Surgical management of rectal cancer with synchronous treatment of prostate cancer.

PURPOSE: To assess the safety and efficacy of synchronous treatments for rectal (RC) and prostate (PC) cancers. METHODS: Single-center retrospective study (2007-2021) of patients treated with neoadjuvant radiotherapy (RT) and total mesorectal excision (TME) for RC with synchronous PC treatment. The endpoints were 30-day postoperative severe complications, R0 resection rates, 3-year disease-free survival (DFS) and 3-year overall survival (OS). RESULTS: Among the 16 patients, 15 (93.7%) received neoadjuvant pelvic RT (40-50.4 Gray) followed by either transperineal high dose rate prostate brachytherapy (62.5%), prostate external RT boost (25.0%), or androgen deprivation therapy (ADT) alone (6.3%). One (6.3%) patient received neoadjuvant rectal brachytherapy and ADT. Pelvic RT was combined with chemotherapy in 87.5% of cases. TME was performed in all patients with low anterior resection (87.5%) or abdominoperineal resection (12.5%), primarily using minimally invasive surgery (87.5%). The R0 resection rate was 93.8%. Six (37.5%) patients experienced 30-day Clavien-Dindo grade IIIb complications, including one (7.1%) anastomotic leak. After a median follow-up of 39.0 months, 63.6% of diverting ileostomies were reversed. Three-year DFS from RC was 71.4% (CI 40.2-88.3) and 3-year OS was 84.4% (CI 95% 50.4-95.9). No PC recurrence or death occurred. CONCLUSIONS: Synchronous management of RC and PC with pelvic RT followed by curative prostate RT doses and TME showed acceptable morbidity and oncologic results. Prostate brachytherapy, the most commonly used treatment modality, allowed avoidance of prostatectomy and additional external RT to the rectum. PC should not limit the curative intent of RC, as all recurrences were from rectal origin.

Testosterone recovery after androgen deprivation therapy in localised prostate cancer: Long-term data from two randomised trials.

BACKGROUND AND PURPOSE: To determine the rate and time of testosterone (T) recovery in patients (pts) with localised prostate cancer treated with radiotherapy plus 0-, 6-, 18- or 36-month of androgen deprivation therapy (ADT). MATERIALS AND METHODS: In 1230 pts with prostate cancer randomised into two phase III trials, serum T was measured at baseline, then regularly. T recovery rate was compared between normal vs. abnormal baseline T and with ADT duration with Chi-square test or Fisher's exact test. A multivariable logistic regression model to predict the probability of recovering normal T was performed. RESULTS: Overall, 87.4 % (167/191), 75.9 % (293/386), 54.8 % (181/330) and 43.2 % (80/185) of pts, recovered normal T on the 0-, 6-, 18- or 36-month schedule, respectively (p < 0.001). In patients recovering normal T, the median time to T recovery increased with ADT duration ranging from 0.31, 1.64, 3.06 to 5.0 years for the 0-, 6-, 18- or 36-month schedules, respectively (p < 0.001) and was significantly faster for those with a normal T at baseline (p < 0.001). On multivariable analysis, older age and longer ADT duration are associated with a lower T recovery. CONCLUSIONS: Testosterone recovery rate after ADT depends on several factors including hormonal duration, normal baseline T, age and medical comorbidities. A longer ADT duration is the most important variable affecting T recovery. The data from this report might be a valuable tool to help physicians and patients in evaluating risks and benefits of ADT.

US-guided EM tracked system for HDR brachytherapy: A first in-men randomized study for whole prostate treatment.

PURPOSE: An electromagnetic tracking device (EMT) has been integrated in an HDR 3D ultrasound guidance system for prostate HDR. The aim of this study was to compare the efficiency of HDR workflows with and without EM tracking. METHODS AND MATERIALS: A total of 58 patients with a 15 Gy HDR prostate boost were randomized in two arms and two operation room (OR) procedures using: (1) the EMT investigational device, and (2) the Oncentra prostate system (OCP). OR times were compared for both techniques. RESULTS: The overall procedure median time was about 20% shorter for EMT (63 min) compared to OCP (79 min). The US acquisition and contouring was longer for OCP compared to EMT (23 min vs. 16 min). The catheter reconstruction's median times were 23 min and 13 min for OCP and EMT respectively. For the automatic reconstruction with EMT, 62% of cases required no or few manual corrections. Using the EM technology in an OR environment was challenging. In some cases, interferences or the stiffness of the stylet introduced errors in the reconstruction of catheters. The last step was the dosimetry with median times of 11 min (OCP) and 15.5 min (EMT). Finally, it was observed that there was no learning curve associated with the introduction of this new technology. CONCLUSIONS: The EMT device offers an efficient solution for automatic catheter reconstruction for HDR prostate while reducing the possibility of mis-reconstructed catheters caused by issues of visualization in the US images. Because of that, the overall OR times was shorter when using the EMT system.

