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This file contains details on all late grade {greater than or equal to} 2 esophageal adverse events (I) and esophageal metabolic activity six weeks post-treatment (II).

This file contains details on loco-regional control, progression free survival and overall survival split by treatment arm.

This file contains Supplementary Methods: radiotherapy details (I), treatment schedules (II), definition of Dose Limiting Toxicity (III) and a schedule of assessments (IV).

This file contains details on the pharmacokinetic profile (I) and parameters (II) of olaparib.

Purpose:To identify an MTD of olaparib, a PARP inhibitor, in combination with loco-regional radiotherapy with/without cisplatin for the treatment of non–small cell lung cancer (NSCLC).Patients and Methods:Olaparib dose was escalated in two groups: radiotherapy (66 Gy/24 fractions in 2.75 Gy/fraction) with and without daily cisplatin (6 mg/m2), using time-to-event continual reassessment method with a 1-year dose-limiting toxicity (DLT) period. The highest dose level with a DLT probability Results:Twenty-eight patients with loco-regional or oligometastatic disease (39%) were treated: 11 at olaparib 25 mg twice daily and 17 at 25 mg once daily. The lowest dose level with cisplatin was above the MTD due to hematologic and late esophageal DLT. The MTD without cisplatin was olaparib 25 mg once daily. At a latency of 1–2.8 years, severe pulmonary adverse events (AE) were observed in 5 patients across all dose levels, resulting in 18% grade 5 pulmonary AEs. Exploratory analyses indicate an association with the radiation dose to the lungs. At the MTD, olaparib reduced PAR levels by more than 95% and abolished radiation-induced PARylation. Median follow-up of survivors was 4.1 years. Two-year loco-regional control was 84%, median overall survival in patients with locally advanced NSCLC was 28 months.Conclusions:Combined mildly hypofractionated radiotherapy and low-dose daily cisplatin and olaparib was not tolerable due to esophageal and hematologic toxicity. Severe pulmonary toxicity was observed as well, even without cisplatin. More conformal radiotherapy schedules with improved pulmonary and esophageal sparing should be explored.

This file contains details on pulmonary function changes in diffusion tests (I) and spirometry tests (II), and the incidence of severe pulmonary adverse events by treatment arm (III).

This file contains the radiation doses to organs at risk (I) and details on systemic treatment (II).

This file contains details on DLT (I) and DLT probabilities according to TITE-CRM in the CCRT arm (II) and (SC)RT study arm (III).

Purpose: High-field magnetic resonance-linear accelerators (MR-Linacs), linear accelerators combined with a diagnostic magnetic resonance imaging (MRI) scanner and online adaptive workflow, potentially give rise to novel online anatomic and response adaptive radiation therapy paradigms. The first high-field (1.5T) MR-Linac received regulatory approval in late 2018, and little is known about clinical use, patient tolerability of daily high-field MRI, and toxicity of treatments. Herein we report the initial experience within the MOMENTUM Study (NCT04075305), a prospective international registry of the MRLinac Consortium. Methods and Materials: Patients were included between February 2019 and October 2020 at 7 institutions in 4 countries. We used descriptive statistics to describe the patterns of care, tolerability (the percentage of patients discontinuing their course early), and safety (grade 3-5 Common Terminology Criteria for Adverse Events v.5 acute toxicity within 3 months after the end of treatment). Results: A total 943 patients participated in the MOMENTUM Study, 702 of whom had complete baseline data at the time of this analysis. Patients were primarily male (79%) with a median age of 68 years (range, 22-93) and were treated for 39 different indications. The most frequent indications were prostate (40%), oligometastatic lymph node (17%), brain (12%), and rectal (10%) cancers. The median number of fractions was 5 (range, 1-35). Six patients discontinued MR-Linac treatments, but none due to an inability to tolerate repeated high-field MRI. Of the 415 patients with complete data on acute toxicity at 3 month follow-up, 18 (4%) patients experienced grade 3 acute toxicity related to radiation. No grade 4 or 5 acute toxicity related to radiation was observed. Conclusions: In the first 21 months of our study, patterns of care were diverse with respect to clinical utilization, body sites, and radiation prescriptions. No patient discontinued treatment due to inability to tolerate daily high-field MRI scans, and the acute radiation toxicity experience was encouraging. (c) 2021 Published by Elsevier Inc.

Objective. To evaluate feasibility of chemoradiation as alternative for extensive surgery in patients with locally advanced vulvar cancer and to report on locoregional control, toxicity and survival. Methods. In a multicenter, prospective phase II trial patients with locally advanced vulvar cancer were treated with locoregional radiotherapy combined with sensitizing chemotherapy (capecitabine). Treatment feasibility, percentage locoregional control, survival and toxicity were evaluated. Results. 52 patients with mainly T2/T3 disease were treated according to the study protocol in 10 centers in the Netherlands from 2007 to 2019. Full dose radiotherapy (tumor dose of 64.8Gy) was delivered in 92% and full dose capecitabine in 69% of patients. Most prevalent acute >_ grade 3 toxicities were regarding skin/ mucosa and pain (54% and 37%). Late >_grade 3 toxicity was reported for skin/mucosa (10%), fibrosis (4%), GI incontinence (4%) and stress fracture or osteoradionecrosis (4%). Twelve weeks after treatment, local clinical complete response (cCR) and regional control (RC) rates were 62% and 75%, respectively. After 2 years, local cCR persisted in 22 patients (42%) and RC was 58%. Thirty patients (58%) had no evidence of disease at end of follow-up (median 35 months). In 9 patients (17%) extensive surgery with stoma formation was needed. Progression free survival was 58%, 51% and 45% and overall survival was 76%, 66%, 52% at 1,2, and 5 years. Conclusions. Definitive capecitabine-based chemoradiation as alternative for extensive surgery is feasible in locally advanced vulvar cancer and results in considerable locoregional control with acceptable survival rates with manageable acute and late toxicity. (c) 2021 The Authors. Published by Elsevier Inc. This is an open access article under the CC BY-NC-ND license (http:// creativecommons.org/licenses/by-nc-nd/4.0/).

