Erectile function preservation after salvage radiation therapy for biochemically recurrent prostate cancer after prostatectomy: Five-year results of the SAKK 09/10 randomized phase 3 trial.

Objectives: To evaluate effects of dose intensified salvage radiotherapy (sRT) on erectile function in biochemically recurrent prostate cancer (PC) after radical prostatectomy (RP). Materials and methods: Eligible patients had evidence of biochemical failure after RP and a PSA at randomization of ≤ 2 ng/ml. Erectile dysfunction (ED) was investigated as secondary endpoint within the multicentre randomized trial (February 2011 to April 2014) in patients receiving either 64 Gy or 70 Gy sRT. ED and quality of life (QoL) were assessed using CTCAE v4.0 and the EORTC QoL questionnaires C30 and PR25 at baseline and up to 5 years after sRT. Results: 344 patients were evaluable. After RP 197 (57.3 %) patients had G0-2 ED while G3 ED was recorded in 147 (42.7 %) patients. Subsequently, sexual activity and functioning was impaired. 5 years after sRT, 101 (29.4 %) patients noted G0-2 ED. During follow-up, 44.2 % of patients with baseline G3 ED showed any improvement and 61.4 % of patients with baseline G0-2 ED showed worsening. Shorter time interval between RP and start of sRT (p = 0.007) and older age at randomization (p = 0.005) were significant predictors to more baseline ED and low sexual activity in the long-term. Age (p = 0.010) and RT technique (p = 0.031) had a significant impact on occurrence of long-term ED grade 3 and worse sexual functioning. During follow-up, no differences were found in erectile function, sexual activity, and sexual functioning between the 64 Gy and 70 Gy arm. Conclusion: ED after RP is a known long-term side effect with significant impact on patients' QoL. ED was further affected by sRT, but dose intensification of sRT showed no significant impact on erectile function recovery or prevalence of de novo ED after sRT. Age, tumor stage, prostatectomy and RT-techniques, nerve-sparing and observation time were associated with long-term erectile function outcome.ClinicalTrials.gov. Identifier: NCT01272050.

Pelvic Irradiation for Node-Positive Prostate Cancer After Prostatectomy: Long-Term Results of the Prospective PLATIN-4 and PLATIN-5 Trials.

PURPOSE: After radical prostatectomy (RP), adjuvant or salvage radiation treatment in node-positive prostate cancer is offered to prevent systemic disease. Prospective long-term survival and toxicity data on patients with radiation for nodal disease are still scarce. This study evaluates safety and feasibility of salvage radiation therapy to the pelvic lymph nodes in node-positive prostate cancer after RP. METHODS AND MATERIALS: Between 2009 and 2018, 78 patients with lymph node recurrence after RP (PLATIN-4 trial) or after RP and prostate bed radiation therapy (PLATIN-5 trial) were treated with salvage pelvic lymph node radiation therapy with boost to the involved nodes as field abutment (PLATIN-5) and boost to the prostate bed (PLATIN-4). Androgen deprivation therapy was started 2 months before radiation and recommended for 24 months. The primary endpoint was safety and feasibility of the intensity modulated radiation therapy-image guided radiation therapy technique based on the rate of treatment discontinuations and incidence of Common Terminology Criteria for Adverse Events grade 3+ toxicity. Secondary endpoints were progression-free survival and overall survival. RESULTS: No treatment discontinuations were reported in either trial. Median overall survival was not reached in PLATIN-4 and was 117 months in PLATIN-5. Median progression-free survival was 66 months in PLATIN-4 and 39 months in PLATIN-5. Late grade 3+ genitourinary and gastrointestinal toxicities were observed in 4% of patients at 24 months of follow-up. CONCLUSIONS: Salvage radiation therapy to the prostate bed and pelvic lymphatic drainage combined with long-term androgen deprivation therapy is a curative treatment option for patients with node-positive prostate cancer after RP, with excellent in-field disease control. Pelvic lymph node radiation therapy as field abutment after prostate bed radiation therapy is feasible with long-term survival and no high-grade toxicity.

Longitudinal monitoring of Apparent Diffusion Coefficient (ADC) in patients with prostate cancer undergoing MR-guided radiotherapy on an MR-Linac at 1.5 T: a prospective feasibility study.

