First fully automated planning solution for robotic radiosurgery - comparison with automatically planned volumetric arc therapy for prostate cancer.

BACKGROUND: For conventional radiotherapy treatment units, automated planning can significantly improve plan quality. For robotic radiosurgery, systems for automatic generation of clinically deliverable plans do not yet exist. For prostate stereotactic body radiation therapy (SBRT), few studies have systematically compared VMAT with robotic treatment. MATERIAL AND METHODS: The multi-criteria autoplanning optimizer, developed at our institute, was coupled to the commercial treatment planning system of our robotic treatment unit, for fully automated generation of clinically deliverable plans (autoROBOT). The system was then validated by comparing autoROBOT plans with manually generated plans. Next, the autoROBOT system was used for systematic comparisons between autoROBOT plans and VMAT plans, that were also automatically generated (autoVMAT). CTV-PTV margins of 3 mm were used for autoROBOT (clinical routine) and autoVMAT plan generation. For autoVMAT, an extra plan was generated with 5 mm margin (often applied for VMAT). Plans were generated for a 4 × 9.5 Gy fractionation scheme. RESULTS: Compared to manual planning, autoROBOT improved rectum D[Formula: see text] (16%), V[Formula: see text] (75%) and D[Formula: see text] (41%), and bladder D[Formula: see text] (37%) (all p [Formula: see text] .002), with equal PTV coverage. In the autoROBOT and autoVMAT comparison, both with 3 mm margin, rectum doses were lower for autoROBOT by 5% for rectum D[Formula: see text] (p=.002), 33% for V[Formula: see text] (p=.001) and 4% for D[Formula: see text] (p=.05), with comparable PTV coverage and other OAR sparing. With 5 mm margin for VMAT, 18/20 plans had a PTV coverage lower than requested (<95%) and all plans had higher rectum doses than autoROBOT (mean percentage differences of 13% for D[Formula: see text], 69% for V[Formula: see text] and 32% for D[Formula: see text] (all p<.001)). CONCLUSIONS: The first system for fully automated generation of clinically deliverable robotic plans was built. Autoplanning did largely enhance robotic plan quality, compared to manual planning. Using autoplanning for both the robotic system and VMAT, superiority of non-coplanar robotic treatment compared to coplanar VMAT for prostate SBRT was demonstrated.

Long-term follow-up after active surveillance or curative treatment: quality-of-life outcomes of men with low-risk prostate cancer.

PURPOSE: To compare long-term (4-10 years) quality of life (QoL) of men with low-risk prostate cancer (PCa) treated by different modalities and a reference group without PCa. METHODS: In this cross-sectional study, four groups were sent a one-time QoL-questionnaire; PCa patients (1) following the structured Prostate cancer Research International Active Surveillance protocol, (2) who underwent radical prostatectomy (RP) in the context of the European Randomized study of Screening for Prostate Cancer-section Rotterdam, (3) who underwent radiotherapy (RT) at an academic hospital in The Netherlands, and (4) an age-matched reference group of men without PCa. The QoL-questionnaire addressed prostate-specific health (EPIC), generic health (SF-12), and anxiety (STAI-6). Statistical significance (p ≤ 0.05) and clinical relevance (≥0.5 SD) of differences between groups were assessed. RESULTS: The AS, RP, RT, and reference group response rates amounted to 74% (122/165), 66% (70/106), 66% (221/335), and 75% (205/273), respectively. At a mean of 6.6 years of follow-up, active surveillance (AS)-men reported better urinary function [M = 93.0 (SD = 10.6) vs. 80.0 (SD = 19.1), p ≤ 0.001], less urinary incontinence [M = 90.0 (SD = 14.6) vs. 70.1 (SD = 28.8), p ≤ 0.001], and better sexual function [M = 40.9 (SD = 24.6) vs. 14.8 (17.7), p ≤ 0.001, clinically relevant] than RP-men. Compared to RT, AS-men reported better sexual function [M = 40.9 (SD = 24.6) vs. 25.8 (SD = 25.0), p = 0.069]. The four groups reported similarly low anxiety levels; the number of highly anxious men (STAI ≥ 44) ranged from 8 to 13%. For all QoL domains, men on AS and men without PCa reported very similar scores. CONCLUSIONS: Prostate-specific function of AS-men was significantly better than that of RP-men. When comparing AS to RT, a borderline significant difference in sexual function was seen. Men who followed an AS strategy for a long-term period were not anxious and accepted it well, suggesting that AS may be a good treatment option for men with low-risk PCa.

Hypofractionated versus conventionally fractionated radiotherapy for patients with prostate cancer (HYPRO): late toxicity results from a randomised, non-inferiority, phase 3 trial.

