Late Genitourinary Research Articles

Moderate hypofractionated radiotherapy vs conventional fractionated radiotherapy in localized prostate cancer: a systemic review and meta-analysis from Phase III randomized trials.

PurposeTo determine the efficacy and late toxicities of moderate (2.5–4 Gy) hypofractionated radiotherapy (H-RT) in localized prostate cancer, a meta-analysis of published randomized clinical trials comparing moderate H-RT with conventional fractionated RT (C-RT) was performed.Materials and methodsSystematic search on published randomized clinical trials in English according to Cochrane review guidelines in databases of Pubmed, Embase, Cochrane, web of science, and Wiley Online Library was carried out. Outcomes of interests were biochemical and clinical disease failure (BCDF), biochemical failure (BF), overall survival (OS), and late toxicities.ResultsSeven of the 365 studies fulfilled inclusion criteria with 8,156 participants. Compared with C-RT, moderate H-RT showed a lower BF rate (risk ratio [RR] =0.80, 95% CI: 0.68–0.95, P=0.009), while did not improve OS (RR =0.68, 95% CI: 0.78–1.02, P=0.10). There was no significant difference in BCDF rates between H-RT and C-RT (RR =0.92, 95% CI: 0.82–1.02, P=0.12). The H-RT was deeply grouped into dose-escalated H-RT (with a higher biologically effective dose [BED1.5] than C-RT) and no dose-escalated H-RT; dose-escalated H-RT significantly decreased BCDF rate compared with C-RT (RR =0.84, 95% CI: 0.73–0.96, P=0.01). Regarding late toxicities, there is no significant difference in late gastrointestinal (GI; RR =0.97, 95% CI: 0.71–1.33, P=0.85) and genitourinary (GU) toxicities (RR =1.04, 95% CI: 0.87–1.24, P=0.69). When subgrouped into dose-escalated H-RT (with a higher BED5 compared with C-RT) and no dose-escalated H-RT, dose-escalated H-RT increased GI toxicity (RR =1.62, 95% CI: 1.26–2.09, P=0.0002) and GU toxicity (RR =1.28, 95% CI: 1.05–1.55, P=0.01), while no dose-escalated H-RT significantly lowered GI toxicity (RR =0.81, 95% CI: 0.70–0.94, P=0.005) and placed no influence on GU toxicity (RR =1.02, 95% CI: 0.88–1.20, P=0.77).ConclusionThis meta-analysis provides reliable evidence that moderate H-RT decreases BF rate, while does not improve OS. Compared with C-RT, H-RT with an increase in BED1.5 improved BCDF rates significantly, and accordingly, an increase in BED5 will result in elevated late GI and GU toxicities.

A Phase 1 Pilot Study of Preoperative Radiation Therapy for Prostate Cancer: Long-Term Toxicity and Oncologic Outcomes

Neoadjuvant radiation therapy (RT) improves disease control in various cancers and has become an established oncologic treatment strategy. During 2001 to 2004, we conducted a phase 1 pilot study assessing the role of short-course preoperative RT (PreORT) for men with unfavorable intermediate- and high-risk localized prostate cancer. Herein, we present long-term follow-up toxicity and oncologic outcomes. Eligible patients had histologically proven prostate cancer, cT1-T2N0M0 disease, prostate-specific antigen >15 to 35ng/mL regardless of Gleason score, or prostate-specific antigen 10 to 15ng/mL with Gleason score ≥7. Patients received 25Gy in 5 consecutive daily fractions (5Gy per fraction) to the prostate only, followed by radical prostatectomy within 14days after RT completion. Primary outcomes were intraoperative morbidity and late genitourinary (GU) and gastrointestinal toxicities. In total, 15 patients were enrolled; 14 patients completed PreORT followed by radical prostatectomy, which also included bilateral lymph node dissections in 13 cases. Median follow-up was 12.2years (range, 6.7-16.3). Late GU toxicity was common, with 2 patients (13.3%) experiencing G2 toxicity and 6 patients (40%) G3 toxicity. There were no patients with G4 to G5 late GU toxicity. Late gastrointestinal toxicity was infrequent, with only 1 patient (6.7%) experiencing transient G2 proctitis. At last follow-up, 8 (53.3%) and 6 (40%) patients experienced biochemical and metastatic disease recurrence, respectively. The use of PreORT in men with high-risk prostate cancer is associated with unexpected high rates of late GU toxicity. Future studies examining the role of RT preradical prostatectomy must cautiously select RT technique and dose schedule. Importantly, long-term follow-up data are essential to fully determine the therapeutic index of PreORT in the management of localized disease.

Outcomes and prognostic factors in intermediate-risk prostate cancer: multi-institutional analysis of the Spanish RECAP database.

