[Protontherapy : principles, advantages, limitations, indications, perspectives...and some Belgian peculiarities]. / La protonthérapie : principes, avantages, limitations, indications, perspectives...et quelques histoires belges.

Most radiotherapy treatments are nowadays delivered with linear accelerators producing photons. This robust radiation technique improved outstandingly during the last three decades, allowing treatments for most tumoural indications with an exquisite accuracy, a formidable effectiveness, a low toxicity, and a very low cost for the society. Therefore, the reasons for using and developing the more expensive hadron therapy and more particularly proton therapy may seem futile. In the current article targeting the general practitioners readership, we look at the principles of this innovative technique, its inherent advantages and limitations, the current and future indications, the challenges and perspectives for the future. We conclude with an overview of the Belgian landscape in terms of installation, operation, access and reimbursement procedures.

L'essentiel des traitements de radiothérapie sont délivrés à l'aide d'accélérateurs linéaires produisant des photons. La technique est robuste et a connu une évolution fulgurante ces trois dernières décennies, apportant une efficacité redoutable et une extrême précision dans de nombreuses indications tumorales, avec les avantages d'un risque de toxicité réduit et d'un coût sociétal extrêmement faible. Dès lors, quel intérêt y aurait-il à utiliser et développer des traitements de radiothérapie par hadrons, et plus particulièrement par protons, sachant que les coûts d'installation et de production sont, au bas mot, décuplés par rapport aux photons ? Dans cet article destiné en première intention aux praticiens de santé généralistes, nous abordons les principes de fonctionnement, les avantages et limitations inhérents à la technique, les indications actuelles et celles qui se profilent, les défis et perspectives à venir. Nous terminons, enfin, par un tour d'horizon du paysage belge en termes d'installation, de fonctionnement, d'accès et de modalités de remboursement.

Clinical implications of dose to functional lung volumes in the trimodality treatment of esophageal cancer.

BACKGROUND: Trimodality treatment, i.e., neoadjuvant chemoradiotherapy (nCRT) followed by surgery, for locally advanced esophageal cancer (EC) improves overall survival but also increases the risk of postoperative pulmonary complications. Here, we tried to identify a relation between dose to functional lung volumes (FLV) as determined by 4D-CT scans in EC patients and treatment-related lung toxicity. MATERIALS AND METHODS: All patients with EC undergoing trimodality treatment between 2017 and 2022 in UZ Leuven and scanned with 4D-CT-simulation were selected. FLVs were determined based on Jacobian determinants of deformable image registration between maximum inspiration and expiration phases. Dose/volume parameters of the anatomical lung volume (ALV) and FLV were compared between patients with versus without postoperative pulmonary complications. Results of pre- and post-nCRT pulmonary function tests (PFTs) were collected and compared in relation to radiation dose. RESULTS: Twelve out of 51 EC patients developed postoperative pulmonary complications. ALV was smaller while FLV10Gy and FLV20Gy were larger in patients with complications (respectively 3141 ± 858mL vs 3601 ± 635mL, p = 0.025; 360 ± 216mL vs 264 ± 139mL, p = 0.038; 166 ± 106mL vs 118 ± 63mL, p = 0.030). No differences in ALV dose-volume parameters were detected. Baseline FEV1 and TLC were significantly lower in patients with complications (respectively 90 ± 17%pred vs 102 ± 20%pred, p = 0.033 and 93 ± 17%pred vs 110 ± 13%pred, p = 0.001), though no other PFTs were significantly different between both groups. DLCO was the only PFT that had a meaningful decrease after nCRT (85 ± 17%pred vs 68 ± 15%pred, p < 0.001) but was not related to dose to ALV/FLV. CONCLUSION: Small ALV and increasing FLV exposed to intermediate (10 to 20 Gy) dose are associated to postoperative pulmonary complications. Changes of DLCO occur during nCRT but do not seem to be related to radiation dose to ALV or FLV. This information could attribute towards toxicity risk prediction and reduction strategies for EC.