A Monte Carlo dose recalculation pipeline for durable datasets: an I-125 LDR prostate brachytherapy use case.

Monte Carlo (MC) dose datasets are valuable for large-scale dosimetric studies. This work aims to build and validate a DICOM-compliant automated MC dose recalculation pipeline with an application to the production of I-125 low dose-rate prostate brachytherapy MC datasets. Built as a self-contained application, the recalculation pipeline ingested clinical DICOM-RT studies, reproduced the treatment into the Monte Carlo simulation, and outputted a traceable and durable dose distribution in the DICOM dose format. MC simulations with TG43-equivalent conditions using both TOPAS andegs_brachyMC codes were compared to TG43 calculations to validate the pipeline. The consistency of the pipeline when generating TG186 simulations was measured by comparing simulations made with both MC codes. Finally,egs_brachysimulations were run on a 240-patient cohort to simulate a large-scale application of the pipeline. Compared to line source TG43 calculations, simulations with both MC codes had more than 90% of voxels with a global difference under ±1%. Differences of 2.1% and less were seen in dosimetric indices when comparing TG186 simulations from both MC codes. The large-scale comparison ofegs_brachysimulations with treatment planning system dose calculation seen the same dose overestimation of TG43 calculations showed in previous studies. The MC dose recalculation pipeline built and validated against TG43 calculations in this work efficiently produced durable MC dose datasets. Since the dataset could reproduce previous dosimetric studies within 15 h at a rate of 20 cases per 25 min, the pipeline is a promising tool for future large-scale dosimetric studies.

Image-Guided Brachytherapy for Rectal Cancer: Reviewing the Past Two Decades of Clinical Investigation.

(1) Background: The introduction of total mesorectal excision (TME) for rectal cancer has led to improvement in local recurrence (LR) outcomes. Furthermore, the addition of preoperative external beam radiotherapy to TME reduces LR to less than 6%. As a trade-off to these gradual improvements in local therapies, the oncology community's work is now focusing on mitigating treatment-related toxicities. In other words, if a small proportion of 4-6% of rectal cancer patients benefit from additional local therapy beyond TME, the burden of acute and long-term side effects must be considered with care. (2) Methods: With the introduction of better-quality imaging for tumor visualization and treatment planning, a new conformed radiation treatment was introduced with high-dose-rate endorectal brachytherapy. The treatment concept was tested in phase I and II studies: first in the pre-operative setting, and then as a boost after external beam radiation therapy, as a dose-escalation study, to achieve higher local tumor control. (3) Results: HDREBT is safe and effective in achieving a high tumor regression rate and was well tolerated in a phase II multicenter and two matched-pair studies. (4) Conclusions: HDREBT is a conformed radiation therapy that is safe and effective, and is presently explored in a phase III dose-escalation study in the NOM of patients with operable rectal cancer.

MORPHEUS Phase II-III Study: A Pre-Planned Interim Safety Analysis and Preliminary Results.

BACKGROUND: We explored image-guided adaptive endorectal brachytherapy patients electing non-operative management for rectal cancer. We present the first pre-planned interim analysis. METHODS: In this open-label phase II-III randomized study, patients with operable cT2-3ab N0 M0 rectal cancer received 45 Gy in 25 fractions of pelvic external beam radiotherapy (EBRT) with 5-FU/Capecitabine. They were randomized 1:1 to receive either an EBRT boost of 9 Gy in 5 fractions (Arm A) or three weekly adaptive brachytherapy (IGAEBT) boosts totaling 30 Gy (Arm B). Patient characteristics and toxicity are presented using descriptive analyses; TME-free survival between arms with the intention to treat the population is explored using the Kaplan-Meier method. RESULTS: A total of 40 patients were in this analysis. Baseline characteristics were balanced; acute toxicities were similar. Complete clinical response (cCR) was 50% (n = 10/20) in Arm A and 90% in Arm B (n = 18/20). Median follow-up was 1.3 years; 2-year TME-free survival was 38.6% (95% CI: 16.5-60.6%) in the EBRT arm and 76.6% (95% CI: 56.1-97.1%) in the IGAEBT arm. CONCLUSIONS: Radiation intensification with IGAEBT is feasible. This interim analysis suggests an improvement in TME-free survival when comparing IGAEBT with EBRT, pending confirmation upon completion of this trial.