To retrospectively assess outcomes and to identify prognostic factors in patients diagnosed with intermediate-risk (IR) prostate cancer (PCa) treated with primary external beam radiotherapy (EBRT). Data were obtained from the multi-institutional Spanish RECAP database, a population-based prostate cancer registry in Spain. All IR patients (NCCN criteria) who underwent primary EBRT were included. The following variables were assessed: age; prostate-specific antigen (PSA); Gleason score; clinical T stage; percentage of positive biopsy cores (PPBC); androgen deprivation therapy (ADT); and radiotherapy dose. The patients were stratified into one of three risk subcategories: (1) favourable IR (FIR; GS 6, ≤ T2b or GS 3 + 4, ≤ T1c), (2) marginal IR (MIR; GS 3 + 4, T2a-b), and (3) unfavourable IR (UIR; GS 4 + 3 or T2c). Biochemical relapse-free survival (BRFS), disease-free survival (DFS), cancer-specific survival (CSS), and overall survival (OS) were assessed. A total of 1754 patients from the RECAP database were included and stratified by risk group: FIR, n = 781 (44.5%); MIR, n = 252 (14.4%); and UIR, n = 721 (41.1%). Mean age was 71years (range 47-86). Mean PSA was 10.4ng/ml (range 6-20). The median radiotherapy dose was 74Gy, with mean doses of 72.5Gy (FIR), 73.4Gy (MIR), and 72.8Gy (UIR). Most patients (88%) received ADT for a median of 7.1months. By risk group (FIR, MIR, UIR), ADT rates were, respectively, 88.9, 86.5, and 86.9%. Only patients with ≥ 24months of follow-up post-EBRT were included in the survival analysis (n = 1294). At a median follow-up of 52months (range 24-173), respective 5- and 10-year outcomes were: OS 93.6% and 79%; BRFS 88.9% and 71.4%; DFS 96.1% and 89%; CSS 98.9% and 94.6%. Complication rates (≥ grade 3) were: acute genitourinary (GU) 2%; late GU 1%; acute gastrointestinal (GI) 2%; late GI 1%. There was no significant association between risk group and BRFS or OS. However, patients with favourable-risk disease had significantly better 5- and 10-year DFS than patients with UIR: 98.7% vs. 92.4% and 92% vs. 85.8% (p = 0.0005). CSS was significantly higher (p = 0.0057) in the FIR group at 5 (99.7% vs. 97.3%) and 10 years (96.1% vs. 93.4%). On the multivariate analyses, the following were significant predictors of survival: ADT (BRFS and DFS); dose ≥ 74Gy (BRFS); age (OS). This is the first nationwide study in Spain to report long-term outcomes of patients with intermediate-risk PCa treated with EBRT. Survival outcomes were good, with a low incidence of both acute and late toxicity. Patients with unfavourable risk characteristics had significantly lower 5- and 10-year disease-free survival rates. ADT and radiotherapy dose ≥ 74Gy were both significant predictors of treatment outcomes.

Impact of image guidance on toxicity and tumour outcome in moderately hypofractionated external-beam radiotherapy for prostate cancer.

To report toxicity and efficacy outcome of moderately hypofractionated image-guided external-beam radiotherapy in a large series of patients treated for prostate cancer (PCa). Between 10/2006 and 12/2015, 572 T1-T3N0M0 PCa patients received 70.2Gy in 26 fractions at 2.7Gy/fraction: 344 patients (60%) with three-dimensional conformal radiotherapy (3D-CRT) and 228 (40%) with intensity-modulated radiotherapy (IMRT). Radiation Therapy Oncology Group/European Organization for Research and Treatment of Cancer criteria and Houston definition (nadir + 2) were used for toxicity and biochemical failure evaluation, respectively. Median age was 74years (interquartile range 69-77). Compared with 3D-CRT, in IMRT group more high-risk patients (29% vs 18%; P = 0.002) and more high-volume target (75% vs 60%; P < 0.001) were included. Acute gastro-intestinal (GI) toxicity G > 1 were registered in 8% and in 11% IMRT and 3D-CRT patients, respectively, whereas late GI G > 1 were observed in 2% and 16% IMRT and 3D-CRT patients, respectively. Acute genito-urinary (GU) toxicity G > 1 were registered in 26% and 40% IMRT and 3D-CRT patients, respectively, whereas late GU G > 1 occurred in 5% IMRT and 15% 3D-CRT patients. Multivariate proportional hazard Cox models confirmed significantly greater risk of late toxicity with 3D-CRT compared to IMRT for GU > 1 (P = 0.004) and for GI > 1 (P < 0.001). With a median 4-year follow-up, overall survival (OS), clinical progression-free survival (cPFS) and biochemical PFS (bPFS) for the whole series were 91%, 92% and 91%, respectively. cPFS and bPFS were significantly different by risk groups. Multivariate Cox models for bPFS and cPFS showed no difference between irradiation techniques and a significant impact of risk group and initial PSA. Moderately hypofractionated radiotherapy is a viable treatment option for localized PCa with excellent tumour control and satisfactory toxicity profile. IMRT seems associated with a reduction in toxicity, whereas tumour control was equal between IMRT and 3D-CRT patients and depended mainly on the risk category.

Toxicity and clinical outcomes with definitive three-dimensional conformal radiotherapy (3DCRT) and concurrent cisplatin chemotherapy in locally advanced cervical carcinoma.

