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Purpose: This study aimed to develop and validate a Monte Carlo (MC) model for the Papillon+ contact x-ray brachytherapy (CXB) device, producing 50 kilovolt (kV) X-rays, specifically focusing on its application with a 25 mm diameter rectal applicator for contact therapy., Material and Methods: The validation process involved depth dose and transverse dose profile measurements using EBT3 gafchromic films positioned in a plastic water low energy range phantom. The half-value layer (HVL) was further measured and derived from the simulated X-ray spectra., Results: Excellent agreement within ±2% was achieved between the measured and simulated on-axis depth dose curves for the 25 mm rectal applicator. Transverse dose profile measurements showed a high level of agreement between the simulation and measurements, on average 3.1% in contact with the applicator at the surface of the phantom and on average 1.7% at 10 mm depth. A close agreement within 5.5% was noticed concerning the HVL between the measurement and simulation. The simulated gamma spectra and 2D-dose distribution demonstrated a soft X-ray energy spectrum and a uniform dose distribution in contact with the applicator., Conclusions: An MC model was successfully developed for the Papillon+ eBT device with a 25 mm diameter rectal applicator. The validated model, with its demonstrated accuracy in depth dose and transverse dose profile simulations, is a valuable tool for quality assurance and patient safety and, in a later phase, may be used for treatment planning, dose calculations and tissue inhomogeneity corrections., (Copyright © 2024 American Brachytherapy Society. Published by Elsevier Inc. All rights reserved.)

Purpose: To develop an approach to the diagnosis and treatment of prostate cancer using one platform for fusion biopsy, followed by focal gland ablation utilizing permanent prostate brachytherapy with and without a rectal spacer., Material and Methods: Prostate phantoms containing multiparametric magnetic resonance imaging (mpMRI) regions of interest (ROI) underwent fusion biopsy, followed by image co-registration of positive sites to a treatment planning brachytherapy program. A partial hemi-ablation and both posterior lobes using a Mick applicator and linked stranded seeds were simulated. Dummy sources were modeled as iodine-125 ( 125 I) with a prescribed dose of at least 210 Gy to gross tumor (GTV) and clinical target volume (CTV), as defined by mpMRI visible ROI and surrounding negative biopsy sites. Computer tomograms (CT) were performed post-implant prior to and after rectal spacer insertion. Different prostate and rectal constraints were compared with and without the spacer., Results: The intra-operative focal volumes of CTV ranged from 6.2 to 14.9 cc (mean, 11.3 cc), and the ratio of focal volume/whole prostate volume ranged between 0.19 and 0.42 (mean, 0.31). The intra- and post-operative mean focal D 90 of GTV, CTV, and for the entire prostate gland was 265 Gy and 235 Gy, 214 Gy and 213 Gy, and 66.1 Gy and 57 Gy, respectively. On average, 13 mm separation was achieved between the prostate and the rectum (range, 12-14 mm) on post-operative CT. The mean doses in Gy to 2 cc of the rectum (D 2cc ) without spacer vs. with spacer were 39.8 Gy vs. 32.6 Gy, respectively., Conclusions: Doses above 200 Gy and the implantation of seeds in clinically significant region for focal therapy in phantoms are feasible. All rectal dosimetric parameters improved for the spacer implants, as compared with the non-spacer implants. Further validation of this concept is warranted in clinical trials., (Copyright © 2024 Termedia.)

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%., (Copyright © 2023 Elsevier Inc. All rights reserved.)

Background and Purpose: Dose-escalation in rectal cancer (RCa) may result in an increased complete response rate and thereby enable omission of surgery and organ preservation. In order to implement dose-escalation, it is crucial to develop a technique that allows for accurate image-guided radiotherapy. The aim of the current study was to determine the performance of a novel liquid fiducial marker (BioXmark®) in RCa patients during the radiotherapy course by assessing its positional stability on daily cone-beam CT (CBCT), technical feasibility, visibility on different imaging modalities and safety., Materials and Methods: Prospective, non-randomized, single-arm feasibility trial with inclusion of twenty patients referred for neoadjuvant chemoradiotherapy for locally advanced RCa. Primary study endpoint was positional stability on CBCT. Furthermore, technical aspects, safety and clinical performance of the marker, such as visibility on different imaging modalities, were evaluated., Results: Seventy-four markers from twenty patients were available for analysis. The marker was stable in 96% of the cases. One marker showed clinically relevant migration, one marker was lost before start of treatment and one marker was lost during treatment. Marker visibility was good on computed tomography (CT) and CBCT, and moderate on electronic portal imaging ( EPI ). Marker visibility on magnetic resonance imaging (MRI) was poor during response evaluation., Conclusion: The novel liquid fiducial marker demonstrated positional stability. We provide evidence of the feasibility of the novel fiducial marker for image-guided radiotherapy on daily cone beam CT for RCa patients., Competing Interests: The authors declare the following financial interests/personal relationships which may be considered as potential competing interests: Authors Berbée, Verhaegen and Van Limbergen hold a patent for a rectal brachytherapy applicator: “Endorectal probe device for effecting radiation treatment of colorectal cancerous tissue in the rectum of a human or animal subject.”, filed December 2016, F. Verhaegen, M. Bellezzo, E. van Limbergen, M. Berbée, B. Reniers, G. Fonseca, EP16204735. The patent has been licensed to Varian Medical Systems, Inc. The conduction of the trial was funded by Nanovi and the BioXmark® fiducials were provided without costs. Nanovi was not involved in the study design, collection, analysis and interpretation of data, writing of the manuscript or the decision to submit the manuscript for publication., (© 2022 MAASTRO.)