BACKGROUND: Several studies have reported a low α to ß ratio for prostate cancer, suggesting that hypofractionation could enhance the biological tumour dose without increasing genitourinary and gastrointestinal toxicity. We tested this theory in the phase 3 HYPRO trial for patients with intermediate-risk and high-risk prostate cancer. We have previously reported acute incidence of genitourinary and gastrointestinal toxicity; here we report data for late genitourinary and gastrointestinal toxicity. METHODS: In this randomised non-inferiority phase 3 trial, done in seven radiotherapy centres in the Netherlands, we enrolled intermediate-risk or high-risk patients aged between 44 and 85 years with histologically confirmed stage T1b-T4 NX-0MX-0 prostate cancer, a prostate-specific antigen concentration of 60 ng/mL or lower, and WHO performance status of 0-2. A web-based application was used to randomly assign (1:1) patients to receive either standard fractionation with 39 fractions of 2 Gy in 8 weeks (five fractions per week) or hypofractionation with 19 fractions of 3·4 Gy in 6·5 weeks (three fractions per week). Randomisation was done with the minimisation procedure, stratified by treatment centre and risk group. The primary endpoint was to detect a 10% enhancement in 5-year relapse-free survival with hypofractionation. A key additional endpoint was non-inferiority of hypofractionation in cumulative incidence of grade 2 or worse acute and late genitourinary and gastrointestinal toxicity. We planned to reject inferiority of hypofractionation for late genitourinary toxicity if the estimated hazard ratio (HR) was less than 1·11 and for gastrointestinal toxicity was less than 1·13. We scored toxicity with the Radiation Therapy Oncology Group and European Organisation for Research and Treatment of Cancer (RTOG/EORTC) criteria from both physicians' records (clinical record form) and patients' self-assessment questionnaires. Analyses were done in the intention-to-treat population. Patient recruitment for the HYPRO trial was completed in 2010. The trial was registered with www.controlled-trials.com, number ISRCTN85138529. FINDINGS: Between March 19, 2007, and Dec 3, 2010, 820 patients (410 in both groups) were randomly assigned. Analyses for late toxicity included 387 assessable patients in the standard fractionation group and 395 in the hypofractionation group. The median follow-up was 60 months (IQR 51·2-67·3). The database for all analyses (both groups and both genitourinary and gastrointestinal toxicities) was locked on March 26, 2015. The incidence of grade 2 or worse genitourinary toxicity at 3 years was 39·0% (95% CI 34·2-44·1) in the standard fractionation group and 41·3% (36·6-46·4) in the hypofractionation group. The estimated HR for the cumulative incidence of grade 2 or worse late genitourinary toxicity was 1·16 (90% CI 0·98-1·38), suggesting that non-inferiority could not be shown. The incidence of grade 2 or worse gastrointestinal toxicity at 3 years was 17·7% (14·1-21·9) in standard fractionation and 21·9% (18·1-26·4) hypofractionation. With an estimated HR of 1·19 (90% CI 0·93-1·52) for the cumulative incidence of grade 2 or worse late gastrointestinal toxicity, we could not confirm non-inferiority of hypofractionation for cumulative late gastrointestinal toxicity. Cumulative grade 3 or worse late genitourinary toxicity was significantly higher in the hypofractionation group than in the standard fractionation group (19·0% [95% CI 15·2-23·2] vs 12·9% [9·7-16·7], respectively; p=0·021), but there was no significant difference between cumulative grade 3 or worse late gastrointestinal toxicity (2·6% [95% CI 1·2-4·7]) in the standard fractionation group and 3·3% [1·7-5·6] in the hypofractionation group; p=0·55). INTERPRETATION: Our data could not confirm that hypofractionation was non-inferior for cumulative late genitourinary and gastrointestinal toxicity compared with standard fractionation. Before final conclusions can be made about the utility of hypofractionation, efficacy outcomes need to be reported. FUNDING: The Dutch Cancer Society.

Hypofractionated versus conventionally fractionated radiotherapy for patients with localised prostate cancer (HYPRO): final efficacy results from a randomised, multicentre, open-label, phase 3 trial.

BACKGROUND: Studies have reported a low α/ß ratio for prostate cancer, suggesting that hypofractionation could enhance the biological tumour dose without increasing genitourinary and gastrointestinal toxicity. In the multicentre phase 3, HYpofractionated irradiation for PROstate cancer (HYPRO) trial, hypofractionated radiotherapy was compared with conventionally fractionated radiotherapy for treatment of prostate cancer. We have previously reported acute and late incidence of genitourinary and gastrointestinal toxicity; here we report protocol-defined 5-year relapse-free survival outcomes. METHODS: We did an open-label, randomised, phase 3 trial at seven Dutch radiotherapy centres. We enrolled patients with intermediate-risk to high-risk T1b-T4NX-N0MX-M0 localised prostate cancer, a prostate-specific antigen concentration of 60 µg/L or less, and a WHO performance status of 0-2. We used a web-based application to randomly assign (1:1) patients to either hypofractionated radiotherapy of 64·6 Gy (19 fractions of 3·4 Gy, three fractions per week) or conventionally fractionated radiotherapy of 78·0 Gy (39 fractions of 2·0 Gy, five fractions per week). Based on an estimated α/ß ratio for prostate cancer of 1·5 Gy, the equivalent total dose in fractions of 2·0 Gy was 90·4 Gy for hypofractionation compared with 78·0 Gy for conventional fractionation. The primary endpoint was relapse-free survival. All analyses were done on an intention-to-treat basis in all eligible patients. The HYPRO trial completed recruitment in 2010 and follow-up is ongoing. This trial is registered with ISRCTN, number ISRCTN85138529. FINDINGS: Between March 19, 2007, and Dec 3, 2010, 820 patients were enrolled, of whom 804 were eligible and assessable for intention-to-treat analyses. Of these, 407 were assigned hypofractionated radiotherapy and 397 were allocated conventionally fractionated radiotherapy. 537 (67%) of 804 patients received concomitant androgen deprivation therapy for a median duration of 32 months (IQR 10-44). Median follow-up was 60 months (IQR 51-69). Treatment failure was reported in 169 (21%) of 804 patients, 80 (20%) in the hypofractionation group and 89 (22%) in the conventional fractionation group. 5-year relapse-free survival was 80·5% (95% CI 75·7-84·4) for patients assigned hypofractionation and 77·1% (71·9-81·5) for those allocated conventional fractionation (adjusted hazard radio 0·86, 95% CI 0·63-1·16; log-rank p=0·36). There were no treatment-related deaths. INTERPRETATION: Hypofractionated radiotherapy was not superior to conventional radiotherapy with respect to 5-year relapse-free survival. Our hypofractionated radiotherapy regimen cannot be regarded as the new standard of care for patients with intermediate-risk or high-risk prostate cancer. FUNDING: Dutch Cancer Society.