Inter-observer evaluation of a GPU-based multicriteria optimization algorithm combined with plan navigation tools for HDR brachytherapy.

PURPOSE: Recently, a GPU-based multicriteria optimization (gMCO) algorithm was integrated in a graphical user interface (gMCO-GUI) that allowed real-time plan navigation through a set of Pareto-optimal plans for high-dose-rate (HDR) brachytherapy. This work reports on the inter-observer evaluation of the gMCO algorithm into the clinical workflow. METHODS AND MATERIALS: Twenty HDR brachytherapy prostate cancer patients were retrospectively replanned with the gMCO algorithm. The reference clinical plans were each generated by experienced physicists using inverse planning followed by graphical optimization and approved by a radiation oncologist (RO). Each case was replanned with the gMCO algorithm by generating 2000 Pareto-optimal plans with four different objective functions. Two physicists were asked to rank the objective functions according to their preferences by choosing one preferred plan for each plans pool and ranking them using gMCO-GUI. The optimized dwell positions and dwell times of the gMCO plans that were ranked first were exported to Oncentra Prostate where a blinded comparison of the gMCO plans with the clinical plans was conducted by three ROs. RESULTS: The median planning time of the two physicists was 9 min. Both physicists preferred the objective function with target sub-regions to cover specific target regions. Regarding the blinded comparison, the gMCO plans were preferred 19, 17, and 12 times by the three ROs, in which eight gMCO plans were unanimously preferred compared with the clinical plans. CONCLUSIONS: The plan quality and the planning time were similar between the two physicists and within what is observed in the clinic. Moreover, the gMCO plans evaluated favorably by ROs compared to the reference clinical plans.

The addition of androgen deprivation therapy and pelvic lymph node treatment to prostate bed salvage radiotherapy (NRG Oncology/RTOG 0534 SPPORT): an international, multicentre, randomised phase 3 trial.