Simple Summary: Contact X-ray brachytherapy (CXB) after neoadjuvant (chemo)radiotherapy for rectal cancer is applied in selected patients aiming at organ preservation. However, limited data exist on features observed on endoscopy and MRI after treatment with CXB. On endoscopy, features observed in most patients 6 months after CXB are a flat, white scar, indicative for a clinical complete response (cCR), or tumor mass. On MRI, features indicative for a residual tumor are a focal tumor signal on T2W-MRI and a mass-like high signal on DWI. Due to treatment-related features observed early in follow-up, an irregular ulcer on endoscopy and a diffuse "reactive" mucosal signal on DWI, the distinction between a cCR and a residual tumor generally can be made at 6 months of follow-up. These results can help clinicians to interpret imaging features following CXB, ultimately, to identify patients with a cCR for Watch-and-Wait and to identify patients with a residual tumor for subsequent total mesorectal excision. After neoadjuvant (chemo)radiotherapy for rectal cancer, contact X-ray brachytherapy (CXB) can be applied aiming at organ preservation. This explorative study describes the early features on endoscopy and MRI after CXB. Patients treated with CXB following (chemo)radiotherapy and a follow-up of >= 12 months were selected. Endoscopy and MRI were performed every 3 months. Expert readers scored all the images according to structured reporting templates. Thirty-six patients were included, 15 of whom obtained a cCR. On endoscopy, the most frequently observed feature early in follow-up was an ulcer, regardless of whether patients developed a cCR. A flat, white scar and tumor mass were common at 6 months. Focal tumor signal on T2W-MRI and mass-like high signal on DWI were generally absent in patients with a cCR. An ulceration on T2W-MRI and "reactive" mucosal signal on DWI were observed early in follow-up regardless of the final tumor response. The distinction between a cCR and a residual tumor generally can be made at 6 months. Features associated with a residual tumor are tumor mass on endoscopy, focal tumor signal on T2W-MRI, and mass-like high signal on DWI. Early recognition of these features is necessary to identify patients who will not develop a cCR as early as possible.

Background A uniform definition of a clinical near-complete response (near-CR) after neoadjuvant (chemo)radiotherapy for rectal cancer is lacking. A clear definition is necessary for uniformity in clinical practice and trial enrolment for organ-preserving treatments. This review aimed to provide an overview of the terminology, criteria, and features used in the literature to define a near-CR. Methods A systematic review was performed based on the PRISMA statement. PubMed and Embase were searched up to May 2021 to identify the terminology, criteria, and features used to define a near-CR after (chemo)radiotherapy for rectal cancer. Studies with no clear cut-off point between a cCR and near-CR, studies using Response Evaluation Criteria In Solid Tumours, and studies including only complete responders were excluded. Results A total of 1876 articles were found, of which 23 were included. Patients were managed by watchful waiting and/or additional local treatment in 11 and 17 of 23 studies respectively. Response evaluation included digital rectal examination (DRE) and/or endoscopy with MRI in 18 studies. The majority of studies used the term ‘near-complete response’. In most studies, minor irregularities or a smooth induration with DRE and a small flat ulcer on endoscopy were considered to indicate a near-CR. On MRI, five studies used features (obvious downstaging with or without heterogeneous/irregular fibrosis on T2-weighted MRI or small spot of high signal on diffusion-weighted imaging), five studies used TNM criteria (ycT2), and four used magnetic resonance tumour regression grade (mrTRG) (mrTRG1–2/mrTRG2) to describe a near-CR. Conclusion The terminology, criteria, and features used to describe a near-CR vary substantially, which can partly be explained by the different treatment strategies patients are selected for (watchful waiting or additional local treatment). A reproducible definition of near-CR is required.

Background The STAR-TReC trial is an international multi-center, randomized, phase II study assessing the feasibility of short-course radiotherapy or long-course chemoradiotherapy as an alternative to total mesorectal excision surgery. A new target volume is used for both (chemo)radiotherapy arms which includes only the mesorectum. The treatment planning QA revealed substantial variation in dose to organs at risk (OAR) between centers. Therefore, the aim of this study was to determine the treatment plan variability in terms of dose to OAR and assess the effect of a national study group meeting on the quality and variability of treatment plans for mesorectum-only planning for rectal cancer. Methods Eight centers produced 25 × 2 Gy treatment plans for five cases. The OAR were the bowel cavity, bladder and femoral heads. A study group meeting for the participating centers was organized to discuss the planning results. At the meeting, the values of the treatment plan DVH parameters were distributed among centers so that results could be compared. Subsequently, the centers were invited to perform replanning if they considered this to be necessary. Results All treatment plans, both initial planning and replanning, fulfilled the target constraints. Dose to OAR varied considerably for the initial planning, especially for dose levels below 20 Gy, indicating that there was room for trade-offs between the defined OAR. Five centers performed replanning for all cases. One center did not perform replanning at all and two centers performed replanning on two and three cases, respectively. On average, replanning reduced the bowel cavity V20Gy by 12.6%, bowel cavity V10Gy by 22.0%, bladder V35Gy by 14.7% and bladder V10Gy by 10.8%. In 26/30 replanned cases the V10Gy of both the bowel cavity and bladder was lower, indicating an overall lower dose to these OAR instead of a different trade-off. In addition, the bowel cavity V10Gy and V20Gy showed more similarity between centers. Conclusions Dose to OAR varied considerably between centers, especially for dose levels below 20 Gy. The study group meeting and the distribution of the initial planning results among centers resulted in lower dose to the defined OAR and reduced variability between centers after replanning. Trial registration The STAR-TReC trial, ClinicalTrials.gov Identifier: NCT02945566. Registered 26 October 2016, https://clinicaltrials.gov/ct2/show/NCT02945566).