"Scan-(pre)Plan-Treat" Workflow for Bone Metastases Using the Ethos Therapy System: A Single-Center, In Silico Experience.

Purpose: To report on the accuracy of automated delineation, treatment plan quality, and duration of an in-silico "scan-(pre)plan-treat" (SPT) workflow for vertebral bone metastases using a 1 × 8 Gy regimen. Method and Materials: The cloud-based emulator system of the Ethos therapy system was used to adapt an organ-at-risk-sparing preplan created on the diagnostic CT to the anatomy-of-the-day using the cone beam CT made before treatment. Results: SPT using the Ethos emulator system resulted in relatively good coverage of the PTV and acceptable dose to the OAR. Delivery time and plan homogeneity was the best for 7-field IMRT plan template. Conclusions: A SPT workflow formula results in a highly conformal treatment delivery while maintaining an acceptable timeframe for the patient on the treatment couch.

From once-weekly to semi-weekly whole prostate gland stereotactic radiotherapy with focal boosting: Primary endpoint analysis of the multicenter phase II hypo-FLAME 2.0 trial.

BACKGROUND AND PURPOSE: The hypo-FLAME trial showed that once-weekly (QW) focal boosted prostate stereotactic body radiotherapy (SBRT) is associated with acceptable acute genitourinary (GU) and gastrointestinal (GI) toxicity. Currently, we investigated the safety of reducing the overall treatment time (OTT) of focal boosted prostate SBRT from 29 to 15 days. MATERIAL AND METHODS: Patients with intermediate- and high-risk prostate cancer were treated with SBRT delivering 35 Gy in 5 fractions to the whole prostate gland with an iso-toxic boost up to 50 Gy to the intraprostatic lesion(s) in a semi-weekly (BIW) schedule. The primary endpoint was radiation-induced acute toxicity (CTCAE v5.0). Changes in quality of life (QoL) were examined in terms of proportions achieving a minimal clinically important change (MCIC). Finally, acute toxicity and QoL scores of the BIW schedule were compared with the results of the prior QW hypo-FLAME schedule (n = 100). RESULTS: Between August 2020 and February 2022, 124 patients were enrolled and treated BIW. No grade ≥3 GU or GI toxicity was observed. The 90-days cumulative incidence of grade 2 GU and GI toxicity rates were 47.5% and 7.4%, respectively. Patients treated QW scored significant less grade 2 GU toxicity (34.0%, p = 0.01). No significant differences in acute GI toxicity were observed. Furthermore, patients treated QW had a superior acute bowel and urinary QoL. CONCLUSION: Semi-weekly prostate SBRT with iso-toxic focal boosting is associated with acceptable acute GU and GI toxicity. Based on the comparison between the QW and BIW schedule, patients should be counselled regarding the short-term advantages of a more protracted schedule. Registration number ClinicalTrials.gov: NCT04045717.

The use of electronic Patient Reported Outcomes in follow-up after palliative radiotherapy: A survey study in Belgium.

Objective: Electronic Patient-Reported Outcome Measures (ePROMs) could be used to monitor patients' symptoms after treatment. However, ePROM implementation in clinical practice has been challenging, especially in (palliative) radiation oncology. The aim of this study was to explore the opinions of healthcare providers (HCP) active in radiation oncology in Belgium on the use of ePROMs for symptom follow-up after palliative radiotherapy. Methods: An anonymous online survey was conducted with different HCP in radiation oncology in Belgium. Participants were recruited through several professional organizations with approximately 390 members actively working in the field of radiation oncology. The survey used was a self-developed questionnaire, based on existing literature on implementation of (e)PROMs in cancer care, our previous research on this topic as well as our personal experience in the field of oncology and palliative care. Results: Of the 128 respondents, 26% had experience with ePROMs in clinical practice. Eighty-four percent considered ePROMs beneficial for patients' health and symptom knowledge, symptom self-management and active participation in care. ePROMs could help HCP to focus on detection of relevant symptoms and improve their management. Almost 75% were willing to implement and use ePROMs. Assigning ePROM introduction and follow-up to a dedicated person, such as a nurse navigator, was suggested to promote ePROM implementation and use in clinical practice. Conclusion: Despite limited experience with ePROMs in clinical care for palliative radiotherapy patients, the majority of respondents is willing to implement and use ePROMs for this particular patient population. Innovation: This is one of the first studies specifically focusing on experiences and opinions of HCP in radiation oncology on the use of ePROMs for symptom follow-up in palliative radiotherapy. HCP should be actively involved in implementation of ePROMs after palliative radiotherapy, to translate their vision of their ideals in practice.