BACKGROUND: In men with a detectable prostate-specific antigen (PSA) level after prostatectomy for prostate cancer, salvage prostate bed radiotherapy (PBRT) results in about 70% of patients being free of progression at 5 years. A three-group randomised trial was designed to determine whether incremental gains in patient outcomes can be achieved by adding either 4-6 months of short-term androgen deprivation therapy (ADT) to PBRT, or both short-term ADT and pelvic lymph node radiotherapy (PLNRT) to PBRT. METHODS: The international, multicentre, randomised, controlled SPPORT trial was done at 283 radiation oncology cancer treatment centres in the USA, Canada, and Israel. Eligible patients (aged ≥18 years) were those who after prostatectomy for adenocarcinoma of the prostate had a persistently detectable or an initially undetectable and rising PSA of between 0·1 and 2·0 ng/mL. Patients with and without lymphadenectomy (N0/Nx) were eligible if there was no clinical or pathological evidence of lymph node involvement. Other eligibility criteria included pT2 or pT3 disease, prostatectomy Gleason score of 9 or less, and a Zubrod performance status of 0-1. Eligible patients were randomly assigned to receive PBRT alone at a dose of 64·8-70·2 Gy at 1·8 Gy per fraction daily (group 1), PBRT plus short-term ADT (group 2), or PLNRT (45 Gy at 1·8 Gy per fraction, and then a volume reduction made to the planning target volume for the remaining 19·8-25 ·2 Gy) plus PBRT plus short-term ADT (group 3). The primary endpoint was freedom from progression, in which progression was defined as biochemical failure according to the Phoenix definition (PSA ≥2 ng/mL over the nadir PSA), clinical failure (local, regional, or distant), or death from any cause. A planned interim analysis of 1191 patents with minimum potential follow-up time of 5 years applied a Haybittle-Peto boundary of p<0·001 (one sided) for comparison of 5-year freedom from progression rates between the treatment groups. This trial is registered with ClinicalTrials.gov, NCT00567580. The primary objectives of the trial have been completed, although long-term follow-up is continuing. FINDINGS: Between March 31, 2008, and March 30, 2015, 1792 eligible patients were enrolled and randomly assigned to the three treatment groups (592 to group 1 [PBRT alone], 602 to group 2 [PBRT plus short-term ADT], and 598 to group 3 [PLNRT plus PBRT plus short-term ADT]). 76 patients subsequently found to be ineligible were excluded from the analyses; thus, the evaluable patient population comprised 1716 patients. At the interim analysis (n=1191 patients; data cutoff May 23, 2018), the Haybittle-Peto boundary for 5-year freedom from progression was exceeded when group 1 was compared with group 3 (difference 17·9%, SE 2·9%; p<0·0001). The difference between groups 2 and 3 did not exceed the boundary (p=0·0063). With additional follow-up beyond the interim analysis (the final planned analysis; data cutoff May 26, 2021), at a median follow-up among survivors of 8·2 years (IQR 6·6-9·4), the 5-year freedom from progression rates in all 1716 eligible patients were 70·9% (95% CI 67·0-74·9) in group 1, 81·3% (78·0-84·6) in group 2, and 87·4% (84·7-90·2) in group 3. Per protocol criteria, freedom from progression in group 3 was superior to groups 1 and 2. Acute (≤3 months after radiotherapy) grade 2 or worse adverse events were significantly more common in group 3 (246 [44%] of 563 patients) than in group 2 (201 [36%] of 563; p=0·0034), which, in turn, were more common than in group 1 (98 [18%] of 547; p<0·0001). Similar findings were observed for grade 3 or worse adverse events. However, late toxicity (>3 months after radiotherapy) did not differ significantly between the groups, apart from more late grade 2 or worse blood or bone marrow events in group 3 versus group 2 (one-sided p=0·0060) attributable to the addition of PLNRT in this group. INTERPRETATION: The results of this randomised trial establish the benefit of adding short-term ADT to PBRT to prevent progression in prostate cancer. To our knowledge, these are the first such findings to show that extending salvage radiotherapy to treat the pelvic lymph nodes when combined with short-term ADT results in meaningful reductions in progression after prostatectomy in patients with prostate cancer. FUNDING: National Cancer Institute.

Advantages of TRUS-based delineation for high-dose-rate prostate brachytherapy planning.

PURPOSE: To evaluate the variability of prostate contours delineated on computed tomography (CT) and transrectal ultrasound (TRUS). MATERIAL AND METHODS: A TRUS-based high-dose-rate (HDR) brachytherapy procedure was introduced in 2016 in our center. The first thirty patients were additionally imaged with CT immediately after the treatment. In 2018, four different radiation oncologists (ROs: 1, 2, 3, 4) contoured the prostate on both modalities. A volume comparison was performed between CT and TRUS imaging. Using prostate gold fiducial makers, a rigid registration between CT and TRUS was done in 20 of the 30 patients studied. Jaccard index (JI) was computed to evaluate the inter-observer volume delineation agreement. RESULTS: The ratio of TRUS/CT volumes was 0.82 (95% CI: 0.79-0.87%). The mean JI was 87% for CT and 92% for TRUS, when comparing all four ROs; CT and TRUS JIs were significantly different (p < 0.001). The mean JI for the prostate on CT was significantly more consistent (p < 0.001) when comparing RO1, 2, and 3 together (RO1-2, RO1-3, and RO2-3; mean = 89%) than when comparing RO4 (newest to clinical practice) to others (RO1-4, RO2-4, and RO3-4; mean = 85%). For TRUS planning, the mean JI was not significantly different (p > 0.05) when comparing all ROs. CONCLUSIONS: The inter-observer and intra-observer variability were statistically significantly smaller on TRUS compared to CT-based planning, despite varying ROs clinical experiences. The superior soft tissue contrast offered by TRUS obviates the effect of the ROs experience on prostate contour volumes and enables more reproducible prostate delineation.

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.

Dose to the bladder neck is not correlated with urinary toxicity in patients with prostate cancer treated with HDR brachytherapy boost.