This study aimed to retrospectively evaluate the toxicity and clinical outcomes in patients of locally advanced cervical cancer treated with three-dimensional conformal radiotherapy (3DCRT) and concurrent chemotherapy. Two hundred and ten newly diagnosed patients of locally advanced cervical cancer of FIGO 2009 Stage II-III treated with 3DCRT (46 Gy/23 fractions/4½ weeks) and weekly concurrent Cisplatin (40 mg/m2), from January 2013 to 2015 were analyzed. A planning computed tomography was performed and contouring was done according to published guidelines. External radiotherapy was followed by Intracavitary brachytherapy delivered to a dose of 9 Gy HDR in 2-fractions, given one week apart. The endpoints were treatment related toxicities and clinical outcomes. Local control (LC), overall survival (OS) and disease free survival (DFS) were evaluated and toxicities were documented using the common terminology criteria for adverse events (v3.0) (CTCAE). The median follow up time was 37 (range, 19-54) months. The 3 year OS, DFS and LC were 84.2%, 80.6% and 81% respectively. Grade ≥3 acute skin, upper and lower gastrointestinal (GI) and genitourinary (GU) toxicity was observed in 3 (1.4%), 11 (5.2%), 12 (5.7%) and 0 (0%) patients, respectively. Grade ≤2 hematological toxicity was observed in 154 (73.3%) patients. Grade ≥3 late GI and GU toxicity was seen in 9 (4.2%) patients and 2 (0.9%) patients, respectively. 3DCRT with concurrent chemotherapy results in good loco-regional control with acceptable normal tissue toxicity. In the background of indeterminate evidence regarding routine practice of intensity modulated radiotherapy in carcinoma of the cervix, 3DCRT may be considered as the treatment of choice.

High-dose-rate brachytherapy monotherapy versus low-dose-rate brachytherapy with or without external beam radiotherapy for clinically localized prostate cancer

BackgroundTo compare the outcome of high-dose-rate interstitial brachytherapy (HDR-BT) monotherapy and low-dose-rate brachytherapy (LDR-BT) with or without external beam radiotherapy (EBRT) for localized prostate cancer. Methods and materialsWe compared 352 patients treated with HDR-BT as monotherapy (median follow-up time 84 months, NCCN risk classification; low: intermediate: high = 28:145:179) and 486 patients with LDR-BT with or without EBRT (90 months, 194:254:38). HDR-BT treated advanced disease with more hormonal therapy than LDR-BT. LDR-BT excluded patients with T3b–T4 tumor and initial PSA >50 ng/ml. Inverse probability of treatment weighting (IPTW) involving propensity scores was used to reduce background selection bias. ResultsThe actuarial 5-year biochemical failure-free survival rates (bNED) were 92.9% and 95.6% (p = 0.25) in the HDR-BT and LDR-BT groups, respectively, and it was 100% and 97.3% (p = 0.99) in the low-risk, 95.6% and 94.3% (p = 0.19) in the intermediate, 89.6% and 94.9% (p = 0.26) in the high-risk groups, and 93.1% and 94.9% (p = 0.98) in selected high-risk group excluding T3b-4 and initial PSA ≥50. IPTW correction also indicated no difference in bNED between LDR-BT and HDR-BT groups. LDR-BT showed a higher incidence of genitourinary (GU) toxicity grade ≥2 than that of HDR-BT in the acute phase and grade 1 toxicity in late phase. Acute GU toxicity grade ≥1 predicted late GU toxicity grade ≥2. External beam radiotherapy plus LDR-BT elevated GI toxicity than LDR-BT only group. Accumulated incidence of late grade ≥2 GU and GU toxicity was equivalent between HDR-BT and LDR-BT. No grade 4 or 5 toxicities were detected in either modality. ConclusionHDR-BT monotherapy showed an equivalent outcome to that of LDR-BT with or without EBRT for low-, intermediate- and selected high-risk patients. LDR-BT showed equivalent incidence of grade ≥2 late GI and GU toxicities and higher grade ≥2 acute GU toxicity as that of HDR-BT as a monotherapy.

Salvage High-Dose Rate (HDR) Brachytherapy as a Treatment for Locally Recurrent Prostate Cancer after Primary Radiation Therapy

Salvage brachytherapy is a treatment option for patients with locally recurrent prostate cancer following definitive radiotherapy. We report the tumor control and toxicity outcomes from using high-dose rate (HDR) brachytherapy (BT) alone for local salvage. Between 2013 and 2017, thirty-two patients with biopsy-proven (n = 23) or radiologically-evident (n = 9) locally recurrent prostate cancer were treated with salvage HDR brachytherapy. Dose-fractionation schedules included: 19Gy single fraction (n = 24), 15Gy single fraction (n = 5), 26Gy in two fractions (n = 2) and 31.5Gy in three fractions (n = 1). Three patients received treatment to the whole gland; the remaining 29 received focal therapy mapped according to combined pelvic magnetic resonance (MR) imaging and template biopsy findings (n = 21) or MR imaging alone (n = 8). The median time from completion of primary treatment to salvage HDR BT was 57 months. Seventeen patients received androgen deprivation therapy (ADT) as part of their primary treatment. In all cases, ADT had been discontinued prior to salvage HDR BT and was not re-commenced following the procedure. Biochemical progression-free survival (bPFS) using the Kaplan-Meier method was defined according to the Phoenix standard of nadir prostate-specific antigen (PSA) plus ≥2mg/ml. Acute and late genitourinary (GU) and gastrointestinal (GI) toxicities were evaluated using the Common Terminology Criteria for Adverse Events, version 4.0. Late toxicity was defined as that occurring ≥90 days after completion of salvage brachytherapy. Median follow-up after salvage HDR brachytherapy was 24 months. Median PSA nadir value was 0.8 reached at a median of 5 months from day of implant. The 2-year biochemical progression-free survival rate was 60.0%. The 2-year local relapse rate was 9.3% with 8 out of the 11 recurrences occurring at distant sites. Acute and late GU and GI toxicities are shown in Table 1. Two patients developed late grade 3 urinary toxicity, both urethral strictures requiring surgical correction. No late GI complications of grade 2 or higher were encountered with no reports of rectal fistulae or requirement for defunctioning colostomy.Abstract SU_28_2277; Table 1Number of patients presenting with acute (<90 days) and late (≥90 days) genitourinary and gastrointestinal toxicities following salvage high-dose rate brachytherapyToxicityACUTELATEGenitourinarynnGrade 1/22219Grade 302Grade 400GastrointestinalGrade 1/241Grade 300Grade 400 Open table in a new tab High-dose rate brachytherapy is an effective modality for the salvage treatment of locally recurrent prostate cancer with very good local control rates and an acceptable long-term toxicity profile. The high rate of distant relapse underscores the current challenge of accurate staging of systemic disease and appropriate patient selection in the salvage setting. The use of more sensitive imaging modalities such as PSMA-PET may improve this in the future.