Potential Molecular Mechanisms behind the Ultra-High Dose Rate "FLASH" Effect.

FLASH radiotherapy, or the delivery of a dose at an ultra-high dose rate (>40 Gy/s), has recently emerged as a promising tool to enhance the therapeutic index in cancer treatment. The remarkable sparing of normal tissues and equivalent tumor control by FLASH irradiation compared to conventional dose rate irradiation­the FLASH effect­has already been demonstrated in several preclinical models and even in a first patient with T-cell cutaneous lymphoma. However, the biological mechanisms responsible for the differential effect produced by FLASH irradiation in normal and cancer cells remain to be elucidated. This is of great importance because a good understanding of the underlying radiobiological mechanisms and characterization of the specific beam parameters is required for a successful clinical translation of FLASH radiotherapy. In this review, we summarize the FLASH investigations performed so far and critically evaluate the current hypotheses explaining the FLASH effect, including oxygen depletion, the production of reactive oxygen species, and an altered immune response. We also propose a new theory that assumes an important role of mitochondria in mediating the normal tissue and tumor response to FLASH dose rates.

Urethral and bladder dose-effect relations for late genitourinary toxicity following external beam radiotherapy for prostate cancer in the FLAME trial.

PURPOSE OR OBJECTIVES: The FLAME trial (NCT01168479) showed that by adding a focal boost to conventional fractionated EBRT in the treatment of localized prostate cancer, the five-year biochemical disease-free survival increased, without significantly increasing toxicity. The aim of the present study was to investigate the association between radiation dose to the bladder and urethra and genitourinary (GU) toxicity grade ≥2 in the entire cohort. MATERIAL AND METHODS: The dose-effect relations of the urethra and bladder dose, separately, and GU toxicity grade ≥2 (CTCAE 3.0) up to five years after treatment were assessed. A mixed model analysis for repeated measurements was used, adjusting for age, diabetes mellitus, T-stage, baseline GU toxicity grade ≥1 and institute. Additionally, the association between the dose and separate GU toxicity subdomains were investigated. RESULTS: Dose-effect relations were observed for the dose (Gy) to the bladder D2 cm3 and urethra D0.1 cm3, with adjusted odds ratios of 1.14 (95% CI 1.12-1.16, p < 0.0001) and 1.12 (95% CI 1.11-1.14, p < 0.0001), respectively. Additionally, associations between the dose to the urethra and bladder and the subdomains urinary frequency, urinary retention and urinary incontinence were observed. CONCLUSION: Further increasing the dose to the bladder and urethra will result in a significant increase in GU toxicity following EBRT. Focal boost treatment plans should incorporate a urethral dose-constraint. Further treatment optimization to increase the focal boost dose without increasing the dose to the urethra and other organs at risk should be a focus for future research, as we have shown that a focal boost is beneficial in the treatment of prostate cancer.

Using ePROMs for follow-up after palliative radiotherapy: An exploratory study with patients and health care providers.