BACKGROUND: Hybrid MRI linear accelerators (MR-Linac) might enable individualized online adaptation of radiotherapy using quantitative MRI sequences as diffusion-weighted imaging (DWI). The purpose of this study was to investigate the dynamics of lesion apparent diffusion coefficient (ADC) in patients with prostate cancer undergoing MR-guided radiation therapy (MRgRT) on a 1.5T MR-Linac. The ADC values at a diagnostic 3T MRI scanner were used as the reference standard. PATIENTS AND AND METHODS: In this prospective single-center study, patients with biopsy-confirmed prostate cancer who underwent both an MRI exam at a 3T scanner (MRI3T) and an exam at a 1.5T MR-Linac (MRL) at baseline and during radiotherapy were included. Lesion ADC values were measured by a radiologist and a radiation oncologist on the slice with the largest lesion. ADC values were compared before vs. during radiotherapy (during the second week) on both systems via paired t-tests. Furthermore, Pearson correlation coefficient and inter-reader agreement were computed. RESULTS: A total of nine male patients aged 67 ± 6 years [range 60 - 67 years] were included. In seven patients, the cancerous lesion was in the peripheral zone, and in two patients the lesion was in the transition zone. Inter-reader reliability regarding lesion ADC measurement was excellent with an intraclass correlation coefficient of (ICC) > 0.90 both at baseline and during radiotherapy. Thus, the results of the first reader will be reported. In both systems, there was a statistically significant elevation of lesion ADC during radiotherapy (mean MRL-ADC at baseline was 0.97 ± 0.18 × 10-3 mm2/s vs. mean MRL-ADC during radiotherapy 1.38 ± 0.3 × 10-3 mm2/s, yielding a mean lesion ADC elevation of 0.41 ± 0.20 × 10-3 mm2/s, p < 0.001). Mean MRI3T-ADC at baseline was 0.78 ± 0.165 × 10-3 mm2/s vs. mean MRI3T-ADC during radiotherapy 0.99 ± 0.175 × 10-3 mm2/s, yielding a mean lesion ADC elevation of 0.21 ± 0.96 × 10-3 mm2/s p < 0.001). The absolute ADC values from MRL were consistently significantly higher than those from MRI3T at baseline and during radiotherapy (p < = 0.001). However, there was a strong positive correlation between MRL-ADC and MRI3T-ADC at baseline (r = 0.798, p = 0.01) and during radiotherapy (r = 0.863, p = 0.003). CONCLUSIONS: Lesion ADC as measured on MRL increased significantly during radiotherapy and ADC measurements of lesions on both systems showed similar dynamics. This indicates that lesion ADC as measured on the MRL may be used as a biomarker for evaluation of treatment response. In contrast, absolute ADC values as calculated by the algorithm of the manufacturer of the MRL showed systematic deviations from values obtained on a diagnostic 3T MRI system. These preliminary findings are promising but need large-scale validation. Once validated, lesion ADC on MRL might be used for real-time assessment of tumor response in patients with prostate cancer undergoing MR-guided radiation therapy.

[Multimodal treatment of testicular cancer: chemotherapy, surgery or radiotherapy?] / Multimodale Therapie des Hodentumors: wann Chemotherapie, Operation oder Strahlentherapie?

BACKGROUND: Metastatic testicular germ cell tumors patients require histology- and stage-appropriate therapy to achieve optimal therapeutic outcomes. OBJECTIVES: This work focuses on the interdisciplinary presentation of current recommendations for the treatment of metastatic germ cell tumor patients. MATERIALS AND METHODS: The interdisciplinary recommendations were formulated based on the German S3 guideline and supplemented by recent literature. RESULTS: Using a stage-specific and guideline-based treatment approach, interdisciplinary cooperation between urology, oncology, and radiotherapy is mandatory to successfully achieve a high rate of cure and, in the case of complex advanced tumors, also the most effective therapy possible. The question of optimal treatment approaches for seminoma in cSII A/B remains particularly challenging. CONCLUSION: Since treatment of advanced or multiple relapsed germ cell tumor patients remains complex, patients should be referred for an online second opinion ( https://urologie.ekonsil.org ).

First Experience and Prospective Evaluation on Feasibility and Acute Toxicity of Online Adaptive Radiotherapy of the Prostate Bed as Salvage Treatment in Patients with Biochemically Recurrent Prostate Cancer on a 1.5T MR-Linac.

INTRODUCTION: Novel MRI-linear accelerator hybrids (MR-Linacs, MRL) promise an optimization of radiotherapy (RT) through daily MRI imaging with enhanced soft tissue contrast and plan adaptation on the anatomy of the day. These features might potentially improve salvage RT of prostate cancer (SRT), where the clinical target volume is confined by the mobile organs at risk (OAR) rectum and bladder. So far, no data exist about the feasibility of the MRL technology for SRT. In this study, we prospectively examined patients treated with SRT on a 1.5 T MRL and report on workflow, feasibility and acute toxicity. PATIENTS AND METHODS: Sixteen patients were prospectively enrolled within the MRL-01 study (NCT: NCT04172753). All patients were staged and had an indication for SRT after radical prostatectomy according to national guidelines. RT consisted of 66 Gy in 33 fractions or 66.5/70 Gy in 35 fractions in case of a defined high-risk region. On the 1.5 T MRL, daily plan adaption was performed using one of two workflows: adapt to shape (ATS, using contour adaptation and replanning) or adapt to position (ATP, rigid replanning onto the online anatomy with virtual couch shift). Duration of treatment steps, choice of workflow and treatment failure were recorded for each fraction of each patient. Patient-reported questionnaires about patient comfort were evaluated as well as extensive reporting of acute toxicity (patient reported and clinician scored). RESULTS: A total of 524/554 (94.6%) of fractions were successfully treated on the MRL. No patient-sided treatment failures occurred. In total, ATP was chosen in 45.7% and ATS in 54.3% of fractions. In eight cases, ATP was performed on top of the initial ATS workflow. Mean (range) duration of all fractions (on-table time until end of treatment) was 25.1 (17.6-44.8) minutes. Mean duration of the ATP workflow was 20.60 (17.6-25.2) minutes and of the ATS workflow 31.3 (28.2-34.1) minutes. Patient-reported treatment experience questionnaires revealed high rates of tolerability of the treatment procedure. Acute toxicity (RTOG, CTC as well as patient-reported CTC, IPSS and ICIQ) during RT and 3 months after was mild to moderate with a tendency of recovery to baseline levels at 3 months post RT. No G3+ toxicity was scored for any item. CONCLUSIONS: In this first report on SRT of prostate cancer patients on a 1.5 T MRL, we could demonstrate the feasibility of both available workflows. Daily MR-guided adaptive SRT of mean 25.1 min per fraction was well tolerated in this pretreated collective, and we report low rates of acute toxicity for this treatment. This study suggests that SRT on a 1.5 T MRL can be performed in clinical routine and it serves as a benchmark for future analyses.

