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.

Stereotactic Magnetic Resonance-Guided Daily Adaptive SABR (SMART) for Localised Non-Metastatic Pancreatic Cancer: First Reported Clinical Outcomes From the UK.

AIMS: Prognosis of locally advanced pancreatic cancer (LAPC) remains poor with limited therapeutic options. Radiation therapy in pancreatic cancer has been restricted by the disease's proximity to radiosensitive organs at risk (OAR). However, stereotactic magnetic resonance-guided adaptive radiation therapy (SMART) has demonstrated promise in delivering ablative doses safely. We sought to report clinical outcomes from a UK-based Compassionate Access Programme that provided access to SMART to patients with LAPC. MATERIALS AND METHODS: This was a registry retrospective study conducted at a single centre with access to SMART. Patients with LAPC were treated with prescription dose of 40 Gy in 5 fractions. The planning objective was that 98% of PTV received ≥95% of the prescribed dose, prioritising duodenal, stomach and bowel UK SABR consortium constraints. Daily online adaptation was performed using magnetic resonance guidance and on-table re-optimisation. 0-3 months and > 3-month post-treatment-related toxicities, local progression-free survival, metastatic-free survival and overall survival were evaluated. RESULTS: 55 patients were treated with SMART at our institution from 2020 to 2022. Median follow-up from date of diagnosis was 17 months (range 5-37 months). Median age was 69.87% of patients underwent induction chemotherapy. 71% of patients reported 0-1 grade acute toxicity only. No grade >3 acute toxicity was reported. 5 patients (9%) reported a grade 3 toxicity (fatigue, nausea, abdominal pain, duodenal stricture). No grade >3 toxicity after 3 months was reported. 6 (10%) of patients had grade 3 toxicity (fatigue, nausea, abdominal pain, duodenal haemorrhage). Median local PFS post diagnosis was 17 months (95% CI 15.3-18.7). Median OS post diagnosis was 19 months (95% CI 15.9-22.1). One-year local control post SMART was 65%. CONCLUSION: This is the first UK-reported experience of MR-guided daily adaptive pancreatic SABR. SMART shows promise in delivering ablative doses with acceptable toxicity rates and good clinical outcomes.

Improved Dosimetry with Daily Online Adaptive Radiotherapy for Cervical Cancer: Waltzing the Pear.

AIMS: Standard of care radiotherapy for locally advanced cervical cancer includes large margins to ensure the uterocervix remains within the treatment fields over the course of treatment. Daily online cone-beam adaptive radiotherapy corrects for interfractional changes by adjusting the plan to match the target position during each treatment session, thus allowing for significantly reduced clinical target volume (CTV) to planning target volume (PTV) margins. We hypothesise that reduced margins from daily online adaptive radiotherapy will reduce organ at risk dose without compromising target coverage. MATERIALS AND METHODS: Ten patients with cervical cancer (stage IIB-IIIC2) were treated with definitive chemoradiation using daily online cone-beam adaptive radiotherapy in 25-27 fractions. Initial and all adapted treatment plans were generated with CTV to PTV margins versus standard of care image-guided radiotherapy (IGRT) plans as follows: cervix/uterus/gross tumour volume (0.5 versus 1.5 cm), parametria/vagina (0.5 versus 1.0 cm) and nodal chains and gross nodes (0.5 versus 0.5 cm). IGRT plans were created and copied to synthetic computed tomography scans and contours generated from each daily adapted fraction. The dosimetry of each clinically treated online adapted fraction was compared with emulated IGRT plans. Statistical significance was defined as P < 0.05. RESULTS: Daily online cone-beam adaptive radiotherapy significantly improves bowel bag dosimetry compared with IGRT, with a reduction in V40 by an average of 91.3 cm3 [V40 (-6.2%) and V45 (-6.1%)]. The daily adapted plans showed significant improvements in bladder and rectum [V40 (-25.2% and -36.0%) and V30 (-9.7% and -17.1%), respectively]. Additionally, bone marrow had a significantly reduced dose [V10 (-2.7%) and V20 (-3.3%)]. Daily online cone-beam adaptive radiotherapy improved uterocervix CTV coverage and reduced hotspots compared with IGRT [D95% (+1.6%) and Dmax (-0.9%)]. CONCLUSIONS: Reduced CTV to PTV margins achievable with daily online adaptive radiotherapy improves organ at risk dosimetry and target coverage when compared with standard of care IGRT for locally advanced cervical cancer. The clinical impact of improved dosimetry is currently undergoing investigation.

Stereotactic ultrahypofractionated MR-guided radiotherapy for localized prostate cancer - Acute toxicity and patient-reported outcomes in the prospective, multicenter SMILE phase II trial.