OBJECTIVES: Patients treated with palliative radiotherapy may experience symptoms decreasing their quality of life. Electronic patient-reported outcome measures (ePROMs) could provide an opportunity to follow-up patients after treatment. METHODS: A mixed-method study was performed using self-constructed questionnaires, focus groups and interviews with patients and health care professionals (HCP). A qualitative approach was used to code the data. RESULTS: Forty-two patients, 21 radiation-oncologists, 15 general practitioners (GPs) and 24 home-care nurses completed a questionnaire. Ten patients, 6 radiation-oncologists, 14 GPs and 5 nurses were interviewed or participated in a focus group. Although patients and HCP are satisfied with current care, they believe ePROMs could improve follow-up, communication, continuity of care and self-management of symptoms. An easy to use, versatile ePROM platform seems to be important for successful implementation. Self-care tips and contact information should be added to relevant ePROM-questions, on both physical and psychological symptoms. CONCLUSION: Patients and HCP agree that ePROMs could improve systematical clinical follow-up after palliative radiotherapy, with self-management support being the primary objective of such a system. Practice implications ePROMs after palliative radiotherapy seem feasible, the exact patient population that could benefit the most will need to be explored further; as the palliative population is very diverse.

Patterns of Failure Following External Beam Radiotherapy With or Without an Additional Focal Boost in the Randomized Controlled FLAME Trial for Localized Prostate Cancer.

BACKGROUND: Focal dose escalation in external beam radiotherapy (EBRT) showed an increase in 5-yr biochemical disease-free survival in the Focal Lesion Ablative Microboost in Prostate Cancer (FLAME) trial. OBJECTIVE: To analyze the effect of a focal boost to intraprostatic lesions on local failure-free survival (LFS) and regional + distant metastasis-free survival (rdMFS). DESIGN, SETTING, AND PARTICIPANTS: Patients with intermediate- or high-risk localized prostate cancer were included in FLAME, a phase 3, multicenter, randomized controlled trial. INTERVENTION: Standard treatment of 77 Gy to the entire prostate in 35 fractions was compared to an additional boost to the macroscopic tumor of up to 95 Gy during EBRT. OUTCOME MEASUREMENTS AND STATISTICAL ANALYSIS: LFS and rdMFS, measured via any type of imaging, were compared between the treatment arms using Kaplan-Meier and Cox regression analyses. Dose-response curves were created for local failure (LF) and regional + distant metastatic failure (rdMF) using logistic regression. RESULTS AND LIMITATIONS: A total of 571 patients were included in the FLAME trial. Over median follow-up of 72 mo (interquartile range 58-86), focal boosting decreased LF (hazard ratio [HR] 0.33, 95% confidence interval [CI] 0.14-0.78) and rdMF (HR 0.58, 95% CI 0.35-0.93). Dose-response curves showed that a greater dose to the tumor resulted in lower LF and rdMF rates. CONCLUSIONS: A clear dose-response relation for LF and rdMF was observed, suggesting that adequate focal dose escalation to intraprostatic lesions prevents undertreatment of the primary tumor, resulting in an improvement rdMF. PATIENT SUMMARY: Radiotherapy is a treatment option for high-risk prostate cancer. The FLAME trial has shown that a high dose specifically targeted at the tumor within the prostate will result in better disease outcome, with less likelihood of regional and distant disease spread. The FLAME trial is registered on ClinicalTrials.gov as NCT01168479.

Anorectal dose-effect relations for late gastrointestinal toxicity following external beam radiotherapy for prostate cancer in the FLAME trial.

BACKGROUND AND PURPOSE: The phase III FLAME trial (NCT01168479) showed an increase in five-year biochemical disease-free survival, with no significant increase in toxicity when adding a focal boost to external beam radiotherapy (EBRT) for localized prostate cancer [Kerkmeijer et al. JCO 2021]. The aim of this study was to investigate the association between delivered radiation dose to the anorectum and gastrointestinal (GI) toxicity (grade ≥2). MATERIAL AND METHODS: All patients in the FLAME trial were analyzed, irrespective of treatment arm. The dose-effect relation of the anorectal dose parameters (D2cm3 and D50%) and GI toxicity grade ≥2 in four years of follow-up was assessed using a mixed model analysis for repeated measurements, adjusted for age, cardiovascular disease, diabetes mellitus, T-stage, baseline toxicity grade ≥1, hormonal therapy and institute. RESULTS: A dose-effect relation for D2cm3 and D50% was observed with adjusted odds ratios of 1.17 (95% CI 1.13-1.21, p < 0.0001) and 1.20 (95% CI 1.14-1.25, p < 0.0001) for GI toxicity, respectively. CONCLUSION: Although there was no difference in toxicity between study arms, a higher radiation dose to the anorectum was associated with a statistically significant increase in GI toxicity following EBRT for prostate cancer. This dose-effect relation was present for both large and small anorectal volumes. Therefore, further increase in dose to the anorectum should be weighed against the benefit of focal dose escalation for prostate cancer.