Hypofractionated versus conventionally fractionated radiotherapy for patients with prostate cancer (HYPRO): acute toxicity results from a randomised non-inferiority phase 3 trial.

BACKGROUND: In 2007, we began the randomised phase 3 multicentre HYPRO trial to investigate the effect of hypofractionated radiotherapy compared with conventionally fractionated radiotherapy on relapse-free survival in patients with prostate cancer. Here, we examine whether patients experience differences in acute gastrointestinal and genitourinary adverse effects. METHODS: In this randomised non-inferiority phase 3 trial, done in seven radiotherapy centres in the Netherlands, we enrolled intermediate-risk or high-risk patients aged between 44 and 85 years with histologically confirmed stage T1b-T4 NX-0MX-0 prostate cancer, a PSA concentration of 60 ng/mL or lower, and WHO performance status of 0-2. A web-based application was used to randomly assign (1:1) patients to receive either standard fractionation with 39 fractions of 2 Gy in 8 weeks (five fractions per week) or hypofractionation with 19 fractions of 3·4 Gy in 6·5 weeks (three fractions per week). Randomisation was done with minimisation procedure, stratified by treatment centre and risk group. The primary endpoint is 5-year relapse-free survival. Here we report data for the acute toxicity outcomes: the cumulative incidence of grade 2 or worse acute and late genitourinary and gastrointestinal toxicity. Non-inferiority of hypofractionation was tested separately for genitourinary and gastrointestinal acute toxic effects, with a null hypothesis that cumulative incidences of each type of adverse event were not more than 8% higher in the hypofractionation group than in the standard fractionation group. We scored acute genitourinary and gastrointestinal toxic effects according to RTOG-EORTC criteria from both case report forms and patients' self-assessment questionnaires, at baseline, twice during radiotherapy, and 3 months after completion of radiotherapy. Analyses were done in the intention-to-treat population. Patient recruitment has been completed. This study is registered with www.controlled-trials.com, number ISRCTN85138529. FINDINGS: Between March 19, 2007, and Dec 3, 2010, 820 patients were randomly assigned to treatment with standard fractionation (n=410) or hypofractionation (n=410). 3 months after radiotherapy, 73 (22%) patients in the standard fractionation group and 75 (23%) patients in the hypofractionation group reported grade 2 or worse genitourinary toxicity; grade 2 or worse gastrointestinal toxicity was noted in 43 (13%) patients in the standard fractionation group and in 42 (13%) in the hypofractionation group. Grade 4 acute genitourinary toxicity was reported for two patients, one (<1%) in each group. No grade 4 acute gastrointestinal toxicities were observed. We noted no significant difference in cumulative incidence by 120 days after radiotherapy of grade 2 or worse acute genitourinary toxicity (57·8% [95% CI 52·9-62·7] in the standard fractionation group vs 60·5% (55·8-65·3) in the hypofractionation group; difference 2·7%, 90% CI -2·99 to 8·48; odds ratio [OR] 1·12, 95% CI 0·84-1·49; p=0·43). The cumulative incidence of grade 2 or worse acute gastrointestinal toxicity by 120 days after radiotherapy was higher in patients given hypofractionation (31·2% [95% CI 26·6-35·8] in the standard fractionation group vs 42·0% [37·2-46·9] in the hypofractionation group; difference 10·8%, 90% CI 5·25-16·43; OR 1·6; p=0·0015; non-inferiority not confirmed). INTERPRETATION: Hypofractionated radiotherapy was not non-inferior to standard fractionated radiotherapy in terms of acute genitourinary and gastrointestinal toxicity for men with intermediate-risk and high-risk prostate cancer. In fact, the cumulative incidence of grade 2 or worse acute gastrointestinal toxicity was significantly higher in patients given hypofractionation than in those given standard fractionated radiotherapy. Patients remain in follow-up for efficacy endpoints. FUNDING: The Dutch Cancer Society.

Target coverage and organs at risk dose in hypofractionated salvage radiotherapy after prostatectomy.