Radiotherapy and hyperthermia for breast cancer patients at high risk of recurrence.

PURPOSE: To evaluate the long-term efficacy of combined radiotherapy (RT) and hyperthermia (HT) in a large mono-institutional cohort of breast cancer (BC) patients affected by recurrent, newly diagnosed non-resectable or high risk resected tumor. MATERIALS AND METHODS: Records of BC patients treated with RT + HT between 1995 and 2018 were retrospectively analyzed. RT doses of 50-70 Gy concurrent to a twice per week superficial HT were applied. For HT, a temperature between 41 and 42 °C was applied for approximately 1 h. Primary endpoint was local control (LC), secondary endpoints comprised toxicity, overall survival (OS), and progression-free survival (PFS). RESULTS: A total of 191 patients and 196 RT + HT treatments were analyzed. In 154 cases (78.6%) RT + HT was performed for patients with recurrent BC. Among these, 93 (47.4% of the entire cohort) had received RT prior to RT + HT. Median follow up was 12.7 years. LC at 2, 5, and 10 years was 76.4, 72.8, and 69.5%, respectively. OS at 2, 5, and 10 years was 73.5, 52.3, and 35.5%, respectively. PFS at 2, 5, and 10 years was 55.6, 41, and 33.6%, respectively. Predictive factors for LC were tumor stage, distant metastases, estrogen/progesterone receptor expression, resection status and number of HT fractions. At multivariate analysis tumor stage and receptor expression were significant. No acute or late toxicities higher than grade 3 were observed. CONCLUSION: Combined RT + HT offers long-term high LC rates with acceptable toxicity for patients with recurrent, newly diagnosed non-resectable or resected BC at high risk of relapse.

Radiotherapy for hormone-sensitive prostate cancer with synchronous low burden of distant metastases.

PURPOSE: The DEGRO Expert Commission on Prostate Cancer has revised the indication for radiation therapy of the primary prostate tumor in patients with synchronous distant metastases with low metastatic burden. METHODS: The current literature in the PubMed database was reviewed regarding randomized evidence on radiotherapy of the primary prostate tumor with synchronous low metastatic burden. RESULTS: In total, two randomized trials were identified. The larger study, the STAMPEDE trial, demonstrated an absolute survival benefit of 8% after 3 years for patients with low metastatic burden treated with standard of care (SOC) and additional radiotherapy (RT) (EQD2 ≤ 72 Gy) of the primary tumor. Differences in the smaller Horrad trial were not statistically significant, although risk reduction in the subgroup (< 5 bone metastases) was equal to STAMPEDE. The STOPCAP meta-analysis of both trials demonstrated the benefit of local radiotherapy for up to 4 bone lesions and an additional subanalysis of STAMPEDE also substantiated this finding in cases with M1a-only metastases. CONCLUSION: Therefore, due to the survival benefit after 3 years, current practice is changing. New palliative SOC is radiotherapy of the primary tumor in synchronously metastasized prostate cancer with low metastatic burden (defined as ≤ 4 bone metastases, with or without distant nodes) or in case of distant nodes only detected by conventional imaging.

Local Control after Locally Ablative, Image-Guided Radiotherapy of Oligometastases Identified by Gallium-68-PSMA-Positron Emission Tomography in Castration-Sensitive Prostate Cancer Patients (OLI-P).

Progression of prostate-specific antigen (PSA) values after curative treatment of prostate cancer patients is common. Prostate-specific membrane antigen (PSMA-) PET imaging can identify patients with metachronous oligometastatic disease even at low PSA levels. Metastases-directed local ablative radiotherapy (aRT) has been shown to be a safe treatment option. In this prospective clinical trial, we evaluated local control and the pattern of tumor progression. Between 2014 and 2018, 63 patients received aRT of 89 metastases (MET) (68 lymph node (LN-)MET and 21 bony (OSS-)MET) with one of two radiation treatment schedules: 50 Gy in 2 Gy fractions in 34 MET or 30 Gy in 10 Gy fractions in 55 MET. The mean gross tumor volume and planning target volume were 2.2 and 14.9 mL, respectively. The median follow-up time was 40.7 months. Local progression occurred in seven MET, resulting in a local control rate of 93.5% after three years. Neither treatment schedule, target volume, nor type of lesion was associated with local progression. Regional progression in the proximity to the LN-MET was observed in 19 of 47 patients with at least one LN-MET (actuarial 59.3% free of regional progression after 3 years). In 33 patients (52%), a distant progression was reported. The median time to first tumor-related clinical event was 16.6 months, and 22.2% of patients had no tumor-related clinical event after three years. A total of 14 patients (22%) had another aRT. In conclusion, local ablative radiotherapy in patients with PSMA-PET staged oligometastatic prostate cancer may achieve local control, but regional or distant progression is common. Further studies are warranted, e.g., to define the optimal target volume coverage in LN-MET and OSS-MET.