PURPOSE: The purpose of this study was to evaluate whether the dose to bladder neck (BN) is a predictor of acute and late urinary toxicity after high-dose-rate brachytherapy (HDRB) boost for prostate cancer. METHODS AND MATERIALS: Between 2014 and 2016, patients with prostate cancer treated at our institution with external beam radiation therapy and 15 Gy single-fraction HDRB boost for intermediate- and high-risk disease according to D'Amico definition were reviewed. Intraoperative CT scan-based inverse planning and ultrasound-based inverse planning were performed in 173 and 136 patients, respectively. The following structures were prospectively contoured: prostate, urethra, rectum, bladder, and the BN defined as 5 mm around the urethra between the catheter balloon and the prostatic urethra. Dose to the BN was reported only, no constraint was applied. Acute and late urinary toxicity were assessed using the International Prostate Symptom Score (IPSS) and the Common Terminology Criteria for Adverse Events v.4.0. Clinical and dosimetry factors associated with urinary toxicity were analyzed using generalized linear models. RESULTS: A total of 309 patients with median age of 71 years (range 50-89) were included. Median followup was 25 months (range 0-39 months). Using D'Amico definition, 71% of the patients had intermediate-risk disease, whereas 29% had high-risk disease. The mean pretreatment prostate-specific antigen value was 9.65 ng/mL. The mean pretreatment, after 6 weeks and over 6 months IPSSs were 8.34, 12.14, and 10.02, respectively. Urinary obstruction was reported in 14 cases (4.5%). Pretreatment IPSS (p = 0.003) and prostate volume (p = 0.024) were significantly associated with acute and late urinary toxicity. The dose for the most exposed 2 cc (D2cc) of BN was not correlated with acute (p = 0.798) or late urinary toxicity (p = 0.859). BN D2cc was not correlated with urinary obstruction (p = 0.272), but bladder V75 was (p = 0.021). CONCLUSIONS: High pretreatment IPSS, large prostate volume and bladder V75 were the only predictors of acute and late urinary toxicity after HDRB boost in our study. Although BN D2cc was associated with acute and late urinary toxicity after low-dose-rate brachytherapy, no correlation was found after HDRB. A prospective study comparing dose to the BN in HDRB monotherapy would validate the impact of BN dose on acute and late urinary toxicity.

Evaluating the impact of real-time multicriteria optimizers integrated with interactive plan navigation tools for HDR brachytherapy.

PURPOSE: Currently in high-dose-rate (HDR) brachytherapy planning, manual fine-tuning of an objective function is a common practice. Furthermore, automated planning approaches such as multicriteria optimization (MCO) are still limited to the automatic generation of a single treatment plan. This study aims to quantify planning efficiency gains when using a graphics processing unit-based MCO (gMCO) algorithm combined with a novel graphical user interface (gMCO-GUI) that integrates efficient automated and interactive plan navigation tools. METHODS AND MATERIALS: The gMCO algorithm was used to generate 1000 Pareto optimal plans per case for 379 prostate cases. gMCO-GUI was developed to allow plan navigation through all plans. gMCO-GUI integrates interactive parameter selection tools directly with the optimization algorithm to allow plan navigation. The quality of each plan was evaluated based on the Radiation Treatment Oncology Group 0924 protocol and a more stringent institutional protocol (INSTp). gMCO-GUI allows real-time time display of the dose-volume histogram indices, the dose-volume histogram curves, and the isodose lines during the plan navigation. RESULTS: Over the 379 cases, the fraction of Radiation Treatment Oncology Group 0924 protocol valid plans with target coverage greater than 95% was 90.8%, compared with 66.0% for clinical plans. The fraction of INSTp valid plans with target coverage greater than 95% was 81.8%, compared with 62.3% for clinical plans. The average time to compute 1000 deliverable plans with gMCO was 12.5 s, including the full computation of the 3D dose distributions. CONCLUSIONS: Combining the gMCO algorithm with automated and interactive plan navigation tools resulted in simultaneous gains in both plan quality and planning efficiency.

DNA repair gene polymorphisms, tumor control, and treatment toxicity in prostate cancer patients treated with permanent implant prostate brachytherapy.

