = 0.002). Fewer patients treated QW reported moderate-severe problems with bowel QOL during the acute period compared with EOD (14/70 [20%] vs. 40/70 [57%], p < 0.001). Acute urinary QOL was also better in the QW arm, with 52/67 (78%) vs 65/69 (94%) experiencing a MCIC (p = 0.006). There were no significant differences in late urinary or bowel QOL at 2 years or last follow-up. CONCLUSION: Prostate SBRT delivered QW improved acute bowel and urinary QOL compared to EOD. Patients should be counselled regarding the potential for reduced short-term toxicity and improved QOL with QW prostate SBRT.

Targeting the Tumor: Assessing the Impact of Bladder Volume and Position on Accuracy of Radiation Delivery for Patients with Bladder Cancer.

Context Daily variations in bladder size and position can negatively impact the ability to accurately deliver radiation. Aims We attempted to quantify how bladder volumes and positions change over the course of radiotherapy for muscle invasive bladder cancer and the planning target volume (PTV) margins required to account for such changes. Methods and material Cone-beam computed tomography (CT) images of 28 patients during their first, second, and third fractions and weekly thereafter were acquired. Bladders were contoured and the volume, centre of mass, and the maximal positions were recorded and compared to the planning CT scan. Statistical analysis Bladder parameters were analysed using regression analysis examining for time trends and correlation to the patient, tumour, or treatment-related factors. Results There was great variability in the mean bladder volumes during the radiotherapy courses (154.17 +/- 129.38 cm3). There were no statistically significant trends for volume changes. Deviations in bladder positions were seen but were small in magnitude. No patient factors were identified which could help predict bladder changes clinically. Bladder variability resulted in a high percentage of fractions (39.6%) in which part of the bladder was outside the PTV. Calculated PTV margins (for 90% of the population to receive 95% of the prescription dose) were 1.48 cm right, 1.15 cm left, 2.13 cm posterior, 1.52 cm anterior, 2.23 cm superior, and 0.52 cm inferior. Conclusions Because of random bladder changes, a significant number of fractions were treated in which the clinical target volume (CTV) fell outside of the PTV. Methods to minimize the amount of CTV that is missed on a fraction to fraction basis should be explored.

Population-based referrals for adjuvant radiotherapy after radical prostatectomy in men with prostate cancer: impact of randomized trials.

INTRODUCTION: To examine the impact of published randomized controlled trial (RCT) data on referrals for adjuvant radiotherapy (RT) in patients who had high-risk pathologic features after radical prostatectomy (RP). METHODS: In this population-based, retrospective Canadian study, all patients who received a diagnosis of prostate adenocarcinoma and underwent RP from 2003-2008 were identified through the Manitoba Cancer Registry. Manual review of pathology reports was performed, and patients who had high-risk pathologic features of extracapsular extension, seminal vesicle invasion, or positive surgical margins were included. Referrals for adjuvant RT were examined before and after publication of RCT data to determine their influence on practice. Multivariable logistic regression was used to identify factors related to referral. RESULTS: Of the 1080 identified patients, 546 (50.6%) had ≥ 1 high-risk pathologic feature. Only 78 (14.3%) of the 546 patients were referred for adjuvant RT within 6 months of RP. Year of diagnosis, in relation to the publication of the RCT, was not significantly associated with referral (P =.60). Higher pT stage (P < .0001), Gleason score (P =.035), and increased distance from cancer center (P =.004) were associated with referral. CONCLUSION: In patients who had high-risk pathologic features after RP, referral rates for adjuvant RT were low and did not increase after presentation of RCT. Men who had higher pT stage, Gleason score, and rural residence were more likely to be referred.

The dosimetric quality of brachytherapy implants in patients with small prostate volume depends on the experience of the brachytherapy team.

PURPOSE: To investigate the dosimetric outcome of brachytherapy in patients with small prostate volume (PV). METHODS AND MATERIALS: Forty-three patients with small PV (<25 cm(3)) as determined using transrectal ultrasound and 120 patients with non-small PV (>25 cm(3)) that had received (125)I seed implants were reviewed in a retrospective cohort study. Implantations were performed under transrectal ultrasound guidance, and the prescription dose was 145 Gy. A CT and MRI scan of the pelvis were performed 1 month after implantation for dosimetric study. RESULTS: Compared with non-small PV patients, patients with small PV experienced larger 1-month edema (p<0.001); lower dose to 90% (the isodose enclosing 90% of PV and representing a minimum dose to that volume of the prostate [D(90)]) of the prostate (p=0.03); higher intracapsular seed density (p<0.001); and were less likely to achieve D(90)>or=140 Gy (p=0.013) in a postimplant dosimetric study. The number of patients with D(90)<140 Gy decreased steadily in both subsets of patients as the implant program matured (odds ratio=0.56 per year, p<0.001), but the small prostate group exhibited more improvement compared with the non-small prostate patients over the same time period. Multivariate analysis revealed that brachytherapy team experience rather than the size of prostate was a more important predictive factor of implant quality (p<0.001). CONCLUSIONS: This single institution experience demonstrated a significant learning curve in the initial years of a prostate brachytherapy program, especially for patients with small prostates. A small prostate itself is not a contraindication of brachytherapy. The quality of implant for patients with small prostates depends more on the skill of the brachytherapy team.