Introduction: The various rectal endoluminal radiation techniques all have steep, but different, dose gradients. In rectal contact brachytherapy (CXB) doses are typically prescribed and reported to the applicator surface and not to the gross tumor volume (GTV), clinical target volume (CTV) or organs at risk (OAR), which is crucial to understand tumor response and toxicity rates. To quantify the above-described problem, we performed a dose modeling study using a fixed prescription dose at the surface of the applicator and varied tumor response scenarios., Methods: Endorectal ultrasound-based 3D-volume-models of rectal tumors and the rectal wall were used to simulate the delivered dose to GTV, CTV and the rectal wall layers, assuming treatment with Maastro HDR contact applicator for rectal cancer with a fixed prescription dose to the applicator surface (equivalent to 3 × 30 Gy CXB) and various response scenarios., Results: An identical prescribed dose to the surface of the applicator resulted in a broad range of doses delivered to the GTV, CTV and the uninvolved intestinal wall. For example, the equieffective dose in 2 Gy per fraction (EQD2) D90% of the GTV varied between 63 and 231 Gy, whereas the EQD2 D2cc of the rectal wall varied between 97 and 165 Gy., Conclusion: Doses prescribed at the surface are not representative of the dose received by the tumor and the bowel wall. This stresses the relevance of dose reporting and prescription to GTV and CTV volumes and OAR in order to gain insight between delivered dose, local control and toxicity and to optimize treatment protocols., (Copyright © 2022 American Brachytherapy Society. Published by Elsevier Inc. All rights reserved.)

Aim: To determine a dose response relationship of disintegration of a hyaluronic acid (HA) and hyaluronidase (HAS) used in prostate cancer radiotherapy., Materials and Methods: Five in-vitro models are applicated with 3 ml (ml) HA. For dissolution varying doses of HAS were used: 6 ml, 3 ml, 1.5 ml, and 0 ml. One ml contains 150 International Units (IU). Each HAS was added with saline till the complementary amount of 6 ml. One phantom was solely implanted with a HA 3 ml acting as a control. Length, width and height were measured on different time points: 1st day 4 times, 2nd day 3 times, third day 2 times, and then once daily during one week, with a final measurement 2 weeks after implantation. The experiments were performed in duplicate to exclude variations and confirm the results., Results: The fastest dissolution was observed with the highest concentration of HAS, already observed at the first time point 2 h after implantation, with volume decrease of 50% on the second day, and less than 1 ml residue (33%) on day 4. The 2 other concentrations of HAS also showed a volume decrease, with less than 2 ml (66%) on day 4. All the applied quantities of HAS are observed with a residue of less than 1 ml after 7 days. After 14 days the control phantom and the saline filled one remains on steady state volume (3 ml)., Conclusions: A dose response was observed by HAS injection: highest volumes of HAS dissolute most swiftly. Using a ratio of HA:HAS of 1:2 results in a decrease to half of initial volume within 24 h. This is of special interest when used in clinical practice following erroneous positioning, and dissolution is urgently needed., (© 2022 The Authors. Published by Elsevier B.V. on behalf of European Society for Radiotherapy and Oncology.)