Background and purpose: Introducing moderately hypofractionated salvage radiotherapy (SRT) following prostatectomy obligates investigation of its effects on clinical target volume (CTV) coverage and organ-at-risk (OAR) doses. This study assessed interfractional volume and dose changes in OARs and CTV in moderately hypofractionated SRT and evaluated the 8-mm planning target volume (PTV) margin. Materials and methods: Twenty patients from the PERYTON-trial were included; 10 received conventional SRT (35 × 2 Gy) and 10 hypofractionated SRT (20 × 3 Gy). OARs were delineated on 539 pre-treatment Cone Beam CT (CBCT) scans to compare interfractional OAR volume changes. CTVs for the hypofractionated group were delineated on 199 CBCTs. Dose distributions with 4 and 6 mm PTV margins were generated using voxel-wise minimum robustness evaluation of the original 8-mm PTV plan, and dose changes were assessed. Results: Median volume changes for bladder and rectum were -26 % and -10 %, respectively. OAR volume changes were not significantly different between the two treatment schedules. The 8-mm PTV margin ensured optimal coverage for prostate bed and vesicle bed CTV (V95 = 100 % in >97 % fractions). However, bladder V60 <25 % was not achieved in 5 % of fractions, and rectum V60 <5 % was unmet in 33 % of fractions. A 6-mm PTV margin resulted in CTV V95 = 100 % in 92 % of fractions for prostate bed, and in 86 % for vesicle bed CTV. Conclusions: Moderately hypofractionated SRT yielded comparable OAR volume changes to conventionally fractionated SRT. Interfractional changes remained acceptable with a PTV margin of 6 mm for prostate bed and 8 mm for vesicle bed.

Prostate-Specific Membrane Antigen Positron Emission Tomography/Computed Tomography-Based Clinical Target Volume Delineation Guideline for Postprostatectomy Salvage Radiation Therapy: The PERYTON Guideline.

PURPOSE: Prostate-specific membrane antigen positron emission tomography/computed tomography (PSMA PET/CT) scan is the standard imaging procedure for biochemical recurrent prostate cancer postprostatectomy because of its high detection rate at low serum prostate-specific antigen levels. However, existing guidelines for clinical target volume (CTV) in prostate bed salvage external beam radiation therapy (sEBRT) are primarily based on experience-based clinical consensus and have been validated using conventional imaging modalities. Therefore, this study aimed to optimize CTV definition in sEBRT by using PSMA PET/CT-detected local recurrences (LRs). METHODS AND MATERIALS: Patients with suspected LR on PSMA PET/CT postprostatectomy were retrospectively enrolled in 9 Dutch centers. Anonymized scans were centrally reviewed by an expert nuclear medicine physician. Each boundary of the CTV guideline from the Groupe Francophone de Radiothérapie en Urologie (GFRU) was evaluated and adapted to improve the accuracy and coverage of the area at risk of LR (CTV) on PSMA PET/CT. The proposed CTV adaptation was discussed with the radiation oncologists of the participating centers, and final consensus was reached. To assess reproducibility, the participating centers were asked to delineate 3 new cases according to the new PERYTON-CTV, and the submitted contours were evaluated using the Dice similarity coefficient (DSC). RESULTS: After central review, 93 LRs were identified on 83 PSMA PET/CTs. The proposed CTV definition improved the coverage of PSMA PET/CT-detected LRs from 67% to 96% compared with the GFRU-CTV, while reducing the GFRU-CTV by 25%. The new CTV was highly reproducible, with a mean DSC of 0.82 (range, 0.81-0.83). CONCLUSIONS: This study contributes to the optimization of CTV definition in postprostatectomy sEBRT by using the pattern of LR detected on PSMA PET/CT. The PERYTON-CTV is highly reproducible across the participating centers and ensures coverage of 96% LRs while reducing the GFRU-CTV by 25%.

Pretrial Quality Assurance for Hypofractionated Salvage Radiation Therapy After Prostatectomy in the Multi-Institutional PERYTON-trial.

Purpose: The PERYTON trial is a multicenter randomized controlled trial that will investigate whether the treatment outcome of salvage external beam radiation therapy (sEBRT) will be improved with hypofractionated radiation therapy. A pretrial quality assurance (QA) program was undertaken to ensure protocol compliance within the PERYTON trial and to assess variation in sEBRT treatment protocols between the participating centers. Methods and Materials: Completion of the QA program was mandatory for each participating center (N = 8) to start patient inclusion. The pretrial QA program included (1) a questionnaire on the center-specific sEBRT protocol, (2) a delineation exercise of the clinical target volume (CTV) and organs at risk, and (3) a treatment planning exercise. All contours were analyzed using the pairwise dice similarity coefficient (DSC) and the 50th and 95th percentile Hausdorff distance (HD50 and HD95, respectively). The submitted treatment plans were reviewed for protocol compliance. Results: The results of the questionnaire showed that high-quality, state-of-the-art radiation therapy techniques were used in the participating centers and identified variations of the sEBRT protocols used concerning the position verification and preparation techniques. The submitted CTVs showed significant variation, with a range in volume of 29 cm3 to 167 cm3, a mean pairwise DSC of 0.52, and a mean HD50 and HD95 of 2.3 mm and 24.4 mm, respectively. Only in 1 center the treatment plan required adaptation before meeting all constraints of the PERYTON protocol. Conclusions: The pretrial QA of the PERYTON trial demonstrated that high-quality, but variable, radiation techniques were used in the 8 participating centers. The treatment planning exercise confirmed that the dose constraints of the PERYTON protocol were feasible for all participating centers. The observed variation in CTV delineation led to agreement on a new (image-based) delineation guideline to be used by all participating centers within the PERYTON trial.