BACKGROUND: Radiotherapy and brachytherapy are common treatments for localized prostate cancer (PCa). However, very few studies evaluated the association of variations in DNA damage response genes and treatment outcomes and toxicity in brachytherapy-treated patients. PURPOSE: To evaluate the association of inherited germline variations in DNA repair-associated genes with tumor control and treatment toxicity in patients treated with low-dose-rate prostate brachytherapy (LDRB). MATERIAL AND METHODS: The cohort consists of 475 I-125 LDRB patients with a median follow-up of 51 months after seed implantation. Patients were genotyped for 215 haplotype tagging single nucleotide variations (htSNPs) in 29 candidate genes of DNA damage response and repair pathways. Their association with biochemical recurrence (BCR) was assessed using Cox regression models and Kaplan-Meier survival curves. Linear regressions and analysis of covariance (ANCOVA) between early and late International Prostate Symptom Score (IPSS) with htSNPs were used to evaluate the association with urinary toxicity. RESULTS: After adjustment for the established risk factors, six htSNPs in five genes were found to be significantly associated with an altered risk of BCR, with adjusted hazard ratios (HRadj. ) ranging between 3.6 and 11.1 (P < .05). Compared to carriers of the ERCC3 rs4150499C allele, patients homozygous for the T allele (n = 22) had a significant higher risk of BCR with a HR of 11.13 (IC95 = 3.9-32.0; P < .0001; q < 0.001). The Kaplan-Meier survival curve revealed a mean BCR-free survival time reduced from 213 ± 7 to 99 ± 12 months (log-rank P < .0001) for homozygous T carriers compare to noncarriers. For late IPSS (>6 months after treatment), htSNP rs6544990 from MSH2 showed a statistically significant b-coefficient of 1.85 ± 0.52 (P < .001; q < 0.1). Homozygous carriers of the MSH2 rs6544990C allele (n = 62) had a mean late IPSS 3.6 points higher than patients homozygous for the A allele (n = 132). This difference was significant when tested by ANCOVA using pretreatment IPSS as a covariate (P < .01). CONCLUSIONS: This study suggests an association of the intronic variants of the DNA nucleotide excision repair ERCC3 and DNA mismatch repair MSH2 genes with elevated risk of BCR and late urinary toxicity respectively after LDRB. Further validation is required before translational clinical advances.

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.

Image Guided Adaptive Endorectal Brachytherapy in the Nonoperative Management of Patients With Rectal Cancer.

PURPOSE: Organ preservation or nonoperative management of rectal cancer is of growing interest. Image guided adaptive endorectal brachytherapy is a radiation dose escalation modality: we explored its role in elderly patients unfit for surgery and patients refusing surgery. METHODS AND MATERIALS: In this registry study, patients with rectal cancer who were ineligible for surgery received 40 Gy in 16 fractions of pelvic external beam radiation therapy. They subsequently received 3 weekly image guided adaptive brachytherapy boosts of 10 Gy to the residual tumor, for a total of 30 Gy in 3 fractions. Complete clinical response (cCR) and local control were the primary endpoints. RESULTS: 94 patients were included; the median age was 81.1 years. With a median follow-up of 1.9 years, the proportion of cCR was 86.2%, the tumor regrowth proportion was 13.6%, and the cumulative incidence of local relapse was 2.7% at 1 year and 16.8% at 2 years. When considering responders and nonresponders, the 2-year local control was 71.5%. The overall survival at 2 years was 63.6%. Acute rectal grade 1 to 2 toxicity included all patients: 12.8% of patients had late bleeding requiring iron replacement, blood transfusions, or argon plasma therapy. CONCLUSIONS: Results of this registry study, evaluating radiation dose escalation for elderly medically unfit patients with unselected tumors, reveal that a high proportion of patients achieved cCR with a manageable toxicity profile. This technology will likely contribute to the challenging nonoperative management paradigm of rectal cancer.

The association of intraprostatic calcifications and dosimetry parameters with biochemical control after permanent prostate implant.

PURPOSE: The objective of this study was to evaluate the impact of intraprostatic calcifications (IC) on long-term tumor control in patients treated with permanent implant prostate brachytherapy (PIPB). MATERIALS AND METHODS: Data from 609 I-125 patients treated with PIPB were retrospectively reviewed. The presence of IC was determined by reviewing postimplant CT images. Doses delivered were determined using the Monte Carlo (model-based) calculations and the TG43 approach. Biochemical relapses at 7 and 10 years were determined according to Phoenix definition. Long-term biochemical relapse-free survival (bRFS) was determined using Kaplan-Meier estimates with log rank test. Cox proportional hazard models were used for analysis of predictor factors of biochemical recurrence. RESULTS: IC were observed for 11.1% of patients. Clinical stage, PSA, Gleason score, D'Amico risk group, and ADT use were comparable between IC and no IC groups. The 7- and 10-year bRFS for the entire cohort were 94.1% and 90.6%, respectively. The bRFS at 7 years was 90.5% (with IC) vs. 94.5% (without IC) (p = 0.198); the corresponding values at 10 years were 78.8% vs. 91.8% (p = 0.046). On Cox model, only prostatic calcifications were a significant risk factor for biochemical relapse (HR: 2.30, IC 95%: 1.05-5.00, p = 0.037; and HR: 3.94; IC 95%: 1.00-15.38; p = 0.049 for univariate and multivariate analysis, respectively). CONCLUSION: The presence of IC in patients treated with PIPB decreases V100 and D90 for postimplant Monte Carlo dosimetry (compared with TG43); correspondingly, IC are associated with a lower 10-y bRFS. Model-based dose calculations are critical to evaluate potential cold spots due to calcifications.