Adherence to Contouring and Treatment Planning Requirements Within a Multicentric Trial: Results of the Quality Assurance of the SAKK 09/10 trial.

PURPOSE: To evaluate the results of the radiation therapy (RT) quality assurance (QA) program of the phase 3 randomized SAKK 09/10 trial in patients with biochemically recurrent prostate cancer after prostatectomy. METHODS AND MATERIALS: Within the Schweizerische Arbeitsgemeinschaft für Klinische Krebsforschung (SAKK) 09/10 trial testing 64-Gy versus 70-Gy salvage RT, a central collection of treatment plans was performed and thoroughly reviewed by a dedicated medical physicist and radiation oncologist. Adherence to the treatment protocol and specifically to the European Organization for the Research and Treatment of Cancer (EORTC) guidelines for target volume definition (classified as deviation observed yes vs no) and its potential correlation with acute and late toxicity (Common Terminology Criteria for Adverse Events version 4.0) and freedom from biochemical progression (FFBP) were investigated. RESULTS: The treatment plans for 344 patients treated between February 2011 and April 2014 depicted important deviations from the EORTC guidelines and the recommendations per trial protocol. For example, in up to half of the cases, the delineated structures deviated from the protocol (eg, prostate bed in 48.8%, rectal wall [RW] in 41%). In addition, variations in clinical target volume (CTV) and planning target volume (PTV) occurred frequently (eg, CTV and PTV deviations in up to 42.4% and 25.9%, respectively). The detected deviations showed a significant association with a lower risk of grade ≥2 gastrointestinal acute toxicity when the CTV did not overlap the RW versus when the CTV overlapped the RW (odds ratio [OR], 0.43; 95% confidence interval [CI], 0.22-0.85; P = .014), and a higher rate of grade ≥2 late genitourinary (GU) toxicity when the CTV overlapped the RW (OR, 2.58; 95% CI, 1.17-5.72; P = .019). A marginally significant lower risk of grade ≥2 late GU toxicity was observed when the prostate bed did not overlap versus did overlap the RW (OR, 0.51; 95% CI, 0.25-1.03; P = .06). In addition, a marginally significant decrease in FFBP was observed in patients with PTV not including surgical clips as potential markers of the limits of the prostate bed (hazard ratio, 1.44; 95% CI, 0.96-2.17; P = .07). CONCLUSIONS: Despite a thorough QA program, the central review of a phase 3 trial showed limited adherence to treatment protocol recommendations, which was associated with a higher risk of toxicity by means of acute or late gastrointestinal or GU toxicity and showed a trend toward worse FFBP. Data from this QA review might help to refine future QA programs and prostate bed delineation guidelines.

On the probability of lymph node negativity in pN0-staged prostate cancer-a theoretically derived rule of thumb for adjuvant needs.

PURPOSE: The extent of lymphadenectomy and clinical features influence the risk of occult nodes in node-negative prostate cancer. We derived a simple estimation model for the negative predictive value (npv) of histopathologically node-negative prostate cancer patients (pN0) to guide adjuvant treatment. METHODS: Approximations of sensitivities in detecting lymph node metastasis from current publications depending on the number of removed lymph nodes were used for a theoretical deduction of a simplified formulation of npv assuming a false node positivity of 0. RESULTS: A theoretical formula of npv = p(N0IpN0) = (100 - prevalence) / (100 - sensitivityâ€¯× prevalence) was calculated (sensitivity and preoperative prevalence in %). Depending on the number of removed lymph nodes (nLN), the sensitivity of pN0-staged prostate cancer was derived for three sensitivity levels accordingly: sensitivity = f(nLN) = 9â€¯× nLN /100 for 0 ≤ nLN ≤ 8 and f(nLN) = (nLN + 70) /100 for 9 ≤ nLN ≤ 29 and f(nLN) = 1 for nLN ≥ 30. CONCLUSION: We developed a theoretical formula for estimation of the npv in pN0-staged prostate cancer patients. It is a sine qua non to use the formula in a clinically experienced context before deciding to electively irradiate pelvic lymph nodes or to intensify adjuvant systemic treatment.

Toxicity and Efficacy of Local Ablative, Image-guided Radiotherapy in Gallium-68 Prostate-specific Membrane Antigen Targeted Positron Emission Tomography-staged, Castration-sensitive Oligometastatic Prostate Cancer: The OLI-P Phase 2 Clinical Trial.