Objective: The purpose of this review was to summarize the current literature on the assessment and treatment of radiation urethritis and cystitis (RUC) for the development of an evidenced-based management algorithm., Material and Methods: The PubMed/MEDLINE database was searched by a multidisciplinary group of experts in January 2021., Results: In total, 48 publications were identified. Three different types of RUC can be observed in clinical practice: inflammation-predominant, bleeding-predominant, and the combination of inflammation- and bleeding-RUC. There is no consensus on the optimal treatment of RUC. Inflammation-predominant RUC should be treated symptomatically based on the existence of bothersome storage or voiding lower urinary tract symptom as well as on pain. When bleeding-predominant RUC has occurred, hydration and hyperbaric oxygen therapy (HOT) should be used first and, if HOT is not available, oral drugs instead (sodium pentosane polysulfate, aminocaproic acid, immunokine WF 10, conjugated estrogene, or pentoxifylline + vitamin E). If local bleeding persists, focal therapy of bleeding vessels with a laser or electrocoagulation is indicated. In case of generalized bleeding, intravesical installation should be initiated (formalin, aluminium salts, and hyaluronic acid/chondroitin). Vessel embolization is a less invasive treatment with potentially less complications and good clinical outcomes. Open- or robot-assisted surgery is indicated in patients with permanent, life-threatening bleeding, or fistulae., Conclusions: Treatment of RUC, if not self-limiting, should be done according to the type of RUC and in a stepwise approach. Conservative/medical treatment (oral and topic agents) should primarily be used before invasive (transurethral) treatments., (© 2021 The Author(s) Published by S. Karger AG, Basel.)

Purpose: To issue consensus recommendations for contact X-Ray brachytherapy (CXB) for rectal cancer covering pre-treatment evaluation, treatment, dosimetric issues and follow-up. These recommendations cover CXB in the definitive and palliative setting., Methods: Members of GEC ESTRO with expertise in rectal CXB issued consensus-based recommendations for CXB based on literature review and clinical experience. Levels of evidence according to the Oxford Centre for Evidence based medicine guidance are presented where possible., Results: The GEC ESTRO ACROP consensus recommendations support the use of CXB to increase the chances of clinical complete remission and cure for patients who are elderly with high surgical risk, surgically unfit or refusing surgery. For palliative treatment, the use of CXB is recommended for symptomatic relief and disease control. The use of CXB in an organ-preservation setting in surgically fit patients is recommended within the setting of a clinical trial or registry., Conclusions: The GEC ESTRO ACROP recommendations for CXB are provided. Recommendations towards standardisation of reporting and prescription are given. Practitioners are encouraged to follow these recommendations and to develop further clinical trials to examine this treatment modality and increase the evidence base for its use. The routine collection of outcomes both clinical and patient-reported is also encouraged., Competing Interests: JP Gerard is the medical advisor of Ariane Medical Systems Company, Derby, UK F Verhaegen, M Berbee and EJ van Limbergen have submitted a patent on an endorectal probe device a patent for effecting radiation treatment of colorectal cancerous tissue in the rectum of a human or animal subject which is pending to Maastricht University. All other authors state they have no conflicts of interest, (© 2021 The Authors. Published by Elsevier B.V. on behalf of European Society for Radiotherapy and Oncology.)

Oligometastatic cancer is recognized as a separate entity within the spectrum of metastatic disease. It was suggested that patients with oligometastatic disease can obtain long-term survival by giving local ablative therapy (LAT) to all visible disease locations. However, the true extent from which metastatic cancer should be called "oligometastatic" is unknown, although a consensus definition for oligometastatic disease is proposed by research organizations, such as the EORTC (maximum of five metastases in three organs). Different states of the oligometastatic disease are defined, such as synchronous vs. metachronous, oligopersistent vs. oligoprogressive disease. All clinical trials including patients with non-small cell lung cancer (NSCLC) are small and most are not randomized. Two small randomized phase II trials on synchronous disease showed an improvement in progression free survival, with the addition of LAT, and one also demonstrated an overall survival benefit. Immune checkpoint inhibitors (ICI) were not part of the treatment in these trials, while ICI significantly improved long-term outcomes of patients with metastatic NSCLC. Radiotherapy might improve the prognosis of patients treated with ICI because of its immunostimulatory effects and the possibility to eradicate metastatic deposits. Here, we summarize the data for adding ablative radiotherapy to the treatment of oligometastatic NSCLC, especially in the ICI era, and discuss the challenges of combined treatment.