A case-control study using motion-inclusive spatial dose-volume metrics to account for genito-urinary toxicity following high-precision radiotherapy for prostate cancer.

The risk of genitourinary (GU) toxicity is dose-limiting in radiotherapy (RT) for prostate cancer. This study investigated whether motion-inclusive spatial dose/volume metrics explain the GU toxicity manifesting after high-precision RT for prostate cancer. A matched case-control was performed within a cohort of 258 prostate cancer patients treated with daily cone-beam CT (CBCT)-guided RT (prescription doses of 77.4-81.0 Gy). Twenty-seven patients (10.5%) presented late RTOG GU ≥ Grade 2 toxicity and those without symptoms of toxicity prior treatment (N = 7) were selected as cases. Each case was matched with three controls based on pre-treatment GU symptoms, age, Gleason score, follow-up time, and hormone therapy. Thirteen CBCTs per patient were rigidly registered to the planning CT using the recorded treatment shifts, and the bladder was manually contoured on each CBCT. Planned and actually delivered dose/volume metrics (the latter averaged across the CBCTs) were extracted from the bladder and its subsectors, and compared between cases and controls (two-way ANOVA test). There were no significant differences between planned and delivered dose/volume metrics; also, there were no significant differences between cases and controls at any dose level, neither for planned nor delivered doses. The cases tended to have larger bladder volumes during treatment than controls (221 ± 71 cm3 vs 166 ± 73 cm3; p = 0.09). High-precision RT for prostate cancer eliminates differences between planned and delivered dose distributions. Neither planned nor delivered bladder dose/volume metrics were associated to the remaining low risk of developing GU toxicity after high-precision radiotherapy for prostate cancer.

Long-term Outcomes of Radiotherapy Regimen of 72 Gy in 30 Fractions for Prostate Cancer.

The long-term efficacy and safety of moderately hypofractionated intensity-modulated radiation therapy (MH-IMRT) in prostate cancer remains uncertain. This study aimed to evaluate MH-IMRT regimen of 72 Gy in 30 fractions in patients with prostate cancer. The outcomes of 412 consecutive prostate cancer patients, who received MH-IMRT between May 2007 and December 2012, were retrospectively reviewed. The median patient age was 70.9 (range=50-84) years. Late gastrointestinal (GI) and genitourinary (GU) toxicity rates were evaluated according to the CTCAE ver. 3.0. The overall survival, biochemical relapse-free survival rate (bRFS), late GI toxicity, and GU toxicity rates were analyzed with the Kaplan-Meier method. The median follow-up was 71.5 (range, 1.4-124.8) months. The 5-year bRFS rate was 93.2%. The 5-year grade ≥2 late GI and GU toxicity rates were 3.3% and 4.5%, respectively. MH-IMRT regimen of 72 Gy in 30 fractions was effective and safe for prostate cancer patients.

"Give me five" ultra-hypofractionated radiotherapy for localized prostate cancer: non-invasive ablative approach.

Ultra-hypofractionated radiotherapy (RT) is given over a shorter time with larger doses with respect to conventional fractionation in patients with localized prostate cancer (PCa). The use of hypofractionation is supported both from the radiobiological point of view (the low α/β-ratio in PCa and dose escalation) and from the rising number of clinical evidences. The aim of this study is to review our data regarding oncological outcomes, namely biochemical progression-free survival (b-PFS) and clinical progression-free survival (c-PFS), acute and long-term toxicities in patients treated with a ultra-hypofractionated RT. A series of 194 patients with clinically localized PCa treated primarily with ultra-hypofractionated RT using image-guided intensity modulated RT (IG-IMRT) at our Institute from 2012 to 2015 was included in this analysis. According to NCCN risk group classification, 65 (33.5%) patients were low risk, 101 (52.1%) intermediate risk, and 28 (14.4%) high risk. Androgen deprivation therapy (ADT) was given to 61 patients (31.4%). A 169 patients (87.1%) received 35Gy in 5 fractions, while 25 patients (13%) received 32.5Gy in 5 fractions (usually given in patients with comorbidity). The median duration of the treatment was 10 days (IQR 9-12). Biochemical relapse was defined as a rise of prostate specific antigen (PSA) > 2ng/ml above nadir. b-PFS, c-PFS, and freedom from gastro-intestinal (GI) and genito-urinary (GU) toxicity curves were calculated by the Kaplan-Meier method. Log-rank test and multivariate Cox models were used to investigate the role RT dose and heterogeneity by NCCN risk groups adjusting for prognostic factors. Data on acute and late term toxicities were collected according to RTOG/EORTC grading system. With a median follow-up of 30 months, 17 patients experienced PSA failure (9%). The 3-year b-PFS was 87% for all patients and rates stratified for the NCCN risk were 94, 82, and 66% for low-, intermediate-, and high-risk groups, respectively. Log-rank tests indicate that biochemical progression was significantly greater for patients with initial PSA (iPSA) greater than 7ng/ml (P = 0.04), high- and intermediate-risk groups (P = 0.002), low total dose (P = 0.02) and Gleason score (GS) equal or greater than 7 (P = 0.04). No statistically significant association was found with T stage nor ADT. In multivariate analyses, total dose (P = 0.03) and risk groups (P = 0.03) remained significantly associated with recurrence. Acute and late GI and GU toxicity were acceptable. The toxicity of ultra-hypofractionated IG-IMRT in a large clinical cohort of PCa patients was tolerable and confirmed that this treatment is safe and offers excellent tumor control. Moreover, the hypofractionated RT allows to deliver the whole RT over 10 days with a sensible impact in patients' quality of life and potential overall health system and social benefits.