Simple immobilization for stereotactic radiotherapy aimed at pelvic metastases.

Stereotactic body radiotherapy (SBRT) is increasingly applied for pelvic oligometastases of prostate cancer, and currently no simple immobilization method is available for cone beam computed tomography (CBCT)-guided treatment. We assessed patient set-up and intrafraction motion using simple immobilization during CBCT-guided pelvic SBRT. Forty patients were immobilized with basic arm- head- and knee support and either a thermoplastic cushion or a foam cushion. Analysis of 454 CBCTs showed mean intrafraction translation <3.0 mm in 94% of fractions and mean intrafraction rotation <1.5° in 95% of fractions. Therefore, simple immobilization ensured stable patient positioning during CBCT-guided pelvic SBRT.

Dose evaluation of inter- and intra-fraction prostate motion in extremely hypofractionated intensity-modulated proton therapy for prostate cancer.

Inter- and intra-fractional prostate motion can deteriorate the dose distribution in extremely hypofractionated intensity-modulated proton therapy. We used verification CTs and prostate motion data calculated from 1024 intra-fractional prostate motion records to develop a voxel-wise based 4-dimensional method, which had a time resolution of 1 s, to assess the dose impact of prostate motion. An example of 100 fractional simulations revealed that motion had minimal impact on planning dose, the accumulated dose in 95 % of the scenarios fulfilled the clinical goals for target coverage (D95 > 37.5 Gy). This method can serve as a complementary measure in clinical setting to guarantee plan quality.

Skeletal 18F-PSMA-1007 uptake in prostate cancer patients.

Background/objectives: Accurate and uniform interpretation and reporting of metastatic prostate cancer (PCa) lesions on prostate-specific membrane antigen (PSMA) positron emission tomography/computed tomography (PET/CT) are indispensable. 18F-PSMA-1007 is increasingly used because of its favorable imaging characteristics. However, increased non-specific skeletal uptake may be an important pitfall of this radioligand. Therefore, we aimed to assess the interobserver variation in reporting skeletal 18F-PSMA-1007 uptake on PET/CT. Design/methods: In total, 33 18F-PSMA-1007 PET/CT scans of 21 patients with primary PCa and 12 patients with biochemical recurrence were included, and a total of 85 skeletal lesions were evaluated by three independent observers. The primary endpoint was the interobserver variability of the likelihood of malignancy of the skeletal lesions on both patient and lesion level (kappa analysis). Results: Observers qualified most lesions as not malignant (81-91%) and the overall mean interobserver agreement was moderate on both patient (κ: 0.54) and lesion level (κ: 0.55). In 52 lesions without corresponding CT substrate, the rating resulted in not malignant in 95-100%. Availability of additional imaging (60% of lesions) did not improve interobserver agreement (κ: 0.39 on lesion level) and resulted in unchanged rating for all observers in 78%. Conclusion: This interobserver analysis of skeletal 18F-PSMA-1007 uptake resulted in moderate agreement, in line with rates reported in literature. Importantly, the presence of non-specific skeletal uptake without CT substrate, as a potential shortcoming of 18F-PSMA-1007, did not impair interobserver agreement.

Role of Local and/or Metastasis-directed Therapy in Patients with Hormone-sensitive M1a Prostate Cancer-A Systematic Review.

CONTEXT: It remains unclear whether men with hormone-sensitive prostate cancer (PCa) metastasized to nonregional lymph nodes (M1a) benefit from prostate-directed therapy (PDT) and/or metastasis-directed therapy (MDT). OBJECTIVE: To systematically summarize the literature regarding oncological outcomes of de novo and recurrent M1a PCa patients treated with PDT and/or MDT. EVIDENCE ACQUISITION: We searched Medline (Ovid), Embase, and Scopus according to the Preferred Reporting Items for Systematic Reviews and Meta-analyses guidelines for reports on oncological outcomes of de novo or recurrent hormone-sensitive M1a PCa patients treated with PDT (radical prostatectomy or radiotherapy) and/or MDT (nodal radiotherapy or salvage lymph node dissection) with or without androgen deprivation therapy. A descriptive data synthesis and a methodological quality assessment were performed to evaluate the impact of PDT and/or MDT on survival in M1a PCa patients. EVIDENCE SYNTHESIS: A total of 6136 articles were screened and 24 studies were included in this systematic review. In de novo M1a PCa patients, PDT was associated with improved oncological outcomes compared with no PDT. In recurrent M1a PCa, MDT could delay the need for systemic treatment in a selection of patients, but high-level evidence from prospective phase III randomized controlled trials is still awaited. CONCLUSIONS: This systematic review summarized the limited literature data on the management of M1a PCa. Subgroup analyses suggest a role for PDT plus systemic therapy in de novo M1a PCa. MDT to distant nodal metastases delayed the need for systemic therapy in recurrent disease, but robust data are lacking. The predominantly retrospective nature of the included studies and significant heterogeneity in study designs limit the strength of evidence. PATIENT SUMMARY: We reviewed the treatment of patients with prostate cancer that has spread to lymph nodes outside the pelvis without metastases in other organ systems. There is evidence that treatment of the primary prostate tumor improves outcomes in well-selected patients and that treatment targeting distant lymph node metastases can delay the start of systemic treatment.