Several studies have established that radiotherapy (RT) in combination with immunotherapy (IO) has a strong synergistic effect. RT changes the tumor microenvironment, generates local inflammation reactions, and enhances immunostimulatory effects, which are able to assist IO with improving local and systemic tumor control. In several pre-clinical reports, RT in combination with IO reveals regression of tumors locally (irradiated sites) and systemically (non-irradiated sites). Several clinical trials are currently running, mostly as phase I and II studies. This article provides an overview of the randomized, prospective reported and recruiting phase 3 clinical trials of RT in combination with IO. To date, three phase 3 trials have been published on RT and sequential IO with variable results, ranging from no significant difference (Kwon et al. , START) to absolute differences in overall survival of 13.5% after 3 years (PACIFIC), respectively. No phase 3 randomized trials have been published on the simultaneous combination of RT with IO. Thirty trials are presently under way, and still recruiting patients to quantify the response to RT with IO. These studies fall into three categories of research interests: (I) to discover an enhancement effect of IO as induction therapy with RT; (II) to determine the additional effect of concurrent IO on the local effect of RT; and (III) to determine the additional effect of adjuvant or consolidation IO on the local effect of RT. Most of the ongoing studies are a combination of these interests, with 15 trials evaluating the concurrent RT+IO with IO consolidation strategy. The results in coming years will provide more insights in the role of RT as an activator of the immune system, the effect of IO as local sensitizer of RT, the optimal sequencing of IO with RT, and the total RT doses needed to obtain the optimal local and systemic effect., Competing Interests: Conflicts of Interest: All authors have completed the ICMJE uniform disclosure form (available at http://dx.doi.org/10.21037/tlcr-20-304). The series “Radiotherapy in thoracic malignancies” was commissioned by the editorial office without any funding or sponsorship. Dr. De Ruysscher reports grants from Brsitol-Myers Squibb, grants from AstraZeneca, grants from Boehringer Ingelheim, from Philips, from Olink, from Celgene, from Seattle Genetics, from Roche/Genentech, from Merck/Pfizer, outside the submitted work. The authors have no other conflicts of interest to declare., (2021 Translational Lung Cancer Research. All rights reserved.)

The purpose of this report was to systematically review the radiation enhancement factor (REF) effects of immunotherapy on radiotherapy (RT) to the local tumor in comparison with other traditional radiation sensitizers such as cisplatin. PubMed and Medline databases were searched until February 2019. Reports with abscopal effect in the results were excluded. Graphs of the selected papers were digitized using Plot Digitizer (Sourceforge.net) in order to calculate the tumor growth delay (TGD) caused by immunotherapy. To enable comparison between different studies,the TGD were used to define the REF between RT versus the RT/immunotherapy combination. Thirty-two preclinical papers, and nine clinical series were selected. Different mouse models were exposed to RT doses ranging from 1 to 10 fractions of 1.8 to 20 Gray (Gy) per fraction. Endpoints were heterogeneous, ranging from regression to complete local response. No randomized clinical studies were identified. The median preclinical REF effect of different immunotherapy was varying from 1.7 to 9.1. There was no relationship observed either with subclasses of immunotherapy orRT doses. In the clinical studies, RT doses ranged from 1 to 37 fractions of 1.8 to 24 Gy per fraction. Most clinical trials used ipilimumab and interleukin-2. Local control rate in the clinical series ranged from 66% to 100%. A strong REF of immunotherapy (1.7 to 9.1) was observed, this being higher than traditionally sensitizers such as cisplatin (1.1). This result implies that for the same RT dose, a higher local control was achieved with a combination of immunotherapy and RT in preclinical settings. This study therefore supports the use of combined RT and immunotherapy to improve local tumor control in clinical settings without exacerbation of toxicities., Competing Interests: All authors declare to have no conflict of interest., (© 2020 The Author(s). Published with license by Taylor & Francis Group, LLC.)

The extracellular matrix protein fibronectin contains a domain that is rarely found in healthy adults and is almost exclusively expressed by newly formed blood vessels in tumours, particularly in solid tumours, different types of lymphoma and some leukaemias. This domain, called the extra domain B (ED-B), thus has broad therapeutic potential. The antibody L19 has been developed to specifically target ED-B and has shown therapeutic potential when combined with cytokines, such as IL-2. In this review article, we discuss the preclinical research and clinical trials that highlight the potential of ED-B targeting for the imaging and treatment of various types of cancer. ED-B-centred studies also highlight how proper patient stratification is of utmost importance for the successful implementation of novel antibody-based targeted therapies., (© 2020 The Authors. Published by FEBS Press and John Wiley & Sons Ltd.)

Purpose: Dose escalation yields higher complete response to rectal tumors, which may enable the omission of surgery. Dose escalation using 50 kVp contact x-ray brachytherapy (CXB) allow the treatment of a selective volume, resulting in low toxicity and organs-at-risk preservation. However, the use of CXB devices is limited because of its high cost and lack of treatment planning tools. Hence, the MAASTRO applicator (for HDR 192 Ir sources) was developed and characterized by measurements and Monte Carlo simulations to be a cost-effective alternative to CXB devices., Methods and Materials: A cylindrical applicator with lateral shielding was designed to be used with a rectoscope using its tip as treatment surface. Both the applicator and the rectoscope have a slanted edge to potentially allow easier placement against tumors. The applicator design was achieved by Monte Carlo modeling and validated experimentally with film dosimetry, using the Papillon 50 (P50) device as reference., Results: The applicator delivers CXB doses in less than 9 min using a 20375 U source for a treatment area of approximately 20 × 20 mm 2  at 2 mm depth. Normalized at 2 mm, the dose falloff for depths of 0 mm, 5 mm, and 10 mm are 130%, 70%, and 43% for the P50 and 140%, 67%, and 38% for the MAASTRO applicator, respectively., Conclusions: The MAASTRO applicator was designed to use HDR 192 Ir sources to deliver a dose distribution similar to those of CXB devices. The applicator may provide a cost-effective solution for endoluminal boosting with clinical treatment planning system integration., (Copyright © 2020. Published by Elsevier Inc.)