High dose rate brachytherapy for prostate cancer: A prospective toxicity evaluation of a one day schedule including two 13.5 Gy fractions

Background and purposeHigh dose-rate (HDR) brachytherapy (BT) provides a highly conformal method of dose delivery to the prostate. The purpose of this study is to prospectively determine the toxicity of the treatment protocol of 13.5 Gy × 2 fractions. Materials and methodsFrom 2010 through 2017, 119 patients with low (71%) or intermediate-risk prostate cancer were prospectively treated in a single institute with HDR-BT at 13.5 Gy × 2 fractions within one day. Median follow-up time was 4.4 years. ResultsActuarial rates of no biochemical evidence of disease, overall survival and metastasis-free survival for all patients were 96%,98% and 98%, respectively. The cumulative incidence of acute grade 2 and 3 genitourinary (GU) toxicity was 9% and 2%, respectively. The corresponding incidences of late GU toxicity were 18% and 1%. No grade ≥4 of either type of toxicity was detected. Multivariate analysis showed that having higher international prostate symptom score (IPSS; P = 0.041) or higher V200 (P = 0.013) was associated with a higher risk of experiencing any grade of acute GU toxicity. In addition, patients having a higher IPSS (P = 0.019) or a higher V150 (P = 0.033) were associated with a higher grade >1 acute GU toxicity. ConclusionsThe findings of this study show that HDR-BT 13.5 Gy × 2 as monotherapy was safe and effective for prostate cancer patients with low-intermediate risk.

Postoperative Hypofractionated Radiation Therapy in Prostate Carcinoma: A Systematic Review.

A systematic review on toxicity, local control (LC), overall survival (OS), and biochemical relapse-free survival (bRFS) after postoperative hypofractionated radiotherapy (HFRT) on prostate cancer (PCa) was performed. Based on the PRISMA methodology, studies reporting clinical results after adjuvant or salvage HFRT were included. A total of 1,208 patients from 17 eligible studies were included. Median follow-up was 30 months. No case of severe acute gastrointestinal (GI) toxicity was recorded. Grade ≥3 acute genitourinary (GU) toxicity ranged between 0% and 3%. Different rates of grade ≥2 late GI (range=0-8.7%) and GU (range=0-66%) toxicity were recorded. Encouraging results on LC, OS, and bRFS were reported. Acute toxicity does not seem to be increased in patients receiving postoperative HFRT, but the results of late-GU toxicity are conflicting. Further prospective studies are needed before including postoperative HFRT in clinical practice.

Stereotactic body radiotherapy (SBRT) versus high dose rate (HDR) brachytherapy (BT) boost for high-risk (HR) prostate cancer.

12 Background: Declining use of BT has prompted questions regarding the use of SBRT in HR patients. A systematic literature review was conducted to assess toxicity, and biochemical outcomes following SBRT or HDR BT boost in HR patients. Methods: A search was carried out on the PubMed and Embase databases, for studies published between 2007 and 2017, including HR patients treated with SBRT or HDR boost. Results: We identified 11250 articles, with 6 SBRT and 41 HDR boost studies eligible. The median follow-up was 3.5-5.5 and 2.6-10.3 years in SBRT and HDR boost studies, respectively. The five-year bDFS was 41%–96% in HDR and 69%–98% in SBRT boost studies. Toxicity was reported using the Radiation Therapy Oncology Group (RTOG) scale or the Common Terminology Criteria for Adverse Events (CTCAE) scale and/or validated patient reported Quality of Life (QoL) outcomes. Single SBRT and HDR studies reported 1 year IPSS scores &lt; 7, with 2 SBRT reports of excellent outcomes by the EPIC scale. Acute grade 2 (G2) genitourinary (GU) toxicity ranged from 24-46% and 0.4-33% in SBRT and HDR boost studies, respectively. Late G2 GU toxicity occurred in 2.3-25% and 0-22% following SBRT and the HDR boost, respectively. Late grade 3 (G3) GU toxicity was reported in 0-2.3% and 0-10% with SBRT and HDR boost, respectively. Late G3 GU was reported in 0.8% (2/226) and 4% (114/2763) following SBRT and HDR boost, respectively. Acute G2 gastrointestinal (GI) was noted in 8-19% and 0-19% of SBRT and HDR boost studies, respectively. Late G3 GI was reported in 0-10% and 0-4.6% of SBRT and HDR boost studies, respectively. Late G3 GI was reported in 2% (5/226) and 0.6% (18/2829) of SBRT and HDR boost studies, respectively. Conclusions: SBRT boost may be associated with higher acute G2 but lower late G3 GU toxicity but was not shown by QoL reports, and could be due to selection bias, learning curves or other factors. Randomized trials and validated QoL instruments are needed to accurately compare SBRT to HDR boost.