68Ga-PSMA-11 PET, 18F-PSMA-1007 PET, and MRI for Gross Tumor Volume Delineation in Primary Prostate Cancer: Intermodality and Intertracer Variability.

PURPOSE: To assess the intermodality and intertracer variability of gallium-68 (68Ga)- or fluorine-18 (18F)-labeled prostate-specific membrane antigen (PSMA) positron emission tomography (PET) and biparametric magnetic resonance imaging (bpMRI)-based gross tumor volume (GTV) delineation for focal boosting in primary prostate cancer. METHODS: Nineteen prospectively enrolled patients with prostate cancer underwent a PSMA PET/MRI scan, divided into a 1:1 ratio between 68Ga-PSMA-11 and 18F-PSMA-1007, before radical prostatectomy (IWT140193). Four delineation teams performed manual contouring of the GTV based on bpMRI and PSMA PET imaging, separately. Index lesion coverage (overlap%) and interobserver variability were assessed. Furthermore, the distribution of the voxelwise normalized standardized uptake values (SUV%) was determined for the majority-voted (>50%) GTV (GTVmajority) and whole prostate gland to investigate intertracer variability. The median patientwise SUV% contrast ratio (SUV%-CR, calculated as median GTVmajority SUV% / median prostate gland without GTVmajority SUV%) was calculated according to the tracer used. RESULTS: A significant difference in overlap% favoring PSMA PET compared with bpMRI was found in the 18F subgroup (median, 63.0% vs 53.1%; P = .004) but was not present in the 68Ga subgroup (32.5% vs 50.6%; P = .100). Regarding interobserver variability, measured Sørensen-Dice coefficients (0.58 vs 0.72) and calculated mean distances to agreement (2.44 mm vs 1.22 mm) were statistically significantly lower and higher, respectively, for the 18F cohort compared with the 68Ga cohort. For the bpMRI-based delineations, the median Sørensen-Dice coefficient and mean distance to agreement were 0.63 and 1.76 mm, respectively. Median patientwise SUV%-CRs of 1.8 (interquartile range [IQR], 1.6-2.7) for 18F-PSMA and 3.3 (IQR, 2.7-5.9) for 68Ga-PSMA PET images were found. CONCLUSIONS: Both MRI and PSMA PET provided consistent intraprostatic GTV lesion detection. However, the PSMA tracer seems to have a major influence on the contour characteristics, owing to an apparent difference in SUV% distribution in the prostate gland.

Focal Boost to the Intraprostatic Tumor in External Beam Radiotherapy for Patients With Localized Prostate Cancer: Results From the FLAME Randomized Phase III Trial.