Background: Due to superior image quality and daily adaptive planning, MR-guided stereotactic body radiation therapy (MRgSBRT) has the potential to further widen the therapeutic window in radiotherapy of localized prostate cancer. This study reports on acute toxicity rates and patient-reported outcomes after MR-guided adaptive ultrahypofractionated radiotherapy for localized prostate cancer within the prospective, multicenter phase II SMILE trial. Materials and methods: A total of 69 patients with localized prostate cancer underwent MRgSBRT with daily online plan adaptation. Inclusion criteria comprised a tumor stage ≤ T3a, serum PSA value ≤ 20 ng/ml, ISUP Grade group ≤ 4. A dose of 37.5 Gy was prescribed to the PTV in five fractions on alternating days with an optional simultaneous boost of 40 Gy to the dominant intraprostatic lesion defined by multiparametric MRI. Acute genitourinary (GU-) and gastrointestinal (GI-) toxicity, as defined by CTCAE v. 5.0 and RTOG as well as patient-reported outcomes according to EORTC QLQ-C30 and -PR25 scores were analyzed at completion of radiotherapy, 6 and 12 weeks after radiotherapy and compared to baseline symptoms. Results: There were no toxicity-related treatment discontinuations. At the 12-week follow-up visit, no grade 3 + toxicities were reported according to CTCAE. Up until the 12-week visit, in total 16 patients (23 %) experienced a grade 2 GU or GI toxicity. Toxicity rates peaked at the end of radiation therapy and subsided within the 12-week follow-up period. At the 12-week follow-up visit, no residual grade 2 GU toxicities were reported and 1 patient (1 %) had residual grade 2 enteritic symptoms. With exception to a significant improvement in the emotional functioning score following MRgSBRT, no clinically meaningful changes in the global health status nor in relevant subscores were reported. Conclusion: Daily online-adaptive MRgSBRT for localized prostate cancer resulted in an excellent overall toxicity profile without any major negative impact on quality of life.

Dosimetric benefit of online treatment plan adaptation in stereotactic ultrahypofractionated MR-guided radiotherapy for localized prostate cancer.

Background: Apart from superior soft tissue contrast, MR-guided stereotactic body radiation therapy (SBRT) offers the chance for daily online plan adaptation. This study reports on the comparison of dose parameters before and after online plan adaptation in MR-guided SBRT of localized prostate cancer. Materials and methods: 32 consecutive patients treated with ultrahypofractionated SBRT for localized prostate cancer within the prospective SMILE trial underwent a planning process for MR-guided radiotherapy with 37.5 Gy applied in 5 fractions. A base plan, derived from MRI simulation at an MRIdian Linac, was registered to daily MRI scans (predicted plan). Following target and OAR recontouring, the plan was reoptimized based on the daily anatomy (adapted plan). CTV and PTV coverage and doses at OAR were compared between predicted and adapted plans using linear mixed regression models. Results: In 152 out of 160 fractions (95%), an adapted radiation plan was delivered. Mean CTV and PTV coverage increased by 1.4% and 4.5% after adaptation. 18% vs. 95% of the plans had a PTV coverage ≥95% before and after online adaptation, respectively. 78% vs. 100% of the plans had a CTV coverage ≥98% before and after online adaptation, respectively. The D0.2cc for both bladder and rectum were <38.5 Gy in 93% vs. 100% before and after online adaptation. The constraint at the urethra with a dose of <37.5 Gy was achieved in 59% vs. 93% before and after online adaptation. Conclusion: Online adaptive plan adaptation improves target volume coverage and reduces doses to OAR in MR-guided SBRT of localized prostate cancer. Online plan adaptation could potentially further reduce acute and long-term side effects and improve local failure rates in MR-guided SBRT of localized prostate cancer.

An online adaptive plan library approach for intensity modulated proton therapy for head and neck cancer.

BACKGROUND AND PURPOSE: In intensity modulated proton therapy (IMPT), the impact of setup errors and anatomical changes is commonly mitigated by robust optimization with population-based setup robustness (SR) settings and offline replanning. In this study we propose and evaluate an alternative approach based on daily plan selection from patient-specific pre-treatment established plan libraries (PLs). Clinical implementation of the PL strategy would be rather straightforward compared to daily online re-planning. MATERIALS AND METHODS: For 15 head-and-neck cancer patients, the planning CT was used to generate a PL with 5 plans, robustly optimized for increasing SR: 0, 1, 2, 3, 5 mm, and 3% range robustness. Repeat CTs (rCTs) and realistic setup and range uncertainty distributions were used for simulation of treatment courses for the PL approach, treatments with fixed SR (fSR3) and a trigger-based offline adaptive schedule for 3 mm SR (fSR3OfA). Daily plan selection in the PL approach was based only on recomputed dose to the CTV on the rCT. RESULTS: Compared to using fSR3 and fSR3OfA, the risk of xerostomia grade ≥ II & III and dysphagia ≥ grade III were significantly reduced with the PL. For 6/15 patients the risk of xerostomia and/or dysphagia ≥ grade II could be reduced by > 2% by using PL. For the other patients, adherence to target coverage constraints was often improved. fSR3OfA resulted in significantly improved coverage compared to PL for selected patients. CONCLUSION: The proposed PL approach resulted in overall reduced NTCPs compared to fSR3 and fSR3OfA at limited cost in target coverage.