Nivolumab with or without Ipilimumab Combined with Stereotactic Body Radiotherapy in Patients with Metastatic Biliary Tract Cancer: A Randomized Phase 2 Study.

PURPOSE: The purpose of this study was to evaluate the clinical benefits of nivolumab with/without ipilimumab combined with stereotactic body radiotherapy (SBRT) in patients with pretreated metastatic biliary tract cancer (mBTC). PATIENTS AND METHODS: The study was a phase 2 randomized trial with Simon's optimal two-stage design requiring 36 evaluable patients per group after second stage. Sixty-one patients were included from September 2018 to January 2022 and randomized (1:1) to receive SBRT (15 Gy × 1 on day 1 to a primary or metastatic lesion) and nivolumab (3 mg/kg intravenously on day 1 and every 2 weeks) with/without ipilimumab (1 mg/kg intravenously on day 1 and every 6 weeks). Primary endpoint was clinical benefit rate (CBR), defined as the percentage of patients with complete response, partial response, or stable disease. Decision to continue accrual into the second stage depended on the CBR from the first stage. RESULTS: Forty-two patients received SBRT/nivolumab/ipilimumab with a CBR of 31.0% [95% confidence interval (CI), 17.6-47.1]. Five patients (11.9%) achieved partial response with median duration of 4.4 months (range, 1.1-21.5). Nineteen patients received SBRT/nivolumab. This group was closed after the initial stage based on a CBR of 10.5% (95% CI, 1.3-33.1). Adverse events were graded with National Cancer Institute Common Terminology Criteria for Adverse Events version 4.0. Grade ≥3 treatment-related adverse events occurred in 13 (31%) and 3 (16%) patients in the SBRT/nivolumab/ipilimumab and SBRT/nivolumab groups, respectively. One patient died from immune-related hepatitis in the SBRT/nivolumab/ipilimumab group. CONCLUSIONS: Combining SBRT, nivolumab, and ipilimumab is well tolerated, feasible, and shows response in a subgroup of patients with mBTC.

ROAR-A: re-optimization based Online Adaptive Radiotherapy of anal cancer, a prospective phase II trial protocol.

BACKGROUND: Chemo-radiotherapy with curative intent for anal cancer has high complete remission rates, but acute treatment-related gastrointestinal (GI) toxicity is significant. Toxicity occurs due to irradiation of surrounding normal tissue. Current radiotherapy requires the addition of large planning margins to the radiation field to ensure target coverage regardless of the considerable organ motion in the pelvic region. This increases the irradiated volume and radiation dose to the surrounding normal tissue and thereby toxicity. Online adaptive radiotherapy uses artificial intelligence to adjust the treatment to the anatomy of the day. This allows for the reduction of planning margins, minimizing the irradiated volume and thereby radiation to the surrounding normal tissue.This study examines if cone beam computed tomography (CBCT)-guided oART with daily automated treatment re-planning can reduce acute gastrointestinal toxicity in patients with anal cancer. METHODS/DESIGN: The study is a prospective, single-arm, phase II trial conducted at Copenhagen University Hospital, Herlev and Gentofte, Denmark. 205 patients with local only or locally advanced anal cancer, referred for radiotherapy with or without chemotherapy with curative intent, are planned for inclusion. Toxicity and quality of life are reported with Common Terminology Criteria of Adverse Events and patient-reported outcome questionnaires, before, during, and after treatment. The primary endpoint is a reduction in the incidence of acute treatment-related grade ≥ 2 diarrhea from 36 to 25% after daily online adaptive radiotherapy compared to standard radiotherapy. Secondary endpoints include all acute and late toxicity, overall survival, and reduction in treatment interruptions. RESULTS: Accrual began in January 2022 and is expected to finish in January 2026. Primary endpoint results are expected to be available in April 2026. DISCUSSION: This is the first study utilizing online adaptive radiotherapy to treat anal cancer. We hope to determine whether there is a clinical benefit for the patients, with significant reductions in acute GI toxicity without compromising treatment efficacy. TRIAL REGISTRATION: ClinicalTrials.gov Identifier: NCT05438836. Danish Ethical Committee: H-21028093.

MR-guided stereotactic radiotherapy of infra-diaphragmatic oligometastases: Evaluation of toxicity and dosimetric parameters.