PURPOSE: This study investigates whether focal boosting of the macroscopic visible tumor with external beam radiotherapy increases biochemical disease-free survival (bDFS) in patients with localized prostate cancer. PATIENTS AND METHODS: In the phase III, multicenter, randomized controlled Focal Lesion Ablative Microboost in Prostate Cancer trial, 571 patients with intermediate- and high-risk prostate cancer were enrolled between 2009 and 2015. Patients assigned to standard treatment received 77 Gy (fractions of 2.2 Gy) to the entire prostate. The focal boost arm received an additional simultaneous integrated focal boost up to 95 Gy (fractions up to 2.7 Gy) to the intraprostatic lesion visible on multiparametric magnetic resonance imaging. Organ at risk constraints were prioritized over the focal boost dose. The primary end point was 5-year bDFS. Secondary end points were disease-free survival (DFS), distant metastases-free survival, prostate cancer-specific survival, overall survival, toxicity, and health-related quality of life. RESULTS: Median follow-up was 72 months. Biochemical DFS was significantly higher in the focal boost compared with the standard arm (hazard ratio 0.45, 95% CI, 0.28 to 0.71, P < .001). At 5-year follow-up bDFS was 92% and 85%, respectively. We did not observe differences in prostate cancer-specific survival (P = .49) and overall survival (P = .50). The cumulative incidence of late genitourinary and GI toxicity grade ≥ 2 was 23% and 12% in the standard arm versus 28% and 13% in the focal boost arm, respectively. Both for late toxicity as health-related quality of life, differences were small and not statistically significant. CONCLUSION: The addition of a focal boost to the intraprostatic lesion improved bDFS for patients with localized intermediate- and high-risk prostate cancer without impacting toxicity and quality of life. The Focal Lesion Ablative Microboost in Prostate Cancer study shows that a high focal boost strategy to improve tumor control while respecting organ at risk dose constraints is effective and safe.

Optimal 68Ga-PSMA and 18F-PSMA PET window levelling for gross tumour volume delineation in primary prostate cancer.

PURPOSE: This study proposes optimal tracer-specific threshold-based window levels for PSMA PET-based intraprostatic gross tumour volume (GTV) contouring to reduce interobserver delineation variability. METHODS: Nine 68Ga-PSMA-11 and nine 18F-PSMA-1007 PET scans including GTV delineations of four expert teams (GTVmanual) and a majority-voted GTV (GTVmajority) were assessed with respect to a registered histopathological GTV (GTVhisto) as the gold standard reference. The standard uptake values (SUVs) per voxel were converted to a percentage (SUV%) relative to the SUVmax. The statistically optimised SUV% threshold (SOST) was defined as those that maximises accuracy for threshold-based contouring. A leave-one-out cross-validation receiver operating characteristic (ROC) curve analysis was performed to determine the SOST for each tracer. The SOST analysis was performed twice, first using the GTVhisto contour as training structure (GTVSOST-H) and second using the GTVmajority contour as training structure (GTVSOST-MA) to correct for any limited misregistration. The accuracy of both GTVSOST-H and GTVSOST-MA was calculated relative to GTVhisto in the 'leave-one-out' patient of each fold and compared with the accuracy of GTVmanual. RESULTS: ROC curve analysis for 68Ga-PSMA-11 PET revealed a median threshold of 25 SUV% (range, 22-27 SUV%) and 41 SUV% (40-43 SUV%) for GTVSOST-H and GTVSOST-MA, respectively. For 18F-PSMA-1007 PET, a median threshold of 42 SUV% (39-45 SUV%) for GTVSOST-H and 44 SUV% (42-45 SUV%) for GTVSOST-MA was found. A significant pairwise difference was observed when comparing the accuracy of the GTVSOST-H contours with the median accuracy of the GTVmanual contours (median, - 2.5%; IQR, - 26.5-0.2%; p = 0.020), whereas no significant pairwise difference was found for the GTVSOST-MA contours (median, - 0.3%; IQR, - 4.4-0.6%; p = 0.199). CONCLUSIONS: Threshold-based contouring using GTVmajority-trained SOSTs achieves an accuracy comparable with manual contours in delineating GTVhisto. The median SOSTs of 41 SUV% for 68Ga-PSMA-11 PET and 44 SUV% for 18F-PSMA-1007 PET form a base for tracer-specific window levelling. TRIAL REGISTRATION: Clinicaltrials.gov ; NCT03327675; 31-10-2017.

Variation in adjuvant and early salvage radiotherapy after robot-assisted radical prostatectomy for prostate cancer: a population-based cohort study.