BACKGROUND: Local ablative radiotherapy (aRT) of oligometastatic prostate cancer (PCa) is very promising and has become a focus of current clinical research. OBJECTIVE: We hypothesize that aRT is safe and effective in gallium-68 prostate-specific membrane antigen targeted positron emission tomography (PSMA-PET)-staged oligometastatic PCa patients. DESIGN, SETTING, AND PARTICIPANTS: A nonrandomized, prospective, investigator-initiated phase 2 trial recruited patients with oligometastatic PCa (five or fewer lymph node or osseous metastases) after local curative therapy, without significant comorbidity and androgen deprivation therapy (ADT), at two German centers from 2014 to 2018. INTERVENTION: All PSMA-PET-positive metastases were treated with aRT. No systemic therapy was initiated. OUTCOME MEASUREMENTS AND STATISTICAL ANALYSIS: The primary endpoint was treatment-related toxicity (grade ≥2) 24 mo after aRT. A one-sided single-sample test of proportions was planned to test whether the endpoint occurs in <15% of the patients. Key secondary endpoints were time to progression of prostate-specific antigen (PSA) and time to ADT, which were associated with potential prognostic factors by Cox regression. RESULTS AND LIMITATIONS: Of 72 patients, 63 received aRT (13% dropout rate). The median follow-up was 37.2 mo. No treatment-related grade ≥2 toxicity was observed 2 yr after treatment. The median time to PSA progression and time to ADT were 13.2 and 20.6 mo, respectively. Of the patients, 21.4% were free of PSA progression after 3 yr. CONCLUSIONS: It was observed that aRT is safe, and midterm PSA progression and ADT-free time were achieved in one of five patients. Randomized clinical trials are indicated to further evaluate the option of delaying ADT in selected patients. PATIENT SUMMARY: In this clinical trial, 63 patients with up to five metastases of prostate cancer without androgen deprivation therapy were included. We showed that local ablative radiotherapy is safe and that one in five patients had no recurrent prostate-specific antigen value after 3 yr. Local ablative radiotherapy might be an option to avoid systemic therapy in selected patients.

Daily Intravoxel Incoherent Motion (IVIM) In Prostate Cancer Patients During MR-Guided Radiotherapy-A Multicenter Study.

PURPOSE: Daily quantitative MR imaging during radiotherapy of cancer patients has become feasible with MRI systems integrated with linear accelerators (MR-linacs). Quantitative images could be used for treatment response monitoring. With intravoxel incoherent motion (IVIM) MRI, it is possible to acquire perfusion information without the use of contrast agents. In this multicenter study, daily IVIM measurements were performed in prostate cancer patients to identify changes that potentially reflect response to treatment. MATERIALS AND METHODS: Forty-three patients were included, treated with 20 fractions of 3 Gy on a 1.5 T MR-linac. IVIM measurements were performed on each treatment day. The diffusion coefficient (D), perfusion fraction (f), and pseudo-diffusion coefficient (D*) were calculated based on the median signal intensities in the non-cancerous prostate and the tumor. Repeatability coefficients (RCs) were determined based on the first two treatment fractions. Separate linear mixed-effects models were constructed for the three IVIM parameters. RESULTS: In total, 726 fractions were analyzed. Pre-treatment average values, measured on the first fraction before irradiation, were 1.46 × 10-3 mm2/s, 0.086, and 28.7 × 10-3 mm2/s in the non-cancerous prostate and 1.19 × 10-3 mm2/s, 0.088, and 28.9 × 10-3 mm2/s in the tumor, for D, f, and D*, respectively. The repeatability coefficients for D, f, and D* in the non-cancerous prostate were 0.09 × 10-3 mm2/s, 0.05, and 15.3 × 10-3 mm2/s. In the tumor, these values were 0.44 × 10-3 mm2/s, 0.16, and 76.4 × 10-3 mm2/s. The mixed effects analysis showed an increase in D of the tumors over the course of treatment, while remaining stable in the non-cancerous prostate. The f and D* increased in both the non-cancerous prostate and tumor. CONCLUSIONS: It is feasible to perform daily IVIM measurements on an MR-linac system. Although the repeatability coefficients were high, changes in IVIM perfusion parameters were measured on a group level, indicating that IVIM has potential for measuring treatment response.

Moderately hypofractionated radiotherapy as definitive treatment for localized prostate cancer: Pattern of practice in German-speaking countries : A survey of the Prostate Cancer Expert Panel of the German Society of Radiation Oncology (DEGRO) and the Working Party on Radiation Oncology of the German Cancer Society (DKG-ARO).

PURPOSE: Various randomized phase III clinical trials have compared moderately hypofractionated to normofractionated radiotherapy (RT). These modalities showed similar effectiveness without major differences in toxicity. This project was conducted by the Prostate Cancer Expert Panel of the German Society of Radiation Oncology (DEGRO) and the Working Party on Radiation Oncology of the German Cancer Society. We aimed to investigate expert opinions on the use of moderately hypofractionated RT as a definitive treatment for localized prostate cancer in German-speaking countries. METHODS: A 25-item, web-based questionnaire on moderate-hypofractionation RT was prepared by an internal committee. The experts of the DEGRO were asked to complete the questionnaire. RESULTS: Fourteen active members of DEGRO completed the questionnaire. The questions described indications for selecting patients eligible to receive moderate hypofractionation based on clinical and pathological factors such as age, urinary symptoms, and risk-group. The questions also collected information on the technical aspects of selection criteria, including the definition of a clinical target volume, the use of imaging, protocols for bladder and rectal filling, the choice of a fractionation schedule, and the use of image guidance. Moreover, the questionnaire collected information on post-treatment surveillance after applying moderately hypofractionated RT. CONCLUSION: Although opinions varied on the use of moderate-hypofractionation RT, the current survey reflected broad agreement on the notion that moderately hypofractionated RT could be considered a standard treatment for localized prostate cancer in German-speaking countries.