158 Background: Rectal cancer is traditionally treated with total mesorectal excision (TME), with/without neoadjuvant radiotherapy (RT) and chemotherapy. This approach often leads to temporary or permanent colostomies and other long-term morbidity such as urinary and sexual dysfunction in over 60% of patients. Organ preservation is increasingly being pursued in patients with a clinical complete response (cCR) following neoadjuvant treatment, thereby aiming to avoid TME-surgery. Based on preclinical data suggesting immunomodulatory effects of RT, and the synergy of combined PD-L1/VEGF blockade in several tumor types, the TARZAN study (NCT04017455) combines these treatments aiming to increase chances of organ preservation in patients with mainly MMR proficient (pMMR) rectal cancer without the need for chemotherapy. Methods: Patients with clinical stage ≤T3ab N0-1 distal-mid rectal tumors without mesorectal fascia involvement underwent 5x5 Gy RT followed by 3 cycles of atezolizumab and bevacizumab. Response was evaluated by MRI and endoscopy. The primary endpoint was clinical complete and near-complete response (CR) rate at 12 weeks after RT. Secondary endpoints included safety, organ preservation, pathologic (near) CR in case of surgery, and relapse free survival. According to a Simon’s 2-stage design, ≥3 responders were needed in stage I (18 patients) to continue accrual into stage II. Here we report data from stage I. Results: Eighteen patients (14 male, median age 63), all with pMMR tumors, were treated. Six tumors were cN1 on MRI, 10/18 tumors were ≥4cm and for 10/18 patients abdominoperineal resection (APR) appeared necessary due to distal tumor location. At the time of response evaluation, (near-)CR was achieved in 10/18 (56%) patients according to the primary endpoint. With a median follow-up of 20 months, 9/18 (50%) patients remain without TME surgery. Of these 9 patients, 5 underwent local excision to achieve organ preservation and in 5 patients no additional intervention was needed (cCR). The remaining 9 patients underwent TME surgery (4 APR), and pathologic assessment revealed near-CR in two patients, and a pCR in one patient. Three patients developed distant recurrences, one in the organ-sparing group. Neoadjuvant treatment was well-tolerated with grade 3 study drug-related adverse events (AEs) in 1 (5%) patient. Grade 3 surgery-related AEs occurred in 5/9 (55%) patients, including 4 anastomotic leaks and 1 abscess. Conclusions: Neoadjuvant RT followed by atezolizumab and bevacizumab resulted in a promising rate of clinical (near-)CRs in 56% of patients without the need for chemotherapy, reaching the primary endpoint. Accrual is ongoing in stage II, in which an additional 20 patients will be treated. Clinical trial information: NCT04017455 .

Simple Summary The cornerstone in rectal cancer treatment is total mesorectal excision, a major surgical procedure associated with morbidity and mortality, especially in older rectal cancer patients. To avoid major surgery, different radiotherapy techniques are being investigated. Studies on contact X-ray brachytherapy reveal promising oncological results. However, there are limited data on functional outcome and quality of life, which are highly important for older or inoperable patients. This study aims to report the oncological and functional outcome, quality of life, and patients’ experiences of older or inoperable rectal cancer patients treated with contact X-ray brachytherapy to avoid major surgery. This study shows that contact X-ray brachytherapy can provide a good tumor response and is well tolerated, with minimal impact on functional outcome and quality of life. These data suggest contact X-ray brachytherapy can be considered an option for older or inoperable rectal cancer patients to avoid major rectal surgery. Abstract Total mesorectal excision for rectal cancer is a major operation associated with morbidity and mortality. For older or inoperable patients, alternatives are necessary. This prospective study evaluated the oncological and functional outcome and quality of life of older or inoperable rectal cancer patients treated with a contact X-ray brachytherapy boost to avoid major surgery. During follow-up, tumor response and toxicity on endoscopy were scored. Functional outcome and quality of life were assessed with self-administered questionnaires. Additionally, in-depth interviews regarding patients’ experiences were conducted. Nineteen patients were included with a median age of 80 years (range 72–91); nine patients achieved a clinical complete response and in another four local control of the tumor was established. The 12 month organ-preservation rate, progression-free survival, and overall survival were 88%, 78%, and 100%, respectively. A transient decrease in quality of life and bowel function was observed at 3 months, which was generally restored at 6 months. In-depth interviews revealed that patients’ experience was positive despite the side-effects shortly after treatment. In older or inoperable rectal cancer patients, contact X-ray brachytherapy can be considered an option to avoid total mesorectal excision. Contact X-ray brachytherapy is well-tolerated and can provide good tumor control.

BackgroundWith the large-scale introduction of volumetric modulated arc therapy (VMAT), selection of optimal beam angles for coplanar static-beam IMRT has increasingly become obsolete. Due to unavailability of VMAT in current MR-linacs, the problem has re-gained importance. An application for automated IMRT treatment planning with integrated, patient-specific computer-optimization of beam angles (BAO) was used to systematically investigate computer-aided generation of beam angle class solutions (CS) for replacement of computationally expensive patient-specific BAO. Rectal cancer was used as a model case.Materials and Methods23 patients treated at a Unity MR-linac were included. BAOx plans (x=7-12 beams) were generated for all patients. Analyses of BAO12 plans resulted in CSx class solutions. BAOx plans, CSx plans, and plans with equi-angular setups (EQUIx, x=9-56) were mutually compared.ResultsFor x>7, plan quality for CSx and BAOx was highly similar, while both were superior to EQUIx. E.g. with CS9, bowel/bladder Dmean reduced by 22% [11%, 38%] compared to EQUI9 (pConclusionsComputer-generated beam angle CS could replace individualized BAO without loss in plan quality, while reducing planning complexity and calculation times, and resulting in a simpler clinical workflow. CS and BAO largely outperformed equi-angular treatment. With the developed CS, time consuming beam angle re-optimization in daily adaptive MR-linac treatment could be avoided. Further systematic research on computerized development of beam angle class solutions for MR-linac treatment planning is warranted.