Genetic Aspects and Molecular Testing in Prostate Cancer: A Report from a Dutch Multidisciplinary Consensus Meeting.

Background: Germline and tumour genetic testing in prostate cancer (PCa) is becoming more broadly accepted, but testing indications and clinical consequences for carriers in each disease stage are not yet well defined. Objective: To determine the consensus of a Dutch multidisciplinary expert panel on the indication and application of germline and tumour genetic testing in PCa. Design setting and participants: The panel consisted of 39 specialists involved in PCa management. We used a modified Delphi method consisting of two voting rounds and a virtual consensus meeting. Outcome measurements and statistical analysis: Consensus was reached if ≥75% of the panellists chose the same option. Appropriateness was assessed by the RAND/UCLA appropriateness method. Results and limitations: Of the multiple-choice questions, 44% reached consensus. For men without PCa having a relevant family history (familial PCa/BRCA-related hereditary cancer), follow-up by prostate-specific antigen was considered appropriate. For patients with low-risk localised PCa and a family history of PCa, active surveillance was considered appropriate, except in case of the patient being a BRCA2 germline pathogenic variant carrier. Germline and tumour genetic testing should not be done for nonmetastatic hormone-sensitive PCa in the absence of a relevant family history of cancer. Tumour genetic testing was deemed most appropriate for the identification of actionable variants, with uncertainty for germline testing. For tumour genetic testing in metastatic castration-resistant PCa, consensus was not reached for the timing and panel composition. The principal limitations are as follows: (1) a number of topics discussed lack scientific evidence, and therefore the recommendations are partly opinion based, and (2) there was a small number of experts per discipline. Conclusions: The outcomes of this Dutch consensus meeting may provide further guidance on genetic counselling and molecular testing related to PCa. Patient summary: A group of Dutch specialists discussed the use of germline and tumour genetic testing in prostate cancer (PCa) patients, indication of these tests (which patients and when), and impact of these tests on the management and treatment of PCa.

Recommendations for radiation therapy in oligometastatic prostate cancer: An ESTRO-ACROP Delphi consensus.

BACKGROUND AND PURPOSE: Oligometastatic prostate cancer is a new and emerging treatment field with only few prospective randomized studies published so far. Despite the lack of strong level I evidence, metastasis-directed therapies (MDT) are widely used in clinical practice, mainly based on retrospective and small phase 2 studies and with a large difference across centers. Pending results of ongoing prospective randomized trials, there is a clear need for more consistent treatment indications and radiotherapy practices. MATERIAL AND METHODS: A European Society for Radiotherapy and Oncology (ESTRO) Guidelines Committee consisting of radiation oncologists' experts in prostate cancer was asked to answer a dedicated questionnaire, including 41 questions on the main controversial issues with regard to oligometastatic prostate cancer. RESULTS: The panel achieved consensus on patient selection and routine use of prostate-specific membrane antigen positron emission tomography (PSMA PET) imaging as preferred staging and restaging imaging. MDT strategies are recommended in the de novo oligometastatic, oligorecurrent and oligoprogressive disease setting for nodal, bone and visceral metastases. Radiation therapy doses, volumes and techniques were discussed and commented. CONCLUSION: These recommendations have the purpose of providing standardization and consensus to optimize the radiotherapy treatment of oligometastatic prostate cancer until mature results of randomized trials are available.

Complementing Prostate SBRT VMAT With a Two-Beam Non-Coplanar IMRT Class Solution to Enhance Rectum and Bladder Sparing With Minimum Increase in Treatment Time.