Long-term outcomes of stereotactic body radiotherapy for low- and intermediate-risk prostate adenocarcinoma: A multi-institutional consortium study.

84 Background: While a growing body of evidence supports the use of stereotactic body radiotherapy (SBRT) for the treatment of low- and intermediate-risk prostate adenocarcinoma (PCa), some trepidation exists regarding its long-term efficacy and safety. Methods: Men with low- and intermediate-risk PCa, as defined per the National Comprehensive Cancer Network guidelines, who were enrolled on various institutional phase II trials of SBRT between 2000-2012 were included in a multi-institutional consortium. Biochemical relapse (BCR) was defined as PSA &gt; “nadir +2” or initiation of androgen deprivation therapy (ADT). Toxicity data were scored according to the CTCAE v 3.0 or Radiation Therapy Oncology Group scoring systems. Results: A total of 1644 men were eligible for analysis, with a median followup of 7.2 years. 297 patients (18.1%) had at least 9 years of followup. Fractionation schemes ranged from 33.50-40 Gy in 4-5 fractions. 892 patients had low-risk disease and 752 had intermediate-risk disease. 59 patients (3.6%) received short-term ADT. 100 patients (6.0%) experienced BCR, and 7 (0.4%) experienced distant metastases. No patients died of PCa. By Kaplan-Meier analysis, 5- and 10-year BCR-free survival rates were 98% and 94% in the low-risk group and 96% and 90% in the intermediate-risk group (p &lt; 0.05 by log-rank test). 5- and 10-year overall survival rates were 93% and 86% in the low-risk group and 95% and 91% in the intermediate-risk group (p &gt; 0.05 by log-rank test). Five patients (0.3%) experienced grade 3 acute genitourinary (GU) toxicities, including urinary retention, hematuria, and frequency. 30 (2%) experienced grade 3 late GU toxicity, including urinary strictures, hematuria, and retention. One late grade 4 GU toxicity (hemorrhagic urethritis) and one late grade 4 gastrointestinal toxicity (fistula-in-ano) were seen. Conclusions: To the best of our knowledge, this is the largest analysis of long-term outcomes following SBRT for PCa. The results indicate that SBRT has an efficacy and toxicity profile that compares favorably to more widespread forms of treatment, such as conventionally-fractionated external beam radiotherapy and brachytherapy.

Machine Learning on a Genome-wide Association Study to Predict Late Genitourinary Toxicity After Prostate Radiation Therapy

Late genitourinary (GU) toxicity after radiation therapy limits the quality of life of prostate cancer survivors; however, efforts to explain GU toxicity using patient and dose information have remained unsuccessful. We identified patients with a greater congenital GU toxicity risk by identifying and integrating patterns in genome-wide single nucleotide polymorphisms (SNPs). We applied a preconditioned random forest regression method for predicting risk from the genome-wide data to combine the effects of multiple SNPs and overcome the statistical power limitations of single-SNP analysis. We studied a cohort of 324 prostate cancer patients who were self-assessed for 4 urinary symptoms at 2years after radiation therapy using the International Prostate Symptom Score. The predictive accuracy of the method varied across the symptoms. Only for the weak stream endpoint did it achieve a significant area under the curve of 0.70 (95% confidence interval 0.54-0.86; P=.01) on hold-out validation data that outperformed competing methods. Gene ontology analysis highlighted key biological processes, such as neurogenesis and ion transport, from the genes known to be important for urinary tract functions. We applied machine learning methods and bioinformatics tools to genome-wide data to predict and explain GU toxicity. Our approach enabled the design of a more powerful predictive model and the determination of plausible biomarkers and biological processes associated with GU toxicity.

Acute and late toxicities in localized prostate cancer patients treated with low-dose 125I brachytherapy (110 Gy) in combination with external beam radiation therapy versus brachytherapy alone (160 Gy)

PurposeThe aim of this analysis was to compare acute and late toxicities between low-dose-rate brachytherapy (LDR-BT) (110 Gy) in combination with 45 Gy in 25 fractions external beam radiation therapy (EBRT) and LDR-BT (160 Gy) alone for localized prostate cancer.Material and methodsOne hundred five consecutive patients with localized prostate cancer treated from May 2014 to May 2017 were included in this retrospective analysis. Sixty patients received combination therapy and 45 patients received BT monotherapy. The LDR-BT procedure was performed using 125I seeds.ResultsThe median follow-up time was 28 months in both groups. Three-year effect rates were overall survival: 100% in both groups. The biochemical failure rate was 2.3% in the combination group and 0% in the monotherapy group (p = 0.373). No patients died during the study period. In both groups, almost all the patients experienced acute urethritis. There was a significant difference between the combination therapy group (8.3%) and BT monotherapy group (11.1%) in late genitourinary (GU) toxicities ≥ grade 2 (p = 0.035). Only 2 patients (3.3%) in the combination therapy group developed late ≥ grade 2 rectal hemorrhage. There were no significant differences between two groups in hematuria ≥ grade 2 (p = 0.068) or rectal hemorrhage ≥ grade 2 (p = 0.206).ConclusionsTo our knowledge, this is the first report to compare the GU and gastrointestinal toxicities between the combination therapy and BT monotherapy (160 Gy) for localized prostate cancer. Unexpectedly, there were more late GU toxicities (except for hematuria) in the BT monotherapy group.