Background: About 50% of non-small cell lung cancer (NSCLC) patients have metastatic disease at initial diagnosis, which limits their treatment options and, consequently, the 5-year survival rate (15%). Immune checkpoint inhibitors (ICI), either alone or in combination with chemotherapy, have become standard of care (SOC) for most good performance status patients. However, most patients will not obtain long-term benefit and new treatment strategies are therefore needed. We previously demonstrated clinical safety of the tumour-selective immunocytokine L19-IL2, consisting of the anti-ED-B scFv L19 antibody coupled to IL2, combined with stereotactic ablative radiotherapy (SABR)., Methods: This investigator-initiated, multicentric, randomised controlled open-label phase II clinical trial will test the hypothesis that the combination of SABR and L19-IL2 increases progression free survival (PFS) in patients with limited metastatic NSCLC. One hundred twenty-six patients will be stratified according to their metastatic load (oligo-metastatic: ≤5 or poly-metastatic: 6 to 10) and randomised to the experimental-arm (E-arm) or the control-arm (C-arm). The C-arm will receive SOC, according to the local protocol. E-arm oligo-metastatic patients will receive SABR to all lesions followed by L19-IL2 therapy; radiotherapy for poly-metastatic patients consists of irradiation of one (symptomatic) to a maximum of 5 lesions (including ICI in both arms if this is the SOC). The accrual period will be 2.5-years, starting after the first centre is initiated and active. Primary endpoint is PFS at 1.5-years based on blinded radiological review, and secondary endpoints are overall survival, toxicity, quality of life and abscopal response. Associative biomarker studies, immune monitoring, CT-based radiomics, stool collection, iRECIST and tumour growth rate will be performed., Discussion: The combination of SABR with or without ICI and the immunocytokine L19-IL2 will be tested as 1st, 2nd or 3rd line treatment in stage IV NSCLC patients in 14 centres located in 6 countries. This bimodal and trimodal treatment approach is based on the direct cytotoxic effect of radiotherapy, the tumour selective immunocytokine L19-IL2, the abscopal effect observed distant from the irradiated metastatic site(s) and the memory effect. The first results are expected end 2023., Trial Registration: ImmunoSABR Protocol Code: NL67629.068.18; EudraCT: 2018-002583-11; Clinicaltrials.gov: NCT03705403; ISRCTN ID: ISRCTN49817477; Date of registration: 03-April-2019.

Objective: In selected rectal cancer patients with residual local disease following neoadjuvant chemoradiation (CRT) and the preference of an organ preservation pathway, additional treatment with dose escalation by endoluminal radiotherapy (RT) may ultimately result in a clinical complete response. To date, the widespread introduction of selective endoluminal radiation techniques is hampered by a lack of evidence-based guidelines that describe the radiation treatment volume in relation to the residual tumor mass. In order to convert an incomplete response into a complete one with additional treatment such as dose-escalation with endoluminal RT from a theoretical perspective, it seems important to treat all remaining microscopic tumor cells after CRT. In this setting, residual tumor extension beneath normal appearing mucosa (microscopic intramural spread - MIS) becomes relevant for accurate tumor volume and margin estimation. With the goal of providing evidence-based guidelines that define an appropriate treatment volume and patient selection, we present results from a meta-analysis based on individual patient data of studies that have assessed the extent or range of MIS of rectal cancers after neoadjuvant CRT. This meta-analysis should provide an estimate of the residual tumor volume/extension that needs to be targeted by any additional radiation therapy boost in order to achieve complete tumor eradication after initial incomplete or near-complete response following standard CRT., Methods and Materials: A PubMed search was performed. Additional articles were selected based on identification from reference lists. Papers were eligible when reporting MIS in patients who were treated by total mesorectal excision or local excision/transanal endoscopic microsurgery (TEM) after neo-adjuvant long-course CRT. The mean MIS was calculated for the entire group along with the 70th until 95th percentiles. Additional exploratory subgroup analyses were performed., Results: Individual patient data from 349 patients with residual disease from five studies were analyzed. 80% of tumors showed no MIS. In order to appropriately treat MIS in 95% of rectal cancer patients after CRT, a margin of 5.5 mm around the macroscopic tumor would suffice. An exploratory subgroup analysis showed that T-stage after CRT (ypT) and time interval between neoadjuvant CRT and surgery are significant factors predicting the extent of MIS (p < 0.001.) The group of ypT1 had the smallest MIS, followed by the ypT3-4 group, while the ypT2 group had the largest MIS (p < 0.001). Regarding time interval between CRT and surgery, a statistically significant difference was seen when comparing the three time-interval groups (less than 8 weeks, 8-12 weeks, and more than 12 weeks), where waiting more than 12 weeks after CRT resulted in the largest MIS (p < 0.0001)., Conclusion: Based on this meta-analysis, in order to treat the MIS for 95% of rectal cancer patients after CRT, a Clinical Target Volume (CTV) margin of 5.5 mm from the lateral most edge of the macroscopic tumor would suffice. 80% of tumors showed no MIS and would not require an extra CTV margin for treatment. These findings support the feasibility of localized radiotherapy boosts for dose-escalation to improve response among patients with incomplete response after standard CRT and can also be applied in the surgical setting., Competing Interests: Declaration of Competing Interest Authors E.J. Van Limbergen, M. Berbee, A. Verrijssen, F. Verhaegen and J. Melenhorst report a research grant from Varian Medical Systems on “Phase-II trial on endoluminal boosting in rectal cancer using the MAASTRO applicator”. In addition, authors E.J. Van Limbergen, M. Berbee, F. Verhaegen, M. Bellezzo and G. Paiva Fonseca have a patent EP16204735, rectal brachytherapy applicator with royalties paid to Maastro Clinic/University Maastricht., (Copyright © 2019 Elsevier B.V. All rights reserved.)