Highlights • Questionnaires are important tools in assessing the tolerability of new technology. • Patient reported experience of treatment on the MR-Linac is consistently high. • The MR-Linac questionnaire has been validated as relevant and appropriate for use., Introduction With the implementation of new radiotherapy technology, it is imperative that patient experience is investigated alongside efficacy and outcomes. This paper presents the development of a specifically designed validated questionnaire and a first report of international multi-institutional preliminary patient experience of MRI-guided adaptive radiotherapy (MRgART) on the 1.5 T MR-Linac (MRL). Methods A patient experience questionnaire was developed and validated before being distributed to the Elekta MRL Consortium, to gather first patient-reported experience from participating centres worldwide. The final version of the questionnaire contains 18 questions covering a range of themes and was scored on a Likert scale of 0–3. Responses were post-processed so that a score of 0 represents a negative response and 3 represents the most favourable response. These results were analysed for patient-reported experience of treatment on the MRL. Results were also analysed for internal consistency of the questionnaire using Chronbach’s Alpha and the questionnaire contents were validated for relevance using content validity indexes (CVI). Results 170 responses were received from five centres, representing patients with a wide range of tumour treatment sites from four different countries. MRgART was well tolerated with an 84% favourable response across all questions and respondents. When analysed by theme, all reported the highest percentage of results in the favourable categories (2 and 3). Internal consistency in the questionnaire was high (Cronbach’s α = 0.8) and the item-level CVI for each question was 0.78 or above and the Scale-level CVI was 0.93, representing relevant content. Conclusion The developed questionnaire has been validated as relevant and appropriate for use in reporting experience of patients undergoing treatment on the MRL. The overall patient-reported experience and satisfaction from multiple centres within the Elekta MRL Consortium was consistently high. These results can reinforce user confidence in continuing to expand and develop MRL use in adaptive radiotherapy.

Background & purpose Clinical introduction of magnetic resonance (MR)-guided radiotherapy involves treatment planning while taking into account machine-specific characteristics. Our aim was to investigate the feasibility of high-quality MR-linac treatment planning for an MR-linac and to benchmark MR-linac plan quality (IMRT) against current clinical practice (VMAT). Materials & methods Data of eight rectal and eight prostate cancer patients, who received radiotherapy on a conventional CBCT-integrated linac, were selected. Clinically acquired CTs and associated delineations of target volumes and organs-at-risk (OARs) were used for MR-linac treatment planning in Monaco. To investigate treatment planning software bias ‘quasi MR-linac plans' were generated in Pinnacle3 by mimicking MR-linac specific beam characteristics. MR-linac, quasi MR-linac, and clinical plans were compared and differences in target and OAR doses assessed. Differences in plan complexity were determined by the number of segments and monitor units. Results Compared to clinical plans, MR-linac plans showed a statistically significant decrease in plan homogeneity, an increase in PTV Dmean (prostate: 0.6 Gy; rectum: 0.8 Gy) and D1% (prostate: 1.9 Gy; rectum: 2.0 Gy), and increases in OAR dose. Quasi MR-linac plans were comparable to MR-linac plans with respect to OAR dose and plan homogeneity. For rectal cancer an increase was seen in PTV Dmean (0.12 Gy) and D1% (0.5 Gy) compared to regular MR-linac plans. All created plans were clinically equivalent to current clinical practice. Conclusions This study demonstrates the feasibility of creating high-quality MR-linac treatment plans. The results supported the clinical introduction of an MR-linac.

Purpose: To identify an MTD of olaparib, a PARP inhibitor, in combination with loco-regional radiotherapy with/without cisplatin for the treatment of non–small cell lung cancer (NSCLC). Patients and Methods: Olaparib dose was escalated in two groups: radiotherapy (66 Gy/24 fractions in 2.75 Gy/fraction) with and without daily cisplatin (6 mg/m2), using time-to-event continual reassessment method with a 1-year dose-limiting toxicity (DLT) period. The highest dose level with a DLT probability Results: Twenty-eight patients with loco-regional or oligometastatic disease (39%) were treated: 11 at olaparib 25 mg twice daily and 17 at 25 mg once daily. The lowest dose level with cisplatin was above the MTD due to hematologic and late esophageal DLT. The MTD without cisplatin was olaparib 25 mg once daily. At a latency of 1–2.8 years, severe pulmonary adverse events (AE) were observed in 5 patients across all dose levels, resulting in 18% grade 5 pulmonary AEs. Exploratory analyses indicate an association with the radiation dose to the lungs. At the MTD, olaparib reduced PAR levels by more than 95% and abolished radiation-induced PARylation. Median follow-up of survivors was 4.1 years. Two-year loco-regional control was 84%, median overall survival in patients with locally advanced NSCLC was 28 months. Conclusions: Combined mildly hypofractionated radiotherapy and low-dose daily cisplatin and olaparib was not tolerable due to esophageal and hematologic toxicity. Severe pulmonary toxicity was observed as well, even without cisplatin. More conformal radiotherapy schedules with improved pulmonary and esophageal sparing should be explored.