PURPOSE: Enhance rectum and bladder sparing in prostate SBRT with minimum increase in treatment time by complementing dual-arc coplanar VMAT with a two-beam non-coplanar IMRT class solution (CS). METHODS: For twenty patients, an optimizer for automated multi-criterial planning with integrated beam angle optimization (BAO) was used to generate dual-arc VMAT plans, supplemented with five non-coplanar IMRT beams with individually optimized orientations (VMAT+5). In all plan generations, reduction of high rectum dose had the highest priority after obtaining adequate PTV coverage. A CS with two most preferred directions in VMAT+5 and largest rectum dose reductions compared to dual-arc VMAT was then selected to define VMAT+CS. VMAT+CS was compared with automatically generated i) dual-arc coplanar VMAT plans (VMAT), ii) VMAT+5 plans, and iii) IMRT plans with 30 patient-specific non-coplanar beam orientations (30-NCP). Plans were generated for a 4 x 9.5 Gy fractionation scheme. Differences in PTV doses, healthy tissue sparing, and computation and treatment delivery times were quantified. RESULTS: For equal PTV coverage, VMAT+CS, consisting of dual-arc VMAT supplemented with two fixed, non-coplanar IMRT beams with fixed Gantry/Couch angles of 65°/30° and 295°/-30°, significantly reduced OAR doses and the dose bath, compared to dual-arc VMAT. Mean relative differences in rectum Dmean, D1cc, V40GyEq and V60GyEq were 19.4 ± 10.6%, 4.2 ± 2.7%, 34.9 ± 20.3%, and 39.7 ± 23.2%, respectively (all p<0.001). There was no difference in bladder D1cc, while bladder Dmean reduced by 17.9 ± 11.0% (p<0.001). Also, the clinically evaluated urethra D5%, D10%, and D50% showed small, but statistically significant improvements. All patient VX with X = 2, 5, 10, 20, and 30 Gy were reduced with VMAT+CS, with a maximum relative reduction for V10Gy of 19.0 ± 7.3% (p<0.001). Total delivery times with VMAT+CS only increased by 1.9 ± 0.7 min compared to VMAT (9.1 ± 0.7 min). The dosimetric quality of VMAT+CS plans was equivalent to VMAT+5, while optimization times were reduced by a factor of 25 due to avoidance of individualized BAO. Compared to VMAT+CS, the 30-NCP plans were only favorable in terms of dose bath, at the cost of much enhanced optimization and delivery times. CONCLUSIONS: The proposed two-beam non-coplanar class solution to complement coplanar dual-arc VMAT resulted in substantial plan quality improvements for OARs (especially rectum) and reduced irradiated patient volumes with minor increases in treatment delivery times.

Inter-fraction motion robustness and organ sparing potential of proton therapy for cervical cancer.

PURPOSE: Large-field photon radiotherapy is current standard in the treatment of cervical cancer patients. However, with the increasing availability of Pencil Beam Scanning Proton Therapy (PBS-PT) and robust treatment planning techniques, protons may have significant advantages for cervical cancer patients in the reduction of toxicity. In this study, PBS-PT and photon Volumetric Modulated Arc Therapy (VMAT) were compared, examining target coverage and organ at risk (OAR) dose, taking inter- and intra-fraction motion into account. MATERIALS AND METHODS: Twelve cervical cancer patients were included in this in-silico planning study. In all cases, a planning CT scan, five weekly repeat CT scans (reCTs) and an additional reCT 10 min after the first reCT were available. Two-arc VMAT and robustly optimised two- and four-field (2F and 4F) PBS-PT plans were robustly evaluated on planCTs and reCTs using set-up and range uncertainty. Nominal OAR doses and voxel-wise minimum target coverage robustness were compared. RESULTS: Average voxel-wise minimum accumulated doses for pelvic target structures over all patients were adequate for both photon and proton treatment techniques (D98 > 95%, [91.7-99.3%]). Average accumulated dose of the para-aortic region was lower than the required 95%, D98 > 94.4% [91.1-98.2%]. With PBS-PT 4F, dose to all OARs was significantly lower than with VMAT. Major differences were observed for mean bowel bag V15Gy: 60% [39-70%] for VMAT vs 30% [10-52%] and 32% [9-54%] for PBS-PT 2F and 4F and for mean bone marrow V10Gy: 88% [82-97%] for VMAT vs 66% [60-73%] and 67% [60-75%] for PBS-PT 2F and 4F. CONCLUSION: Robustly optimised PBS-PT for cervical cancer patients shows equivalent target robustness against inter- and intra-fraction variability compared to VMAT, and offers significantly better OAR sparing.

M1a prostate cancer: Results of a Dutch multidisciplinary consensus meeting.

Objectives: To determine the consensus of a Dutch multidisciplinary expert panel on the diagnostic evaluation and treatment of de novo and recurrent metastatic prostate cancer (PCa) limited to non-regional lymph nodes (M1a) in daily clinical practice. Materials and methods: The panel consisted of 37 Dutch specialists from disciplines involved in the management of M1a PCa (urology, medical and radiation oncology, radiology, and nuclear medicine). We used a modified Delphi method consisting of two voting rounds and a consensus meeting (video conference). Consensus (good agreement) was defined as the situation in which ≥ 75% of the panelists chose the same option. Results: Consensus existed for 57% of the items. The panel agreed that prostate-specific membrane antigen positron emission tomography/computed tomography (PSMA-PET/CT) is the most appropriate standard imaging modality to identify de novo (100%) and recurrent (97%) M1a PCa. Androgen deprivation therapy (ADT) combined with radiotherapy to the prostate ± the M1a lesion(s) was most frequently considered an option for de novo M1a PCa. For M1a as recurrent disease, ADT alone, deferring treatment, or local radiotherapy to the M1a lesion(s) were judged to be the most important treatment options. However, no specific indications for treatment choice in relation to disease characteristics could be formulated. Conclusions: The Dutch consensus panel preferred PSMA-PET/CT as the standard diagnostic modality to detect M1a PCa. Although potential treatment options were identified, explicit recommendations could not be formulated. This might (partly) be explained by the absence of high-level clinical evidence in this subset of patients. Further research is, therefore, strongly encouraged.