BACKGROUND AND PURPOSE: The SOFT trial is a prospective, multicenter, phase 2 trial investigating magnetic resonance (MR)-guided stereotactic ablative radiotherapy (SABR) for abdominal, soft tissue metastases in patients with oligometastatic disease (OMD) (clinicaltrials.gov ID NCT04407897). We present the primary endpoint analysis of 1-year treatment-related toxicity (TRAE). MATERIALS AND METHODS: Patients with up to five oligometastases from non-hematological cancers were eligible for inclusion. A risk-adapted strategy prioritized fixed organs at risk (OAR) constraints over target coverage. Fractionation schemes were 45-67.5 Gy in 3-8 fractions. The primary endpoint was grade ≥ 4 TRAE within 12 months post-SABR. The association between the risk of gastrointestinal (GI) toxicity and clinical and dosimetric parameters was tested using a normal tissue complication probability model. RESULTS: We included 121 patients with 147 oligometastatic targets, mainly located in the liver (41 %), lymph nodes (35 %), or adrenal glands (14 %). Nearly half of all targets (48 %, n = 71) were within 10 mm of a radiosensitive OAR. No grade 4 or 5 TRAEs, 3.5 % grade 3 TRAEs, and 43.7 % grade 2 TRAEs were reported within the first year of follow-up. We found a significant association between grade ≥ 2 GI toxicity and the parameters GI OAR D0.1cc, D1cc, and D20cc. CONCLUSION: In this phase II study of MR-guided SABR of oligometastases in the infra-diaphragmatic region, we found a low incidence of toxicity despite half of the lesions being within 10 mm of a radiosensitive OAR. GI OAR D0.1cc, D1cc, and D20cc were associated with grade ≥ 2 GI toxicity.

Online adaptive radiotherapy of anal cancer: Normal tissue sparing, target propagation methods, and first clinical experience.

BACKGROUND AND PURPOSE: Online adaptive radiotherapy (oART) potentially spares OARs as PTV margins are reduced. This study evaluates dosimetric benefits, compared to standard non-adaptive radiotherapy (non-ART), target propagation methods, and first clinical treatments of CBCT-guided oART of anal cancer. MATERIALS AND METHODS: Treatment plans with standard non-ART and reduced oART PTV margins were retrospectively generated for 23 consecutive patients with anal cancer. For five patients randomly selected among the 23 patients, weekly CBCT-guided oART sessions were simulated, where the targets were either deformed or rigidly propagated. Preferred target propagation method and dose to OARs were evaluated. Ten consecutive patients with anal cancer were treated with CBCT-guided oART. Target propagation methods and oART procedure time were evaluated. RESULTS: For the retrospective treatment plans, oART resulted in median reductions in bowel bag V45Gy of 11.4 % and bladder V35Gy of 16.1%. Corresponding values for the simulated sessions were 7.5% and 27.1%. In the simulated sessions, 35% of all targets were deformed while 65% were rigidly propagated. Manual editing and rigid propagation were necessary to obtain acceptable target coverage. In the clinical treatments, the primary and some elective targets were rigidly propagated, while other targets were deformed. The median oART procedure time, measured from CBCT acquisition to completion of plan review and QA, was 23 min. CONCLUSIONS: Simulated oART reduced the dose to OARs, indicating potential reduction in toxicity. Rigid propagation of targets was necessary to reduce the need for manual edit. Clinical treatments demonstrated that oART of anal cancer is feasible but time-consuming.

Evaluation of an automated template-based treatment planning system for radiotherapy of anal, rectal and prostate cancer.

Background and purpose: The Ethos system has enabled online adaptive radiotherapy (oART) by implementing an automated treatment planning system (aTPS) for both intensity-modulated radiotherapy (IMRT) and volumetric modulated arc radiotherapy (VMAT) plan creation. The purpose of this study is to evaluate the quality of aTPS plans in the pelvic region. Material and Methods: Sixty patients with anal (n = 20), rectal (n = 20) or prostate (n = 20) cancer were retrospectively re-planned with the aTPS. Three IMRT (7-, 9- and 12-field) and two VMAT (2 and 3 arc) automatically generated plans (APs) were created per patient. The duration of the automated plan generation was registered. The best IMRT-AP and VMAT-AP for each patient were selected based on target coverage and dose to organs at risk (OARs). The AP quality was analyzed and compared to corresponding clinically accepted and manually generated VMAT plans (MPs) using several clinically relevant dose metrics. Calculation-based pre-treatment plan quality assurance (QA) was performed for all plans. Results: The median total duration to generate the five APs with the aTPS was 55 min, 39 min and 35 min for anal, prostate and rectal plans, respectively. The target coverage and the OAR sparing were equivalent for IMRT-APs and VMAT-MPs, while VMAT-Aps.demonstrated lower target dose homogeneity and higher dose to some OARs. Both conformity and homogeneity index were equivalent (rectal) or better (anal and prostate) for IMRT-APs compared to VMAT-MPs. All plans passed the patient-specific QA tolerance limit. Conclusions: The aTPS generates plans comparable to MPs within a short time-frame which is highly relevant for oART treatments.

Gating has a negligible impact on dose delivered in MRI-guided online adaptive radiotherapy of prostate cancer.