ModraDoc006 is a novel oral formulation of docetaxel. The clearance of intravenous docetaxel is higher in medically castrated prostate cancer patients as compared to patients with other types of solid tumours. Oral docetaxel requires co-administration ritonavir (r), which might further impact the pharmacokinetics (PK). We now compare the PK of docetaxel and ritonavir between patients with Hormone Sensitive Prostate Cancer (HSPC), metastatic Castration-Resistant Prostate Cancer (mCRPC) and other metastatic solid tumours, treated on the same dose and weekly schedule of ModraDoc006/r. The docetaxel and ritonavir PK were compared between four patient groups from three clinical phase I trials, including eight male and eight female patients with different types of solid tumours (study 1), seven patients with HSPC (study 2) and five patients with mCRPC (study 3). All patients were treated with ModraDoc006 30 mg and ritonavir 100 mg in the morning, followed by ModraDoc006 20 mg and ritonavir 100 mg in the evening (ModraDoc006/r 30–20/100–100). For comparative purposes, the PK of six mCRPC patients that received 30–20/200–100 in study 3 were also evaluated. The maximum plasma concentration (Cmax) was significantly lower for both docetaxel and ritonavir in the prostate cancer patients as compared to the patients with other types of solid tumours treated at ModraDoc006/r 30–20/100–100. The docetaxel area under the plasma concentration versus time curve (AUC) was significantly different at this dose, with a mean AUC0-48 of 1359 ± 374 ng/mL*h (N = 8) in female patients and 894 ± 223 ng/mL*h (N = 8) in male patients with different solid tumours (study 1), 321 ± 81 (N = 7) in HSPC (study 2) and 367 ± 182 ng/mL*h (N = 5) in mCRPC (study 3). A similar pattern was observed for ritonavir. ModraDoc006/r 30–20/200–100 in six mCRPC patients led to a comparable ritonavir exposure as compared to the patients at 30–20/100–100 in study 1 and increased the docetaxel AUC0–48 to 1266 ± 473 ng/mL*h (N = 6). The exposure to docetaxel and ritonavir was significantly lower in prostate cancer patients as compared to patients with other types of solid tumours, treated on ModraDoc006/r 30–20/100–100. An increase of the ritonavir dose increased the docetaxel exposure in mCRPC patients. Therefore, a different RP2D of ModraDoc006/r is pursued in castrated prostate cancer patients as compared to patients with other types of solid tumours. Study 1: ClinicalTrials.gov Identifier NCT01173913, date of registration August 2, 2010. Study 2: ClinicalTrials.gov Identifier NCT03066154, date of registration February 28, 2017. Study 3: ClinicalTrials.gov Identifier NCT03136640, date of registration May 2, 2017.

Purpose: MR-guided Radiation Therapy (MRgRT) allows for high-precision radiotherapy under real-time MR visualization. This enables margin reduction and subsequent dose escalation which may lead to higher tumor control and less toxicity. The Unity MR-linac (Elekta AB, Stockholm, Sweden) integrates a linear accelerator with a 1.5T diagnostic quality MRI and an online adaptive workflow. A prospective international registry was established to facilitate the evidence-based implementation of the Unity MR-linac into clinical practice, to systemically evaluate long-term outcomes, and to aid further technical development of MR-linac-based MRgRT. Methods and Results: In February 2019, the Multi-OutcoMe EvaluatioN of radiation Therapy Using the MR-linac study (MOMENTUM) started within the MR-linac Consortium. The MOMENTUM study is an international academic-industrial partnership between several hospitals and industry partner Elekta. All patients treated on the MR-linac are eligible for inclusion in MOMENTUM. For participants, we collect clinical patient data (e.g., patient, tumor, and treatment characteristics) and technical patient data which is defined as information generated on the MR-linac during treatment. The data are captured, pseudonymized, and stored in an international registry at set time intervals up to two years after treatment. Patients can choose to provide patient-reported outcomes and consent to additional MRI scans acquired on the MR-linac. This registry will serve as a data platform that supports multicenter research investigating the MR-linac. Rules and regulations on data sharing, data access, and intellectual property rights are summarized in an academic-industrial collaboration agreement. Data access rules ensure secure data handling and research integrity for investigators and institutions. Separate data access rules exist for academic and industry partners. This study is registered at ClinicalTrials.gov with ID: NCT04075305 (https://clinicaltrials.gov/ct2/show/NCT04075305). Conclusion: The multi-institutional MOMENTUM study has been set up to collect clinical and technical patient data to advance technical development, and facilitate evidenced-based implementation of MR-linac technology with the ultimate purpose to improve tumor control, survival, and quality of life of patients with cancer.

Background and purpose: In this study we developed a workflow for fully-automated generation of deliverable IMRT plans for a 1.5 T MR-Linac (MRL) based on contoured CT scans, and we evaluated automated MRL planning for rectal cancer. Methods: The Monte Carlo dose calculation engine used in the clinical MRL TPS (Monaco, Elekta AB, Stockholm, Sweden), suited for high accuracy dose calculations in a 1.5 T magnetic field, was coupled to our in-house developed Erasmus-iCycle optimizer. Clinically deliverable plans for 23 rectal cancer patients were automatically generated in a two-step process, i.e., multi-criterial fluence map optimization with Erasmus-iCycle followed by a conversion into a deliverable IMRT plan in the clinical TPS. Automatically generated plans (AUTOplans) were compared to plans that were manually generated with the clinical TPS (MANplans). Results: With AUTOplanning large reductions in planning time and workload were obtained; 4–6 h mainly hands-on planning for MANplans vs 1 h of mainly computer computation time for AUTOplans. For equal target coverage, the bladder and bowel bag Dmean was reduced in the AUTOplans by 1.3 Gy (6.9%) on average with a maximum reduction of 4.5 Gy (23.8%). Dosimetric measurements at the MRL demonstrated clinically acceptable delivery accuracy for the AUTOplans. Conclusions: A system for fully automated multi-criterial planning for a 1.5 T MR-Linac was developed and tested for rectal cancer patients. Automated planning resulted in major reductions in planning workload and time, while plan quality improved. Negative impact of the high magnetic field on the dose distributions could be avoided.