[Primary treatment of prostate cancer using 1.5 T MR-linear accelerator]. / Stellenwert des 1,5-T-MR-Linearbeschleunigers für die primäre Therapie des Prostatakarzinoms.

BACKGROUND: Hybrid devices of MR-scanners and linear accelerators (MR-Linacs) represent a new and promising extension of radiotherapeutic options for prostate cancer. The potential advantage of magnetic resonance imaging (MRI) over computed tomography (CT) for soft tissue contrast is well-known and leads to more consistent and smaller target volumes and improved normal tissue sparing. OBJECTIVES: This article presents an overview of clinical experience, indications, advantages and challenges of utilizing a 1.5 T MR-Linac in the setting of radiotherapy of prostate cancer. RESULTS: All current indications for radiotherapy of prostate cancer can be treated with an MR-Linac. The advantages include daily MR-based imaging in treatment position and daily adaption of the treatment plan on current anatomy (adaptive radiotherapy). Additionally, functional MRI sequences might be exploited to enhance treatment individualization and response assessment. Ultimately treatment on an MR-Linac might further increase the therapeutic window. The limitations of using MR-Linac include treatment complexity and the duration of each session. CONCLUSIONS: MR-Linacs expand the spectrum of radiotherapeutic options for prostate cancer. Increased precision can be reached with daily MRI-based target volume definition and plan adaption. Clinical studies are necessary to identify patient groups who would benefit most from radiotherapy on a MR-Linac.

Dose-intensified Versus Conventional-dose Salvage Radiotherapy for Biochemically Recurrent Prostate Cancer After Prostatectomy: The SAKK 09/10 Randomized Phase 3 Trial.

BACKGROUND: Salvage radiotherapy (SRT) is utilized for biochemical progression of prostate cancer after radical prostatectomy (RP). OBJECTIVE: To report the outcomes of the SAKK 09/10 trial comparing conventional and dose-intensified SRT. DESIGN, SETTING, AND PARTICIPANTS: SAKK 09/10 was a randomized, multicenter, phase 3 trial that recruited men with biochemical progression after RP. INTERVENTION: Patients were randomly assigned to conventional-dose (64 Gy) or dose-intensified SRT (70 Gy) to the prostate bed without hormonal therapy. OUTCOME MEASUREMENTS AND STATISTICAL ANALYSIS: The primary endpoint was freedom from biochemical progression (FFBP). Secondary endpoints included clinical progression-free survival (PFS), time to hormonal treatment, overall survival (OS), acute and late toxicity (Common Terminology Criteria for Adverse Events v4.0), and quality of life (QoL). RESULTS AND LIMITATIONS: Between February 2011 and April 2014, 350 patients were randomly assigned to 64 Gy (n = 175) or 70 Gy (n = 175). Median prostate-specific antigen at randomization was 0.3 ng/ml. After median follow-up of 6.2 yr, the median FFBP was 8.2 yr in the 64 Gy arm and 7.6 in the 70 Gy arm (log-rank p = 0.4), with a hazard ratio of 1.14 (95% confidence interval 0.82-1.60). The 6-year FFBP rates were 62% and 61%, respectively. No significant differences in clinical PFS, time to hormonal treatment, or OS were observed. Late grade 2 and 3 genitourinary toxicity was observed in 35 (21%) and 13 (7.9%) patients in the 64 Gy arm, and 46 (26%) and seven (4%) in the 70 Gy arm, respectively (p = 0.8). Late grade 2 and 3 gastrointestinal toxicity was observed in 12 (7.3%) and seven patients (4.2%) in the 64 Gy arm, and 35 (20%) and four (2.3%) in the 70 Gy arm, respectively (p = 0.009). There were no significant differences in QoL. CONCLUSIONS: Conventional-dose SRT to the prostate bed is sufficient in patients with early biochemical progression of prostate cancer after RP. PATIENT SUMMARY: The optimal radiation therapy dose for patients who have increased tumor markers after surgery for prostate cancer is unclear. We found that administering a higher dose only increased the gastrointestinal side effects without providing any benefits to the patient. This clinical trial is registered on ClinicalTrials.gov as NCT01272050.

Combining 68Ga-PSMA-PET/CT-Directed and Elective Radiation Therapy Improves Outcome in Oligorecurrent Prostate Cancer: A Retrospective Multicenter Study.