Background: Patient decision aids (PDAs) can support the treatment decision making process and empower patients to take a proactive role in their treatment pathway while using a shared decision-making (SDM) approach making participatory medicine possible. The aim of this study was to develop a PDA for prostate cancer that is accurate and user-friendly., Methods: We followed a user-centered design process consisting of five rounds of semi-structured interviews and usability surveys with topics such as informational/decisional needs of users and requirements for PDAs. Our user-base consisted of 8 urologists, 4 radiation oncologists, 2 oncology nurses, 8 general practitioners, 19 former prostate cancer patients, 4 usability experts and 11 healthy volunteers., Results: Informational needs for patients centered on three key factors: treatment experience, post-treatment quality of life, and the impact of side effects. Patients and clinicians valued a PDA that presents balanced information on these factors through simple understandable language and visual aids. Usability questionnaires revealed that patients were more satisfied overall with the PDA than clinicians; however, both groups had concerns that the PDA might lengthen consultation times (42 and 41%, respectively). The PDA is accessible on http://beslissamen.nl/ ., Conclusions: User-centered design provided valuable insights into PDA requirements but challenges in integrating diverse perspectives as clinicians focus on clinical outcomes while patients also consider quality of life. Nevertheless, it is crucial to involve a broad base of clinical users in order to better understand the decision-making process and to develop a PDA that is accurate, usable, and acceptable.

Recently, the results of the STAMPEDE trial arm H were reported. This trial investigated the effect of radiotherapy to the prostate only on the overall survival of patients with metastatic prostate cancer. Although on the whole the findings of the trial were negative, a significant increase in survival was noted in the prespecified subgroup of patients with a low metastatic burden. As only a few analyses were prespecified, the direction of the subgroup effect was prespecified and consistent with previous observations from the separate but comparable HORRAD trial. The subgroup effect was large and independent of other subgroup variables, and as there is a solid biological rationale for these results, they are to be considered trustworthy, and are likely to change clinical practice. Further research should focus on better specification of the low metastatic burden subgroup, if other locally ablative treatments such as surgery are equivalent, and if ablation of all metastatic lesions would give additional benefit.