IDEAL-GYN (Integrated Dose Escalation for Advanced Localized Gynecologic Cancers): A Dose Escalation Trial of Bowel Sparing Simultaneous Integrated Boosts for Node Positive Cervical and Vulvar Cancers

Node positivity is a negative prognostic factor in gynecologic cancers. It is often technically and logistically challenging to give boosts to involved nodes due to the proximity of critical normal tissue. Sequential boosts often also result in an extended treatment time. Simultaneous integrated boosts (SIB), delivered at the same time as elective nodal treatment, may be a method to deliver sufficient dose to nodal targets in a compact time frame. However, the safety of total doses greater than 55 Gy with daily fractions greater than 2.2 Gy is unknown. Women with intact cervical or vulvar cancers and nodal involvement in the pelvis or para-aortic regions were accrued to a prospective, phase I 3+3 dose escalation trial utilizing SIB technique. All subjects were treated with definitive chemoradiation therapy with concurrent weekly cisplatin, followed by brachytherapy boost in the subjects with cervical cancer. The elective nodal volumes received 45 Gy in 25 X 1.8Gy fractions (fx), while the involved nodes received 25 X 2.4 – 2.8 Gy/fx, escalated in 0.2Gy increments to a final dose of 60-70 Gy. The SIB PTVs were specifically reduced to be 3 mm off the closest small bowel contour even if this brought the PTV within the nodal GTV. A strict dose limit was also applied to the small bowel, such that the D2cc was no greater than 55 Gy. The primary endpoint was to determine the maximum tolerated dose (MTD), defined by the occurrence of G3 or greater acute gastrointestinal (GI) or genitourinary (GU) toxicity. Toxicity defined by the CTCAE v4.0. Secondary endpoints include late GI and GU toxicity, acute hematologic toxicity, survival, and disease control. Twelve subjects were accrued from 2012-2016, 11 with cervical cancer, and one with vulvar cancer. Pelvic nodes were involved in all subjects; para-aortic nodes were also involved in four. The MTD criteria was not met and six subjects successfully completed the 2.8 Gy/fx (70 Gy) dose level. There were no ≥ G3 acute GI or GU toxicities. Eight subjects experienced G2 GI toxicity, four G1. One subject experienced G2 GU toxicity, 2 G1. At a median followup of 1 year, one subject in the 2.8 Gy cohort experienced late G3 GI toxicity at 7 months after completion, one late G2 GI toxicity at 11 months, one late G2 GU toxicity at 12 months, and one late G1 GU toxicity at 11 months. Simultaneous integrated boosts up to 70 Gy in 25 fx (2.8 Gy/fx) to nodal volumes within the pelvic and paraaortic regions did not result in excessive acute toxicity, provided small bowel is adequately spared. Further long-term followup is required in the high dose cohorts to determine if late toxicity is acceptable.

Long-Term Outcomes of Proton Therapy for Prostate Cancer in Japan: Retrospective Analysis of a Multi-institutional Survey

Proton therapy (PT) is spreading worldwide as a new treatment modality. Although PT provides a more focused dose distribution on the tumor compared with X-ray therapy, there remains much controversy about its routine use in prostate cancer treatment. This is the first multi-institutional retrospective survey of the long-term outcomes of PT for prostate cancer in Japan. This retrospective analysis comprises prostate cancer patients treated with PT at 7 centers between January 2008 and December 2011 and was approved by each Institutional Review Board. The NCCN classification was used. The biochemical relapse free survival (bRFS) was based on the Phoenix definition (nadir + 2.0 ng/mL). The rates of bRFS, overall survival (OS) and incidence of late gastrointestinal (GI) and genitourinary (GU) toxicities were estimated using the Kaplan-Meier methods. Toxicities were evaluated with the Common Terminology Criteria for Adverse Events version 4.0. The inclusion criteria for this analysis were as follows: (1) histologically confirmed prostate cancer, (2) no lymph node and distant metastasis, (3) Japanese men, (4) no prior radiotherapy, (5) no castration-resistant prostate cancer, (6) minimum follow-up of 6 months for surviving patients, and (7) written informed consent. The very-high risk group based on NCCN criteria was included in the high-risk group. The total number of prostate cancer patients in all institutions during this period was 1,302 and 11 patients were excluded because of above criteria. Therefore, 1,291 patients were analyzed. The number of patients in the low-risk, intermediate-risk, and high-risk groups were 215, 520, and 556, respectively. The median follow-up period of surviving patients was 69 months (range: 7-107). In total, 98.8% of patients were treated using conventional fractionation (1.8-2.0GyE) schedule (70-82 GyE/35-41 Fr) and 1.2% of patients were treated by hypofractionation schedule (63-66 GyE/ 21-22 Fr); 58.5% and 21.5 %of patients received neoadjuvant and adjuvant androgen deprivation therapy, respectively. The 5-year rates of bRFS and OS in the low-risk, intermediate-risk, and high-risk patients were 97.0%, 91.1%, 83.1% for bRFS, and 98.4%, 96.8%, 95.2% for OS, respectively. T classification, Gleason score, and NCCN classification were significant prognostic factors for bRFS in multivariate analysis. The incidence of grade 2 late GI and GU toxicities were 3.6% and 2.6%, retrospectively, but grade 3 toxicities were observed only 6 and 4 patients, respectively. This retrospective analysis of a multi-institutional survey suggested that PT is favorable and well tolerated for prostate cancer. Based on this result, multi-institutional prospective clinical trial for patients with intermediate risk group will be started to define its role in the treatment of prostate cancer in Japan.