BACKGROUND: In case of oligo-recurrent prostate cancer (PC) following prostatectomy, 68Ga-PSMA-PET/CT can be used to detect a specific site of recurrence and to initiate metastasis-directed radiation therapy (MDT). However, large heterogeneities exist concerning doses, treatment fields and radiation techniques, with some studies reporting focal radiotherapy (RT) to PSMA-PET/CT positive lesions only and other studies using elective RT strategies. We aimed to compare oncological outcomes and toxicity between PET/CT-directed RT (PDRT) and PDRT plus elective RT (eRT; i.e. prostate bed, pelvic or paraaortal nodes) in a large retrospective multicenter study. METHODS: Data of 394 patients with oligo-recurrent 68Ga-PSMA-PET/CT-positive PC treated between 04/2013 and 01/2018 in six different academic institutions were evaluated. Primary endpoint was biochemical-recurrence-free survival (bRFS). bRFS was analyzed using Kaplan-Meier survival curves and log rank testing. Uni- and multivariate analyses were performed to determine influence of treatment parameters. RESULTS: In 204 patients (51.8%) RT was directed only to lesions seen on 68Ga-PSMA-PET/CT (PDRT), 190 patients (48.2%) received PDRT plus eRT. PDRT plus eRT was associated with a significantly improved 3-year bRFS compared to PDRT alone (53 vs. 37%; p = 0.001) and remained an independent factor in multivariate analysis (p = 0.006, HR 0.29, 95% CI 0.12-0.68). This effect was more pronounced in the subgroup of patients who were treated with PDRT and elective prostate bed radiotherapy (ePBRT) with a 3-year bRFS of 61% versus 22% (p <0.001). Acute and late toxicity grade ≥3 was 0.8% and 3% after PDRT plus eRT versus no toxicity grade ≥3 after PDRT alone. CONCLUSIONS: In this large cohort of patients with oligo-recurrent prostate cancer, elective irradiation of the pelvic lymphatics and the prostatic bed significantly improved bRFS when added to 68Ga-PSMA-PET/CT-guided focal radiotherapy. These findings need to be evaluated in a randomized controlled trial.

Salvage-Radiation Therapy and Regional Hyperthermia for Biochemically Recurrent Prostate Cancer after Radical Prostatectomy (Results of the Planned Interim Analysis).

Efforts to improve the outcome of prostate cancer (PC) patients after radical prostatectomy (RP) include adjuvant or salvage radiation therapy (SRT), but still up to 50% of patients develop a disease progression after radiotherapy (RT). Regional hyperthermia (HT) is well-known to improve tumor sensitivity to RT in several entities. Here we report on a planned interim analysis of tolerability and feasibility after recruitment of the first 50 patients of a trial combining SRT and HT. We conducted a prospective multicenter non-randomized Phase-II-Trial (HTProstate-NCT04159051) investigating the implementation of combined moderate-dose escalated SRT (70 Gy in 35 fractions) and locoregional deep HT (7-10 HT sessions). The primary endpoints were the rate of acute genitourinary (GU), gastrointestinal (GI), and HT-related toxicities, completed HT sessions (≥7), and SRT applications per protocol (≥95% of patients). The two-step design included a planned interim analysis for acute GU-, GI- and HT-specific toxicities to ensure patients' safety. Between November 2016 and December 2019, 52 patients entered into the trial. After 50 patients completed therapy and three months of follow-up, we performed the planned interim analysis. 10% of patients developed acute grade 2 GU and 4% grade 2 GI toxicities. No grade ≥3 GU or GI toxicities occurred. HT-specific symptoms grade 2 and 3 were observed in 4% and 2% of all patients. Thus, the pre-specified criteria for safety and continuation of recruitment were met. Moreover, ≥7 HT treatments were applicable, indicating the combination of SRT + HT to be feasible. Evaluation of early QoL showed no significant changes. With its observed low rate of GU and GI toxicities, moderate and manageable rates of HT-specific symptoms, and good feasibility, the combined SRT + HT seems to be a promising treatment approach for biochemical recurrence after RP in PC patients.

Prospective Image Quality and Lesion Assessment in the Setting of MR-Guided Radiation Therapy of Prostate Cancer on an MR-Linac at 1.5 T: A Comparison to a Standard 3 T MRI.