Purpose Day-to-day shape variation in the rectum CTV results in considerable geometric uncertainties during rectal cancer radiotherapy. To ensure coverage a large CTV-to-PTV margin is required. The purpose of this study was to increase the accuracy of treatment delivery by building a population based library of planning CTVs for rectal cancer patients and to evaluate its potential for rectum PTV margin and PTV volume reduction. Methods Analysis was done retrospectively on 33 early-stage rectal cancer patients with daily repeat CTs who received short-course pre-operative radiotherapy in 5 fractions of 5 Gy. We created signed distance maps from the planning rectum CTV to each of the repeat CTVs, from which we calculated the group mean, systematic and random error. The correlation between different regions of the rectum CTV was analyzed and used in combination with the distance maps to create the library of nine planning CTVs. For each of the repeat CTVs the best fitting CTV structure in the library was automatically selected defined by the plan that minimized the mean absolute distance between the repeat and library CTV. Residual distance maps were calculated from which a new PTV margin was constructed. Bootstrapping was performed on the margin difference to assess its significance. Results Residual errors were found to decrease with the number of plans in the library, but adding more than five plans yields negligible further error reduction. Margin reduction of up to 50% was achieved at the upper-anterior site of the mesorectum. The average PTV volume decreased by 15.5% when a library is introduced. Conclusions A library of plans strategy for rectal cancer based on population statistics is feasible and results in a considerably reduced average rectum PTV volume compared to conventional radiotherapy.

Purpose: To assess early changes in rectal tumor volume and morphology on sequential MRIs performed during 5 weeks of chemoradiotherapy. Materials and methods: Thirteen patients underwent weekly T2W-MRI during 5 weeks of preoperative radiotherapy (total 50 Gy), starting after the first week of radiation. Two radiologists visually evaluated tumor volume and morphology and one reader manually segmented tumors for each time point to quantitatively calculate tumor volumes. Evolution in tumor volume/morphology was assessed over time and compared between good responders (tumor regression grade (TRG) 1-2) and poor responders (TRG 3-5). Results: Tumor volumes decreased significantly during radiation. Early signs of response were also visually apparent: in the majority of good responders an early fibrotic transformation (week 2-3) as well as a visually estimated early volume reduction of >1/3 (week 1-2), was observed while these early changes only occurred in a minority of poor responders. Conclusion: Results of this exploratory pilot study suggest that changes in rectal tumor morphology (fibrosis) and volume can already be observed early during radiation, both when measured quantitatively and when assessed visually. These changes appear to be indicative of the final treatment outcome. (C) 2018 Elsevier B.V. All rights reserved.

Purpose To evaluate the feasibility of fiducial markers as a surrogate for gross tumor volume (GTV) position in image-guided radiation therapy of rectal cancer. Methods and Materials We analyzed 35 fiducials in 19 patients with rectal cancer who received short-course radiation therapy or long-course chemoradiation therapy. Magnetic resonance imaging examinations were performed before and after the first week of radiation therapy, and daily pre- and postirradiation cone beam computed tomography scans were acquired in the first week of radiation therapy. Between the 2 magnetic resonance imaging examinations, the fiducial displacement relative to the center of gravity of the GTV (COGGTV) and the COGGTV displacement relative to bony anatomy were determined. Using the cone beam computed tomography scans, inter- and intrafraction fiducial displacement relative to bony anatomy were determined. Results The systematic error of the fiducial displacement relative to the COGGTV was 2.8, 2.4, and 4.2 mm in the left-right, anterior-posterior (AP), and craniocaudal (CC) directions, respectively. Large interfraction systematic errors of up to 8.0 mm and random errors up to 4.7 mm were found for COGGTV and fiducial displacements relative to bony anatomy, mostly in the AP and CC directions. For tumors located in the mid and upper rectum, these errors were up to 9.4 mm (systematic) and 5.6 mm (random) compared with 4.9 mm and 2.9 mm for tumors in the lower rectum. Systematic and random errors of the intrafraction fiducial displacement relative to bony anatomy were ≤2.1 mm in all directions. Conclusions Large interfraction errors of the COGGTV and the fiducials relative to bony anatomy were found. Therefore, despite the observed fiducial displacement relative to the COGGTV, the use of fiducials as a surrogate for GTV position reduces the required margins in the AP and CC directions for a GTV boost using image-guided radiation therapy of rectal cancer. This reduction in margin may be larger in patients with tumors located in the mid and upper rectum compared with the lower rectum.

Background and study aims To facilitate image guidance during radiotherapy of rectal cancer, we investigated the feasibility of fiducial marker placement. This study aimed to evaluate technical success rate and safety of two endoscopic ultrasound (EUS)-guided placement strategies and four fiducial types for rectal cancer patients. Patients and methods This prospective multicenter study included 20 participants who were scheduled to undergo rectal cancer treatment with neoadjuvant short-course radiotherapy or chemoradiation. EUS-guided endoscopy was used for fiducial placement at the tumor site (n = 10) or in the mesorectal fat and in the tumor (n = 10). Four fiducial types were used (Visicoil 0.75 mm, Visicoil 0.50 mm, Cook, Gold Anchor). The endpoints were technical success rate and retention of fiducials, the latter of which was evaluated on cone-beam computed tomography scans during the first five radiotherapy fractions. Results A total of 64 fiducials were placed in 20 patients. For each fiducial type, at least three fiducials were successfully placed in all patients. Technical failure consisted of fiducial blockage within the needle (n = 2) and ejection of two preloaded fiducials at once (n = 4). No serious adverse events were reported. In three patients, one of the fiducials was misplaced without clinical consequences; two in the prostate and one in the intraperitoneal cavity. After a median time of 17 days after placement (range 7 – 47 days), a total of 42/64 (66 %) fiducials were still present (24/44 intratumoral vs. 18/20 mesorectal fiducials, P = 0.009). Conclusions Placement of fiducials in rectal cancer patients is feasible, however, retention rates for intratumoral fiducials were lower (55 %) than for mesorectal fiducials (90 %).