Purpose: The primary aim of the study was to assess the association between having a radiotherapy (RT) department on-site at the surgical centre and the performed postoperative treatment strategy for prostate cancer (PCa) patients. According to the current international guidelines, adjuvant radiotherapy (ART) or a regular prostate-specific antigen (PSA)-based follow-up with (early) salvage radiotherapy ((e)SRT) if needed is recommended in case of adverse pathological characteristics.Material and methods: Prospective data on consecutive robot-assisted radical prostatectomy (RARP) patients in Belgium from 2009 to 2016 were identified in the Belgian Robotic-Assisted-Laparoscopic-Prostatectomy (Be-RALP) database. Multivariable regression was used to evaluate patient- and facility-related factors associated with postoperative radiation treatment.Results: 2072 patients undergoing a RARP, suffering at least one of the following adverse pathological features, i.e., extracapsular extension (ECE), seminal vesicle invasion (SVI) or positive section margins (PSM), and with registered follow-up until 24 months were enrolled. After RARP, ART was applied to 9.1% and (e)SRT to 12.6% of the patients. Multivariable analysis demonstrated that patients were more likely to receive ART or (e)SRT if they were operated in a hospital with a RT department on-site (odds ratio, ART: 1.49 [1.07-2.07]; (e)SRT: 1.55 [1.16-2.06]). Furthermore, the presence of higher tumour category (T-category) and/or PSM on final pathology was associated with a higher chance of getting ART and (e)SRT (p < .01).Conclusion: Variations in ART and (e)SRT are not only driven by patient-related characteristics. In our nationwide cohort, the availability of a RT department on-site at the surgical centre was found to be an independent predictor for ART and (e)SRT, with a 1.5 times higher odds of receiving postoperative RT during the first 24 months after surgery.

Primary endpoint analysis of the multicentre phase II hypo-FLAME trial for intermediate and high risk prostate cancer.

BACKGROUND AND PURPOSE: Local recurrences after radiotherapy for prostate cancer (PCa) often originate at the location of the macroscopic tumour(s). Since PCa cells are known to be sensitive to high fraction doses, hypofractionated whole gland stereotactic body radiotherapy (SBRT) in conjunction with a simultaneous ablative microboost to the macroscopic tumour(s) within the prostate could be a way to reduce the risk of local failure. We investigated the safety of this treatment strategy. MATERIALS AND METHODS: Patients with intermediate or high risk PCa were enrolled in a prospective phase II trial, called hypo-FLAME. All patients were treated with extreme hypofractionated doses of 35 Gy in 5 weekly fractions to the whole prostate gland with an integrated boost up to 50 Gy to the multiparametric (mp) MRI-defined tumour(s). Treatment-related toxicity was measured using the CTCAE v4.0. The primary endpoint of the trial was treatment-related acute toxicity. RESULTS: Between April 2016 and December 2018, 100 men were treated in 4 academic centres. All patients were followed up for a minimum of 6 months. The median mean dose delivered to the visible tumour nodule(s) on mpMRI was 44.7 Gy in this trial. No grade ≥3 acute genitourinary (GU) or gastrointestinal (GI) toxicity was observed. Furthermore, 90 days after start of treatment, the cumulative acute grade 2 GU and GI toxicity rates were 34.0% and 5.0%, respectively. CONCLUSION: Simultaneous focal boosting to the macroscopic tumour(s) in addition to whole gland prostate SBRT is associated with acceptable acute GU and GI toxicity.

Development and External Validation of a Multiparametric Magnetic Resonance Imaging and International Society of Urological Pathology Based Add-On Prediction Tool to Identify Prostate Cancer Candidates for Pelvic Lymph Node Dissection.