BACKGROUND AND PURPOSE: MR-guided radiotherapy (MRgRT) allows real-time beam-gating to compensate for intra-fractional target position variations. This study investigates the dosimetric impact of beam-gating and the impact of PTV margin on prostate coverage for prostate cancer patients treated with online-adaptive MRgRT. MATERIALS AND METHODS: 20 consecutive prostate cancer patients were treated with online-adaptive MRgRT SBRT with 36.25 Gy in 5 fractions (PTV D95% ≥ 95% (N = 5) and PTV D95% ≥ 100% (N = 15)). Sagittal 2D cine MRIs were used for gating on the prostate with a 3 mm expansion as the gating window. We computed motion-compensated dose distributions for (i) all prostate positions during treatment (simulating non-gated treatments) and (ii) for prostate positions within the gating window (gated treatments). To evaluate the impact of PTV margin on prostate coverage, we simulated coverage with smaller margins than clinically applied both for gated and non-gated treatments. Motion-compensated fraction doses were accumulated and dose metrics were compared. RESULTS: We found a negligible dosimetric impact of beam-gating on prostate coverage (median of 0.00 Gy for both D95% and Dmean). For 18/20 patients, prostate coverage (D95% ≥ 100%) would have been ensured with a prostate-to-PTV margin of 3 mm, even without gating. The same was true for all but one fraction. CONCLUSION: Beam-gating has negligible dosimetric impact in online-adaptive MRgRT of prostate cancer. Accounting for motion, the clinically used prostate-to-PTV margin could potentially be reduced from 5 mm to 3 mm for 18/20 patients.

Online adaptive radiotherapy of urinary bladder cancer with full re-optimization to the anatomy of the day: Initial experience and dosimetric benefits.

BACKGROUND AND PURPOSE: Online adaptive radiotherapy (oART) potentially reduces the dose to organs at risk (OARs) as the planning target volume (PTV) margins are reduced compared to a non-adaptive approach (non-ART). This study evaluates the feasibility and dosimetric impact of cone-beam computed tomography (CBCT)-guided oART of urinary bladder cancer for the first patients treated, using patient-specific margins. MATERIALS AND METHODS: Sixteen consecutive patients with muscle-invasive bladder cancer received two or more (median = 23) fractions as oART, and remaining fractions as non-ART. The non-ART fractions were delivered with standard population-based margins, while reduced patient-specific margins based on intra-fractional variations extracted from 2-4 fractions were applied to the primary PTV (PTV-T) during the oART fractions. Target volume and coverage, and dose to OARs were compared between non-ART and oART plans, and the oART procedure time was recorded. RESULTS: In total, 297/512 fractions were delivered as oART with full re-optimization to the anatomy of the day. The median (interquartile range, IQR) oART procedure time, measured from the end of CBCT generation to completion of plan review, and quality assurance was 13.9 (11.9;16.6) min. The median (IQR) volume reduction in PTV-T volume was 33.9 (24.2;45.0)%, comparing oART and non-ART plans, resulting in median (IQR) reductions in bowel bag V45Gy of 18.8 (12.7;27.9)% and rectum V50Gy of 70.7 (35.9;94.8)%. By re-optimizing the plan to the daily anatomy, full target coverage was achieved at all oART fractions. CONCLUSIONS: oART resulted in large reductions in treatment volumes and doses to OARs, compared to non-ART, while ensuring target coverage. This indicates potential reductions in gastrointestinal toxicity.

Robust extraction of biological information from diffusion-weighted magnetic resonance imaging during radiotherapy using semi-automatic delineation.

Background and purpose: Diffusion-Weighted Magnetic Resonance imaging (DWI) quantifies water mobility through the Apparent Diffusion Coefficient (ADC), a promising radiotherapy response biomarker. ADC measurements depend on manual delineation of a region of interest, a time-consuming and observer-dependent process. Here, the aim was to introduce and test the performance of a new, semi-automatic delineation tool (SADT) for ADC calculation within the viable region of the tumour. Materials and methods: Thirty patients with rectal cancer were scanned with DWI before radiotherapy (RT) (baseline) and two weeks into RT (week 2). The SADT was based on intensities in b=1100 s mm-2 DWI and derived ADC maps. ADC values measured using the SADT and manual delineations were compared using Bland-Altman- and correlation analyses. Delineations were repeated to assess intra-observer variation, and repeatability was estimated using repeated DWI scans. Results: ADC measured using the SADT and manual delineation showed strong and moderate correlation at baseline and week 2, respectively, with the SADT measuring systematically smaller values. Intra-observer ADC variation was slightly smaller for the SADT compared to manual delineation both at baseline, [-0.00; 0.03] vs. [-0.02; 0.04] 10-3 mm2 s-1, and week 2, [-0.01; 0.00] vs. [-0.04; 0.07] 10-3 mm2 s-1 (68.3% limits of agreement). The ADC change between baseline and week 2 was larger than the ADC uncertainty ( ± 0.04 · 10-3 mm2 s-1) in all cases except one. Conclusion: The presented SADT showed performance comparable to manual expert delineation, and with sufficient consistency to allow extraction of potential biological information from the viable tumour.