Purpose The HERBERT study was a dose-finding feasibility study of a high-dose rate endorectal brachytherapy (HDREBT) boost after external beam radiotherapy (EBRT) in elderly patients with rectal cancer who were unfit for surgery. This analysis evaluates the association of patient, tumor and dosimetric parameters with tumor response and toxicity after HDREBT in definitive radiotherapy for rectal cancer. Patients and methods The HERBERT study included 38 inoperable patients with T2-3N0-1 rectal cancer. Thirteen fractions of 3 Gy EBRT were followed by three weekly HDREBT applications of 5–8 Gy per fraction. Clinical and dosimetric parameters were tested for correlation with clinical complete response (cCR), sustained partial/complete response (SR), patient reported bowel symptoms, physician reported acute and late proctitis (CTCAE v3) and endoscopically scored toxicity. Results Thirty-five patients completed treatment and were included in the current analyses. Twenty of 33 evaluable patients achieved a cCR, the median duration of a sustained response was 32 months. Tumor volume at diagnosis showed a strong association with clinical complete response (OR 1.15; p = 0.005). No dose–response correlation was observed in this cohort. Prescribed dose to the brachytherapy CTV (D90) correlated with acute and late physician reported proctitis while CTV volume, CTV width and high dose regions in the CTV (D1cc/D2cc) were associated with endoscopic toxicity at the tumor site. Conclusion Tumor volume is the most important predictive factor for tumor response and a higher dose to the brachytherapy CTV increases the risk of severe clinically and endoscopically observed proctitis after definitive radiotherapy in elderly patients with rectal cancer.

Background and purpose A GTV boost is suggested to result in higher complete response rates in rectal cancer patients, which is attractive for organ preservation. Fiducials may offer GTV position verification on (CB)CT, if the fiducial-GTV spatial relationship can be accurately defined on MRI. The study aim was to evaluate the MRI visibility of fiducials inserted in the rectum. Materials and methods We tested four fiducial types (two Visicoil types, Cook and Gold Anchor), inserted in five patients each. Four observers identified fiducial locations on two MRI exams per patient in two scenarios: without (scenario A) and with (scenario B) (CB)CT available. A fiducial was defined to be consistently identified if 3 out of 4 observers labeled that fiducial at the same position on MRI. Fiducial visibility was scored on an axial and sagittal T2-TSE sequence and a T1 3D GRE sequence. Results Fiducial identification was poor in scenario A for all fiducial types. The Visicoil 0.75 and Gold Anchor were the most consistently identified fiducials in scenario B with 7 out of 9 and 8 out of 11 consistently identified fiducials in the first MRI exam and 2 out of 7 and 5 out of 10 in the second MRI exam, respectively. The consistently identified Visicoil 0.75 and Gold Anchor fiducials were best visible on the T1 3D GRE sequence. Conclusion The Visicoil 0.75 and Gold Anchor fiducials were the most visible fiducials on MRI as they were most consistently identified. The use of a registered (CB)CT and a T1 3D GRE MRI sequence is recommended.

The treatment protocols for rectal cancer continue to evolve, with increasing acceptance of a watch-and-wait policy for clinical complete responders to neoadjuvant chemoradiation therapy. It still, however, remains unclear who is likely to achieve a pathological complete response, which unequivocally portends a very favorable overall prognosis. Evolution of modern imaging techniques has paved the way for potential prediction of treatment response based on baseline, on-treatment, early post-treatment and subsequent follow-up imaging alone. Independent of tumor grade and stage, tumor marker levels, tumor size, radiation dose and fractionation, chemotherapy regimen, and extent/type of surgery, imaging biomarkers like circumferential resection margin (CRM), extramural venous space invasion (EMVI), imaging-based tumor regression grade, perfusion/diffusion-based functional imaging parameters, and imaging-based metabolic response have the ability to predict the likelihood of local recurrence and/or distant metastases. Textural features of images can add a further dimension to the predictive power of imaging. Finally, integration of genomic data with imaging biomarkers can potentially discern molecular mechanisms associated with distinct radiographic attributes of tumors. In this review, we evaluate and summarize the evidence to date of each imaging modality as a biomarker and its contribution to personalized decision making in rectal cancer.

Purpose: MRI guidance during radiotherapy has the potential to enable more accurate dose delivery, optimizing the balance between local control and treatment related toxicity. However, the presence of a permanent magnetic field influences the dose delivery, especially around air cavities. Here, electrons are able to return to the surface through which they entered the air cavity (electron return effect, ERE) locally resulting in dose hot- and cold-spots. Where RT of rectal cancer patients might benefit from MRI guidance for margin reduction, air cavities in and around the target volume are frequently present. The purpose of this research is to evaluate the impact of the presence of a 1.5 T transverse magnetic field on dose delivery in patients with rectal cancer. Methods: Ten patients treated with 5 × 5 Gy RT having large changes in pelvic air content were selected out of a cohort of 33 patients. On the planning CT, a 1.5 T, 6 MV, 7-field intensity modulated radiotherapy (IMRT) plan was created. This plan was subsequently recalculated on daily CT scans. For each daily CT, the CTV V{sub 95%} and V{sub 107%} and bowel area V{sub 5Gy}, V{sub 10Gy}, V{sub 15Gy}, V{sub 20Gy}, and V{sub 25Gy} were calculated tomore » evaluate the changes in dose distribution from fraction to fraction. For comparison, the authors repeated this procedure for the 0 T situation. To study the effect of changing air cavities separate from other anatomical changes, the authors also generated artificial air cavities in the CTV of one patient (2 and 5 cm diameter), in the high dose gradient region (2 cm), and in the low dose area (2 cm). Treatment plans were optimized without and with each simulated air cavity. For appearing and disappearing air cavities, the CTV V{sub 95%} and V{sub 107%} were evaluated. The authors also evaluated the ERE separate from attenuation changes locally around appearing gas pockets. Results: For the ten patients, at 1.5 T, the V{sub 95%} was influenced by both appearing and disappearing air, and dropped to