The 5-Year Outcomes of Moderately Hypofractionated Radiation Therapy for Localized Prostate Cancer

Reports of a lower alpha-beta ratio of prostate cancer than that of surrounding normal tissues suggested that hypofractionated radiotherapy using fewer and larger fractional doses could be more effective than conventional radiotherapy. The aim of this study is to evaluate therapeutic outcomes and toxicities of hypofractionated radiotherapy for localized prostate cancer. This is retrospective review of 195 patients with localized prostate cancer who underwent intensity-modulated radiotherapy consisting of 66 Gy delivered in fractions of 3 Gy every other weekday between May 2005 and December 2011. The proportion of risk classifications according to D’Amico classifications, low-risk was 27 patients (13.8%), intermediate-risk was 70 patients (35.9%), and high-risk was 98 patients (50.3%). Patients received androgen deprivation therapy according to our institutional criteria based on perceived low-, intermediate-, or high-risk of their diseases. Biochemical failure was defined as prostate-specific antigen nadir plus 2.0 ng/mL. As for toxicities, the patient-reported outcomes (PROs) were assessed using the expanded prostate cancer index composite at six points such as before radiotherapy (baseline), and 1 month, 3 months, 6 months, 12 months and 24 months after radiotherapy. In addition, the clinician-reported outcomes were assessed based on the Radiation Therapy Oncology Group and European Organization for Research and Treatment of Cancer Toxicity criteria. Over a median follow-up of 69 months (range, 9 to 138 months), 13 of 195 patients experienced biochemical failure within a median of 40 months (range, 14 to 95 months). The 5-year overall survival rate was 97.7%, and the 5-year no biological evidence of disease rate was 95.0%. By the risk classifications, the 5-year bNED rates were 100%, 96.3% and 90.6% for those with low-, intermediate- and high-risk diseases, respectively. PROs showed that there was a significant difference among the average values of the general urinary and bowel domains. The average score of these domains significantly decreased at 1 month after completion of radiotherapy, and then returned to the baseline level at 3 months after radiotherapy. Acute genitourinary (GU) toxicities were graded 0-1 in 168 patients and two in 27 patients; none was graded three or higher. Late GU toxicities were graded 0-1 in 190 patients and two in 5 patients; none was graded three or higher. Gastrointestinal (GI) toxicities were graded 0-1 in 193 patients and two in 2 patients; none was graded three or higher. Using of this protocol of moderately hypofractionated radiotherapy (a total dose of 66 Gy/22 fraction for 7 weeks) yielded satisfactory clinical outcomes with significant reduction of toxicity profiles including PROs, although follow-up period is not long enough to allow a definitive conclusion.

Consideration of Patient Characteristics and Comorbidity in Selecting Candidates for Moderately Hypofractionated Radiation: Secondary Analysis From a Randomized Trial

Randomized trials demonstrate prostate radiation delivered with moderate hypofractionation provides cancer control equivalent to conventional fractionation. While trials demonstrate similar genitourinary (GU) and gastrointestinal (GI) toxicity between treatments, it is uncertain if patients with significant comorbidities, on anticoagulants, or who are older may be at increased risk of toxicity after moderate hypofractionation. Men with localized prostate cancer enrolled in a randomized trial received either conventionally fractionated IMRT (CIMRT; 75.6 Gy in 1.8 Gy fractions) or dose-escalated hypofractionated IMRT (HIMRT; 72 Gy in 2.4 Gy fractions). Late (>= 60 days after IMRT) GI and GU toxicities were prospectively evaluated and scored by modified RTOG criteria. The adult comorbidity evaluation-27 (ACE-27) index categorized severity of comorbidity. Cox proportional hazard models were used for statistical analysis. One hundred one men received CIMRT and 102 HIMRT. The median follow-up was 8.6 years. Eighty-two men were >=70 years, 59 were on anticoagulants at enrollment, and 39 had moderate to severe comorbidity (ACE-27 2-3). Overall, there was no difference in late GU toxicity between treatment arms (P = 0.84, HR = 0.93) and a numeric increase in late GI toxicity after HIMRT (P = 0.09, HR = 2.50). For all patients, anti-coagulation use (P = 0.05, HR = 1.40) trended towards worse late GI toxicity. However, in the subset of men on anticoagulants, there was no difference in GI (P = 0.51) or GU (P = 0.38) toxicity between those treated with CIMRT and HIMRT. Similarly in the subset of men with moderate to severe comorbidity (GI: P = 0.08; GU: P = 0.22) and the subset of men >= 70 years (GI: P = 0.18; GU: P = 0.09), there was no difference in toxicity between treatment arms. On multivariate analysis of men treated with HIMRT, higher rectal dose was associated with worse late GI toxicity (P = 0.03, HR = 1.18), however, there was no increase in late GI or GU toxicity with anticoagulation use (GI: P = 0.30; GU: P = 0.79) or older age (GI: P = 0.13; GU: P = 0.38). Late GI and GU toxicity was not significantly increased in older men, those on anticoagulants, or those with moderate to severe comorbidity when treated with HIMRT on a randomized trial. Therefore, men with these characteristics can be considered for moderately hypofractionated prostate radiation as definitive therapy.