Impact of a dominant intraprostatic lesion (DIL) boost defined by sextant biopsy in permanent I-125 prostate implants on biochemical disease free survival (bDFS) and toxicity outcomes.

BACKGROUND AND PURPOSE: To compare bDFS and toxicity outcomes in a population of intermediate risk prostate cancer patients treated using I-125 LDR brachytherapy with or without DIL boost based on multiple core biopsy maps. MATERIALS AND METHODS: Between January 2005 and December 2013, all our intermediate risk prostate cancer patients treated with LDR I-125 brachytherapy were reviewed. All patients were given 144 Gy to the prostate. A pathologic DIL distribution (defined by sextant biopsy) was contoured prospectively prior to planning, to be covered by the 150% isodose line. Of the 165 patients treated, 55 received a DIL boost. Patients completed prospectively the IPSS questionnaire, a sexual and bowel function questionnaire. Gastro-intestinal toxicities were graded according to CTCAE v4.03. A patient was considered to have erectile dysfunction if he was unable to achieve erection to perform intercourse. BDFS was determined according to the Phoenix consensus definitions. RESULTS: The median follow-up was 78 months. The estimated 7-year bDFS rate was 96% (95% CI, 74-99%) in the DIL group versus 89% (95% CI, 79-94%) in the control group (p = 0.188). There was no difference between groups in urinary, gastro-intestinal or sexual toxicities up to 5 years of follow-up. There was no difference in urinary obstruction with catheterization between DIL versus control groups (3,6 vs 2,8 %, p = 1.00). Only 1 patient in the DIL group had ≥grade 3 toxicity (TURP) and none in the control group. CONCLUSIONS: Boost to DIL defined by sextant biopsy with permanent seed prostate implant shows a trend toward improvement of biochemical control in intermediate risk prostate cancer patient without increasing toxicity.

Duration of Androgen Deprivation Therapy in High-risk Prostate Cancer: A Randomized Phase III Trial.

BACKGROUND: Long-term androgen deprivation therapy (ADT) combined with radiotherapy (RT) is a standard treatment for patients with localized high-risk prostate cancer (HRPC). However, the optimal duration of ADT is not yet defined. OBJECTIVE: The aim of this superiority randomized trial was to compare outcomes of RT combined with either 36 or 18 mo of ADT. DESIGN, SETTING AND PARTICIPANTS: From October 2000 to January 2008, 630 patients with HRPC were randomized, 310 to pelvic and prostate RT combined with 36 mo (long arm) and 320 to the same RT with 18 mo (short arm) of ADT. OUTCOME MEASUREMENTS AND STATISTICAL ANALYSIS: Overall survival (OS) and quality of life (QoL) were primary end points. OS rates were compared with Cox Regression model and QoL data were analyzed through mixed linear model. RESULTS AND LIMITATIONS: With a median follow-up of 9.4 yr, 290 patients had died (147 long arm vs 143 short arm). The 5-yr OS rates (95% confidence interval) were 91% for long arm (88-95%) and 86% for short arm (83-90%), p=0.07. QoL analysis showed a significant difference (p<0.001) in six scales and 13 items favoring 18 mo ADT with two of them presenting a clinically relevant difference in mean scores of ≥10 points. CONCLUSIONS: In localized HRPC, our results support that 36 mo is not superior to 18 mo of ADT. ADT combined with RT can potentially be reduced to 18 mo in selected men without compromising survival or QoL. Thus, 18 mo of ADT appears to represent a valid option in HRPC. PATIENT SUMMARY: In this study, we report outcomes from high-risk prostate cancer patients treated with radiotherapy and either 36 or 18 mo of androgen deprivation therapy. There was no difference in survival between the two groups, with the 18-mo group experiencing a better quality of life.