Oligometastatic Prostate Cancer: Results of a Dutch Multidisciplinary Consensus Meeting.

BACKGROUND: Oligometastatic prostate cancer (OMPC) is a heterogeneous disease state that is imperfectly understood, and its clinical implications are unclear. OBJECTIVE: To determine the consensus of a Dutch multidisciplinary expert panel on biological aspects, treatment goals, and management of OMPC in daily clinical practice. DESIGN, SETTING, AND PARTICIPANTS: The study comprised a modified Delphi method including an explorative survey with various statements and questions, followed by a consensus meeting to discuss and determine the agreement with revised statements and related items. The panel consisted of 34 Dutch representatives from urology, medical and radiation oncology, radiology, nuclear medicine, and basic research. OUTCOME MEASUREMENTS AND STATISTICAL ANALYSIS: Agreement was determined with statements (five-point scale). Consensus was defined as ≥75% panel agreement with a statement. RESULTS AND LIMITATIONS: Consensus existed for 56% of statements. The panel agreed that OMPC comprises a limited metastatic spread in the hormone-sensitive setting, in both the synchronous and the metachronous presentation. Limited metastatic spread was believed to involve three to five metastases and a maximum of two organs. Prostate-specific membrane antigen positron emission tomography/computed tomography scan was currently perceived as the most accurate diagnostic imaging modality. Although there was a consensus that targeted treatment of all metastases in OMPC will delay further dissemination of the disease, opinions on specific treatment regimens were divided. Panel outcomes were limited by the lack of scientific evidence on OMPC. CONCLUSIONS: A multidisciplinary panel reached a consensus that OMPC is a specific disease state requiring a tailored treatment approach. OMPC registries and clinical studies should focus on both the biology and the clinical parameters in relation to optimal treatment strategies in synchronous and metachronous OMPC. PATIENT SUMMARY: A group of Dutch medical specialists agreed that prostate cancer patients having few metastases may benefit from a new therapeutic approach. Clinical studies need to determine which treatment is best for each specific situation.

Fast automated multi-criteria planning for HDR brachytherapy explored for prostate cancer.

We developed a fast and fully-automated, multi-criteria treatment planning workflow for high dose rate brachytherapy (HDR-BT). In this workflow, the patient-CT with catheter reconstructions and dwell positions are imported from the clinical TPS into a novel system for automated dwell time optimisation. The optimised dwell times are then imported into the clinical TPS. The aims of automation were (1) planner-independent, enhanced plan quality, (2) short optimisation times. Our in-house developed system for fully automated, multi-criteria external beam radiotherapy (EBRT) treatment planning (Erasmus-iCycle) was adapted for optimisation of HDR-BT dose distributions. The investigations were performed with planning CT scans with catheter reconstructions and delineations of twenty-five low- and intermediate-risk prostate cancer patients who were previously treated in our center with [Formula: see text] Gy HDR-BT. Automatically generated plans (autoplans) were compared to the corresponding clinical plans. All evaluations were performed in the clinical TPS. The requested 95% tumour coverage was obtained for all autoplans, while this was only observed in 23/25 clinical plans. All autoplans showed a consistent reduction of the [Formula: see text] for the highest prioritised OAR, the urethra. The average and maximum reductions were 6.3%-point and 12.1%-point of the prescribed dose, respectively. In addition, conformality of the autoplans was higher. The autoplans had slightly smaller delivery times. Autoplanning took on average 4.6 s, including computation of the dose kernels.

Salvage radiotherapy after radical prostatectomy: Long-term results of urinary incontinence, toxicity and treatment outcomes.

PURPOSE: For patients with local recurrent disease after radical prostatectomy (35-54%) salvage radiotherapy (SRT) is the treatment of choice. In the post prostatectomy setting, SRT may impose risk at increased toxicity. As data on long-term toxicity, especially on urinary incontinence, are scarce, we report on the long-term treatment outcomes, toxicity and urinary incontinence rates after SRT. MATERIALS AND METHODS: Patients with biochemically recurrent prostate cancer after radical prostatectomy, who were treated with SRT (3D-CRT) at our institution between 1998 and 2012, were included in this retrospective cohort analysis. Primary endpoint was urinary incontinence rate. Secondary endpoints were acute and late grade ≥2 genitourinary (GU) and gastrointestinal (GI) toxicity rates, biochemical progression-free survival (bPFS), distant metastasis-free survival (DMFS), disease specific survival (DSS), and overall survival (OS). RESULTS: 244 patients were included. Median follow-up after SRT was 50 months (range: 4-187 months). Before start of SRT 69.7% of patients were continent for urine. After SRT de novo urinary incontinence complaints (grade ≥ 1) occurred in the respective acute and late phase in 6.1% and 17.6% of patients. Respective acute grade ≥2 GU and GI toxicity was 19.2% and 17.6%. Late grade ≥2 toxicity for GU was 29.9% and for GI was 21.3%, respectively. The respective 5-year bPFS, OS, DSS and DMFS rates were 47.6%, 91.8%, 98.8% and 80.5%. CONCLUSIONS: Experience at our institution with SRT demonstrates that this results in good long-term biochemical control. However, toxicity and urinary incontinence rates were high.