Purpose To evaluate the toxicity and efficacy of the combination of external beam radiation therapy (EBRT) followed by high-dose-rate endorectal brachytherapy (HDREBT) boost in elderly and medically inoperable patients with rectal cancer. Methods and Materials A phase 1 dose-escalation study was performed. Treatment consisted of EBRT (13 × 3 Gy) followed by 3 weekly brachytherapy applications 6 weeks later. The HDREBT dose started at 5 Gy per fraction, increasing with 1 Gy per fraction if dose-limiting toxicity (DLT, defined as grade ≥3 proctitis

Background and purpose To analyse the clinical use of needles and examine the feasibility to meet the planning criteria in three fractions of cervical cancer brachytherapy. Furthermore, to investigate whether the needles with the largest discrepancy between application and loading are essential to treatment planning. Materials and methods For 22 patients we analysed the applied and loaded needle patterns, and examined the dosimetric results for small ( Results On average 5.8 needles were applied and 4.8 loaded per fraction, with average intensity 22% (17% for small, 29% for large CTVHR). Mid-lateral needles were applied and loaded most frequently and intensely. The average CTVHR D90% prescribed dose was 88.8 Gy (SD 4.2) EQD210, the average OAR D 2 cm 3 limit was respected. Omitting the mid-ventral needles, minimal statistically significant differences were found in dose distributions between RP and CP. Conclusions Applying on average 5.8 needles per fraction it was possible to meet the planning criteria for targets and OARs in three BT fractions for both small and large CTVHR. The mid-ventral needles were not essential in treatment planning, unless situated in the vicinity of the GTVres.

Background APO866 is a highly specific inhibitor of nicotinamide phosphoribosyltransferase (NAMPT), inhibition of which reduces cellular NAD + levels. In this study we addressed the potential of NAD + depletion as an anti-cancer strategy and assessed the combination with radiation. Methods The anticipated radiosensitizing property of APO866 was investigated in prostate cancer cell lines PC3 and LNCaP in vitro and in PC3 xenografts in vivo . Results We show that APO866 treatment leads to NAD + depletion. Combination experiments with radiation lead to a substantial decrease in clonogenic cell survival in PC3 and LNCaP cells. In PC3 xenografts, treatment with APO866 resulted in reduced intratumoral NAD + levels and induced significant tumor growth delay. Combined treatment of APO866 and fractionated radiation was more effective than the single modalities. Compared with untreated tumors, APO866 and radiation alone resulted in tumor growth delays of 14days and 33days, respectively, whereas the combination showed a significantly increased tumor growth delay of 65days. Conclusions Our studies show that APO866-induced NAD + depletion enhances radiation responses in tumor cell survival in prostate cancer. However, the in vitro data do not reveal a solid cellular mechanism to exploit further clinical development at this moment.

Introduction: PARP inhibitors are promising radiosensitizers. Currently identified recommended phase II doses of PARP inhibitors in combination with radiotherapy are 10-fold lower than the EMA and FDA approved dose as single agent. The purpose of this study is to investigate the biologically effective dose range of olaparib for its use as radiosensitizer by assessing pharmacokinetics (PK) and pharmacodynamics (PD). Both the inhibition of pre-treatment PAR levels and the inhibition of radiation induced PARylation therefore have to be determined. Methods: We included PK and PD samples of all NSCLC and breast cancer patients treated at olaparib doses up to 50mg bi-daily (BID) in two phase 1 trials combining radical radiotherapy with olaparib. Plasma samples were collected for PK analysis (ranging from steady state pre-dose olaparib until +12/24 hrs after intake) and peripheral blood mononuclear cells (PBMCs) for PD analysis (pre-treatment, +3 hrs and +12/24 hrs after olaparib intake). Breast cancer patients with the primary tumor in situ had biopsies taken pre-treatment and during olaparib treatment (+3 hrs after intake) before the first fraction of radiotherapy. Olaparib concentrations were determined by HPLC-MS/MS. PAR levels were determined by commercially available ELISA, following both the NCI protocol and REP assay (de Haan et al, 2017) that includes ex vivo irradiation of intact cells to activate PARylation by PARP. PAR levels determined by the REP assay were used to calculate PAR level inhibition during treatment. Results: PK/PD data from blood samples were available from 28 NSCLC patients and 7 breast cancer patients treated with radical radiotherapy and olaparib (17 at 25mg once daily (QD), 14 at 25mg BID and 4 at 50mg BID). Repeat biopsies were available from six out of seven breast cancer patients. The plasma olaparib concentrations increased with the dose levels and showed an expected wide intra-patient variation. In tumors the olaparib concentration varied between 178 and 1441 ng/g with a median tumor to plasma ratio of 0.47. PD analyses demonstrate a significant reduction in PAR levels in PBMCs during olaparib treatment (>95% at +3 hrs after olaparib intake for all dose levels, >90% at +12 hrs in the 25mg BID dose level and 66-99% at +24 hrs in the 25mg QD dose level; all p95% in PBMCs and >83% in tumors, thereby showing biological effectivity. The tumor olaparib concentrations determined in this study were all within a range that has been shown to radiosensitize in preclinical models. Together this supports further development of PARP inhibitors as radiosensitizer at low doses. Citation Format: Rosemarie de Haan, Dick Pluim, Manon Verwijs, Gabe Sonke, Michel van den Heuvel, Baukelien van Triest, Marcel Verheij, Conchita Vens. Clinical pharmacokinetic and pharmacodynamic analyses support biological effectivity of the PARP inhibitor olaparib as radiosensitizer at low doses [abstract]. In: Proceedings of the AACR-NCI-EORTC International Conference on Molecular Targets and Cancer Therapeutics; 2019 Oct 26-30; Boston, MA. Philadelphia (PA): AACR; Mol Cancer Ther 2019;18(12 Suppl):Abstract nr C009. doi:10.1158/1535-7163.TARG-19-C009