The objective of this study is to conduct a qualitative and a quantitative image quality and lesion evaluation in patients undergoing MR-guided radiation therapy (MRgRT) for prostate cancer on a hybrid magnetic resonance imaging and linear accelerator system (MR-Linac or MRL) at 1.5 Tesla. This prospective study was approved by the institutional review board. A total of 13 consecutive patients with biopsy-confirmed prostate cancer and an indication for MRgRT were included. Prior to radiation therapy, each patient underwent an MR-examination on an MRL and on a standard MRI scanner at 3 Tesla (MRI3T). Three readers (two radiologists and a radiation oncologist) conducted an independent qualitative and quantitative analysis of T2-weighted (T2w) and diffusion-weighted images (DWI). Qualitative outcome measures were as follows: zonal anatomy, capsule demarcation, resolution, visibility of the seminal vesicles, geometric distortion, artifacts, overall image quality, lesion conspicuity, and diagnostic confidence. All ratings were performed on an ordinal 4-point Likert scale. Lesion conspicuity and diagnostic confidence were firstly analyzed only on MRL. Afterwards, these outcome parameters were analyzed in consensus with the MRI3T. Quantitative outcome measures were as follows: anteroposterior and right left diameter of the prostate, lesion size, PI-RADS score (Prostate Imaging-Reporting and Data System) and apparent diffusion coefficient (ADC) of the lesions. Intergroup comparisons were computed using the Wilcoxon-sign rank test and t tests. A post-hoc regression analysis was computed for lesion evaluation. Finally, inter-/intra-reader agreement was analyzed using the Fleiss kappa and intraclass correlation coefficient. For T2w images, the MRL showed good results across all quality criteria (median 3 and 4). Furthermore, there were no significant differences between MRL and MRI3T regarding capsule demarcation or geometric distortion. For the DWI, the MRL performed significantly less than MRI3T across most image quality criteria with a median ranging between 2 and 3. However, there were no significant differences between MRL and MRI3T regarding geometric distortion. In terms of lesion conspicuity and diagnostic confidence, inter-reader agreement was fair for MRL alone (Kappa = 0.42) and good for MRL in consensus with MRI3T (Kappa = 0.708). Thus, lesion conspicuity and diagnostic confidence could be significantly improved when reading MRL images in consensus with MRI3T (Odds ratio: 9- to 11-fold for the T2w images and 5- to 8-fold for the DWI) (p < 0.001). For measures of lesion size, anterior-posterior and right-left prostate diameter, inter-reader and intersequence agreement were excellent (ICC > 0.90) and there were no significant differences between MRL and MRI3T among all three readers. In terms of Prostate Imaging Reporting and Data System (PIRADS) scoring, no significant differences were observed between MRL and MRI3T. Finally, there was a significant positive linear relationship between lesion ADC measurements (r = 0.76, p < 0.01) between the ADC values measured on both systems. In conclusion, image quality for T2w was comparable and diagnostic even without administration of spasmolytic- or contrast agents, while DWI images did not reach diagnostic level and need to be optimized for further exploitation in the setting of MRgRT. Diagnostic confidence and lesion conspicuity were significantly improved by reading MRL in consensus with MRI3T which would be advisable for a safe planning and treatment workflow. Finally, ADC measurements of lesions on both systems were comparable indicating that, lesion ADC as measured on the MRL could be used as a biomarker for evaluation of treatment response, similar to examinations using MRI3T.

Radiotherapy in nodal oligorecurrent prostate cancer.

OBJECTIVE: The current article encompasses a literature review and recommendations for radiotherapy in nodal oligorecurrent prostate cancer. MATERIALS AND METHODS: A literature review focused on studies comparing metastasis-directed stereotactic ablative radiotherapy (SABR) vs. external elective nodal radiotherapy (ENRT) and studies analyzing recurrence patterns after local nodal treatment was performed. The DEGRO Prostate Cancer Expert Panel discussed the results and developed treatment recommendations. RESULTS: Metastasis-directed radiotherapy results in high local control (often > 90% within a follow-up of 1-2 years) and can be used to improve progression-free survival or defer androgen deprivation therapy (ADT) according to prospective randomized phase II data. Distant progression after involved-node SABR only occurs within a few months in the majority of patients. ENRT improves metastases-free survival rates with increased toxicity in comparison to SABR according to retrospective comparative studies. The majority of nodal recurrences after initial local treatment of pelvic nodal metastasis are detected within the true pelvis and common iliac vessels. CONCLUSION: ENRT with or without a boost should be preferred to SABR in pelvic nodal recurrences. In oligometastatic prostate cancer with distant (extrapelvic) nodal recurrences, SABR alone can be performed in selected cases. Application of additional systemic treatments should be based on current guidelines, with ADT as first-line treatment for hormone-sensitive prostate cancer. Only in carefully selected patients can radiotherapy be initially used without additional ADT outside of the current standard recommendations. Results of (randomized) prospective studies are needed for definitive recommendations.

Management of Germ Cell Tumours of the Testes in Adult Patients: German Clinical Practice Guideline, PART II - Recommendations for the Treatment of Advanced, Recurrent, and Refractory Disease and Extragonadal and Sex Cord/Stromal Tumours and for the Management of Follow-Up, Toxicity, Quality of Life, Palliative Care, and Supportive Therapy.

OBJECTIVES: We developed the first German evidence- and consensus-based clinical guideline on diagnosis, treatment, and follow-up of germ cell tumours (GCT) of the testes in adult patients. We present the guideline content in 2 separate publications. The present second part summarizes therecommendations for the treatment of advanced disease stages and for the management of follow-up and late effects. MATERIALS AND METHODS: An interdisciplinary panel of 42 experts including 1 patient representative developed the guideline content. Clinical recommendations and statements were based on scientific evidence and expert consensus. For this purpose, evidence tables for several review questions, which were based on systematic literature searches (last search in March 2018), were provided. Thirty-one experts, who were entitled to vote, rated the final clinical recommendations and statements. RESULTS: Here we present the treatment recommendations separately for patients with metastatic seminoma and non-seminomatous GCT (stages IIA/B and IIC/III), for restaging and treatment of residual masses, and for relapsed and refractory disease stages. The recommendations also cover extragonadal and sex cord/stromal tumours, the management of follow-up and toxicity, quality-of-life aspects, palliative care, and supportive therapy. CONCLUSION: Physicians and other medical service providers who are involved in the diagnostics, treatment, and follow-up of GCT (all stages, outpatient and inpatient care as well as rehabilitation) are the users of the present guideline. The guideline also comprises quality indicators for measuring the implementation of the guideline recommendations in routine clinical care; these data will be presented in a future publication.