PURPOSE: We sought to expand current prediction tools for lymph node invasion in patients with prostate cancer using current state-of-the-art available tumor information, including multiparametric magnetic resonance imaging based tumor stage and detailed biopsy information. MATERIALS AND METHODS: We selected patients with prostate cancer for study who had available registered information on ISUP (International Society of Urological Pathology) based biopsy grading and multiparametric magnetic resonance imaging, and who had undergone radical prostatectomy with extended pelvic lymph node dissection. We developed a lymph node invasion prediction tool in 420 patients and externally validated it in 187. A concordance index was estimated to quantify the discriminative performance of the model. RESULTS: In the development cohort a median of 21 lymph nodes were removed per patient and 71 patients (16.9%) were diagnosed with lymph node invasion. Statistically significant predictors of lymph node invasion were the initial prostate specific antigen value, multiparametric magnetic resonance imaging based T stage, maximum tumor length in 1 core in mm and ISUP grade group corresponding to the maximum tumor involvement in 1 core. The predictive accuracy of this lymph node invasion prediction tool was 79.7% after fivefold internal cross validation and 72.5% after external validation. CONCLUSIONS: We report a contemporary, externally validated prediction tool for lymph node invasion in patients with prostate cancer. This prediction tool is a response to the paradigm shift from systematic to targeted biopsies by incorporating additional core specific biopsy information instead of the percent of positive cores. This new tool will also overcome stage migration, which is a potential risk when multiparametric magnetic resonance imaging information is used in digital rectal examination based nomograms.

Targeting the Hedgehog pathway in combination with X­ray or carbon ion radiation decreases migration of MCF­7 breast cancer cells.

The use of carbon ion therapy for cancer treatment is becoming more widespread due to the advantages of carbon ions compared with X­rays. Breast cancer patients may benefit from these advantages, as the surrounding healthy tissues receive a lower dose, and the increased biological effectiveness of carbon ions can better control radioresistant cancer cells. Accumulating evidence indicates that the Hedgehog (Hh) pathway is linked to the development and progression of breast cancer, as well as to resistance to X­irradiation and the migratory capacity of cancer cells. Hence, there is an increasing interest in targeting the Hh pathway in combination with radiotherapy. Several studies have already investigated this treatment strategy with conventional radiotherapy. However, to the best of our knowledge, the combination of Hh inhibitors with particle therapy has not yet been explored. The aim of the present study was to investigate the potential of the Hh inhibitor GANT61 as an effective modulator of radiosensitivity and migration potential in MCF­7 breast cancer cells, and compare potential differences between carbon ion irradiation and X­ray exposure. Although Hh targeting was not able to radiosensitise cells to any radiation type used, the combination of GANT61 with X­rays or carbon ions (energy: 95 MeV/n; linear energy transfer: 73 keV/µm) was more effective in decreasing MCF­7 cell migration compared with either radiation type alone. Gene expression of the Hh pathway was affected to different degrees in response to X­ray and carbon ion irradiation, as well as in response to the combination of GANT61 with irradiation. In conclusion, combining Hh inhibition with radiation (X­rays or carbon ions) more effectively decreased breast cancer cell migration compared with radiation treatment alone.

Stereotactic body radiation therapy with optional focal lesion ablative microboost in prostate cancer: Topical review and multicenter consensus.

Stereotactic body radiotherapy (SBRT) for prostate cancer (PCa) is gaining interest by the recent publication of the first phase III trials on prostate SBRT and the promising results of many other phase II trials. Before long term results became available, the major concern for implementing SBRT in PCa in daily clinical practice was the potential risk of late genitourinary (GU) and gastrointestinal (GI) toxicity. A number of recently published trials, including late outcome and toxicity data, contributed to the growing evidence for implementation of SBRT for PCa in daily clinical practice. However, there exists substantial variability in delivering SBRT for PCa. The aim of this topical review is to present a number of prospective trials and retrospective analyses of SBRT in the treatment of PCa. We focus on the treatment strategies and techniques used in these trials. In addition, recent literature on a simultaneous integrated boost to the tumor lesion, which could create an additional value in the SBRT treatment of PCa, was described. Furthermore, we discuss the multicenter consensus of the FLAME consortium on SBRT for PCa with a focal boost to the macroscopic intraprostatic tumor nodule(s).