Purpose: A clinical complete response is seen after neoadjuvant chemoradiation for rectal tumors in 15%-20% of patients. These patients can potentially be spared mutilating total mesorectal excision surgery through a watch-and-wait policy. Recent studies show that dose escalation by a radiation boost increases the clinical complete response rate. The boost dose to the tumor can be administered through external beam radiotherapy or through internal radiotherapy using techniques like contact therapy, low-dose-rate or high-dose-rate brachytherapy (BT). However, limited information is available concerning treatment-related toxicity of these techniques. With this systematic review, we aim to summarize and compare published data concerning acute and late toxicity after contact X-ray therapy (CXT) and BT for rectal cancer., Methods and Materials/results: Thirty-eight studies reporting toxicity after endorectal radiation techniques for rectal cancer were included, resulting in 3682 patients for analysis. Direct comparison of toxicity by the different radiation modes was hampered by various combinations of endorectal techniques, a lack of clear reporting of toxicity scores, dose prescription, technique used, and treated volumes. ≥ Grade 3 rectal toxicity was reported in 2.9% of patients having received only CXT; 6.3% of patients who received only BT had Grade 3 rectal toxicity, and BT also caused Grade 3 urinary toxicity in 1 patient., Conclusion: All techniques reported some ≥ Grade 3 toxicity. Toxicity after CXT was confined to the rectum, whereas after BT, urogenital toxicity and skin toxicity were seen as well. Unfortunately, few specific conclusions could be drawn regarding the dose-related risk of toxicity for the various techniques due to nonuniform reporting strategies and missing information. To enable future comparisons and improvements, the endorectal radiation field urgently needs consensus guidelines on dose reporting, dose prescription, treatment volume specification, and toxicity reporting., (Copyright © 2018 American Brachytherapy Society. Published by Elsevier Inc. All rights reserved.)

Purpose: Dose escalation to rectal tumors leads to higher complete response rates and may thereby enable omission of surgery. Important advantages of endoluminal boosting techniques include the possibility to apply a more selective/localized boost than using external beam radiotherapy. A novel brachytherapy (BT) rectal applicator with lateral shielding was designed to be used with a rectoscope for eye-guided positioning to deliver a dose distribution similar to the one of contact x-ray radiotherapy devices, using commonly available high-dose-rate 192 Ir BT sources., Methods and Materials: A cylindrical multichannel BT applicator with lateral shielding was designed by Monte Carlo modeling, validated experimentally with film dosimetry and compared with results found in the literature for the Papillon 50 (P50) contact x-ray radiotherapy device regarding rectoscope dimensions, radiation beam shape, dose fall-off, and treatment time., Results: The multichannel applicator designed is able to deliver 30 Gy under 13 min with a 20350 U (5 Ci) source. The use of multiple channels and lateral shielding provide a uniform circular treatment surface with 22 mm in diameter. The resulting dose fall-off is slightly steeper (maximum difference of 5%) than the one generated by the P50 device with the 22 mm applicator., Conclusions: A novel multichannel rectal applicator for contact radiotherapy with high-dose-rate 192 Ir sources that can be integrated with commercially available treatment planning systems was designed to produce a dose distribution similar to the one obtained by the P50 device., (Copyright © 2018 American Brachytherapy Society. Published by Elsevier Inc. All rights reserved.)

Recently, we have shown that the administration of the tumour-targeted antibody-based immunocytokine L19-IL2 after radiotherapy (RT) resulted in synergistic anti-tumour effect. Here we show that RT and L19-IL2 can activate a curative abscopal effect, with a long-lasting immunological memory. Ionizing radiation (single dose of 15Gy, 5 × 2Gy or 5 × 5Gy) was delivered to primary C51 colon tumour-bearing immunocompetent mice in combination with L19-IL2 and response of secondary non-irradiated C51 or CT26 colon tumours was evaluated. 15Gy + L19-IL2 triggered a curative (20%) abscopal effect, which was T cell dependent. Moreover, 10Gy + L19-IL2 treated and cured mice were re-injected after 150 days with C51 tumour cells and tumour uptake was assessed. Age-matched controls (matrigel injected mice treated with 10Gy + L19-IL2, mice cured after treatment with surgery + L19-IL2 and mice cured after high dose RT 40Gy + vehicle) were included. Several immunological parameters in blood, tumours, lymph nodes and spleens were investigated. Treatment with 10Gy + L19-IL2 resulted in long-lasting immunological memory, associated with CD44 + CD127 + expression on circulating T cells. This combination treatment can induce long-lasting curative abscopal responses, and therefore it has also great potential for treatment of metastatic disease. Preclinical findings have led to the initiation of a phase I clinical trial (NCT02086721) in our institute investigating stereotactic ablative radiotherapy with L19-IL2 in patients with oligometastatic solid tumours.

The advent of immunotherapy is currently revolutionizing the field of oncology, where different drugs are used to stimulate different steps in a failing cancer immune response chain. This review gives a basic overview of the immune response against cancer, as well as the historical and current evidence on the interaction of radiotherapy with the immune system and the different forms of immunotherapy. Furthermore the review elaborates on the many open questions on how to exploit this interaction to the full extent in clinical practice.

Brachytherapy is employed to treat a wide variety of cancers. However, an accurate treatment verification method is currently not available. This study describes a pre-treatment verification system that uses an imaging panel (IP) to verify important aspects of the treatment plan. A detailed modelling of the IP was only possible with an extensive calibration performed using a robotic arm. Irradiations were performed with a high dose rate (HDR) 192 Ir source within a water phantom. An empirical fit was applied to measure the distance between the source and the detector so 3D Cartesian coordinates of the dwell positions can be obtained using a single panel. The IP acquires 7.14 fps to verify the dwell times, dwell positions and air kerma strength (Sk). A gynecological applicator was used to create a treatment plan that was registered with a CT image of the water phantom used during the experiments for verification purposes. Errors (shifts, exchanged connections and wrong dwell times) were simulated to verify the proposed verification system. Cartesian source positions (panel measurement plane) have a standard deviation of about 0.02 cm. The measured distance between the source and the panel (z-coordinate) have a standard deviation up to 0.16 cm and maximum absolute error of  ≈0.6 cm if the signal is close to sensitive limit of the panel. The average response of the panel is very linear with Sk. Therefore, Sk measurements can be performed with relatively small errors. The measured dwell times show a maximum error of 0.2 s which is consistent with the acquisition rate of the panel. All simulated errors were clearly identified by the proposed system. The use of IPs is not common in brachytherapy, however, it provides considerable advantages. It was demonstrated that the IP can accurately measure Sk, dwell times and dwell positions.

Radiotherapy (RT) for prostate cancer (PC) has steadily evolved over the last decades, with improving biochemical disease-free survival. Recently population based research also revealed an association between overall survival and doses ≥ 75.6 Gray (Gy) in men with intermediate- and high-risk PC. Examples of improved RT techniques are image-guided RT, intensity-modulated RT, volumetric modulated arc therapy, and stereotactic ablative body RT, which could facilitate further dose escalation. Brachytherapy is an internal form of RT that also developed substantially. New devices such as rectum spacers and balloons have been developed to spare rectal structures. Newer techniques like protons and carbon ions have the intrinsic characteristics maximising the dose on the tumour while minimising the effect on the surrounding healthy tissue, but clinical data are needed for confirmation in randomised phase III trials. Furthermore, it provides an overview of an important discussion issue in PC treatment between urologists and radiation oncologists: the comparison between radical prostatectomy and RT. Current literature reveals that all possible treatment modalities have the same cure rate, but a different toxicity pattern. We recommend proposing the possible different treatment modalities with their own advantages and side-effects to the individual patient. Clinicians and patients should make treatment decisions together ( shared decision-making ) while using patient decision aids., Competing Interests: The authors declare that there is no conflict of interests regarding the publication of this paper.

Objective: The purpose of this study was to give an overview of the measures used to prevent chronic radiation proctitis (CRP) and to provide an algorithm for the treatment of CRP., Methods: Medical literature databases including PubMed and Medline were screened and critically analyzed for relevance in the scope of our purpose., Results: CRP is a relatively frequent late side effect (5-20%) and mainly dependent on the dose and volume of irradiated rectum. Radiation treatment (RT) techniques to prevent CRP are constantly improving thanks to image-guided RT and intensity-modulated RT. Also, newer techniques like protons and new devices such as rectum spacers and balloons have been developed to spare rectal structures. Biopsies do not contribute to diagnosing CRP and should be avoided because of the risk of severe rectal wall damage, such as necrosis and fistulas. There is no consensus on the optimal treatment of CRP. A variety of possibilities is available and includes topical and oral agents, hyperbaric oxygen therapy, and endoscopic interventions., Conclusions: CRP has a natural history of improving over time, even without treatment. This is important to take into account when considering these treatments: first be conservative (topical and oral agents) and be aware that invasive treatments can be very toxic.

Background and Purpose: Recently, we have shown that radiotherapy (RT) combined with the immunocytokine L19-IL2 can induce long-lasting antitumour effects, dependent on ED-B expression and infiltration of cytotoxic T cells. On the other hand, in certain tumours, IL2 treatment can trigger a natural killer cell (NK) immune response. The aim of this study is to investigate the therapeutic effect of our combination therapy in the ED-B positive F9 teratocarcinoma model, lacking MHCI expression and known to be dependent on NK immune responses., Material and Methods: In syngeneic F9 tumour bearing 129/FvHsd mice tumour growth delay was evaluated after local tumour irradiation (10Gy) combined with systemic administration of L19-IL2. Immunological responses were investigated using flow cytometry., Results: Tumour growth delay of L19-IL2 can be further improved by a single dose of RT administered before immunotherapy, but not during immunotherapy. Furthermore, treatment of L19-IL2 favours a NK response and lacks cytotoxic T cell tumour infiltrating immune cells, which may be explained by the absence of MHCI expression., Conclusion: An additive effect can be detected when the NK dependent F9 tumour model is treated with radiotherapy and L19-IL2 and therefore this combination could be useful in the absence of tumoural MHCI expression., (Copyright © 2015 The Authors. Published by Elsevier Ireland Ltd.. All rights reserved.)