MR-Linac Radiotherapy - The Beam Angle Selection Problem

BACKGROUND: With 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 METHODS: 23 patients treated at a Unity MR-linac were included. BAO(x) plans (x=7-12 beams) were generated for all patients. Analyses of BAO(12) plans resulted in CS(x) class solutions. BAO(x) plans, CS(x) plans, and plans with equi-angular setups (EQUI(x), x=9-56) were mutually compared. RESULTS: For x>7, plan quality for CS(x) and BAO(x) was highly similar, while both were superior to EQUI(x). E.g. with CS(9), bowel/bladder D(mean) reduced by 22% [11%, 38%] compared to EQUI(9) (p<0.001). For equal plan quality, the number of EQUI beams had to be doubled compared to BAO and CS. CONCLUSIONS: Computer-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

Gross tumour volume delineation in anal cancer on T2-weighted and diffusion-weighted MRI - Reproducibility between radiologists and radiation oncologists and impact of reader experience level and DWI image quality

Abstract Purpose To assess how gross tumour volume (GTV) delineation in anal cancer is affected by interobserver variations between radiologists and radiation oncologists, expertise level, and use of T2-weighted MRI (T2W-MRI) vs. diffusion-weighted imaging (DWI), and to explore effects of DWI quality. Methods and materials We retrospectively analyzed the MRIs (T2W-MRI and b800-DWI) of 25 anal cancer patients. Four readers (Senior and Junior Radiologist; Senior and Junior Radiation Oncologist) independently delineated GTVs, first on T2W-MRI only and then on DWI (with reference to T2W-MRI). Maximum Tumour Diameter (MTD) was calculated from each GTV. Mean GTVs/MTDs were compared between readers and between T2W-MRI vs. DWI. Interobserver agreement was calculated as Intraclass Correlation Coefficient (ICC), Dice Similarity Coefficient (DSC) and Hausdorff Distance (HD). DWI image quality was assessed using a 5-point artefact scale. Results Interobserver agreement between radiologists vs. radiation oncologists and between junior vs. senior readers was good–excellent, with similar agreement for T2W-MRI and DWI (e.g. ICCs 0.72–0.94 for T2W-MRI and 0.68–0.89 for DWI). There was a trend towards smaller GTVs on DWI, but only for the radiologists (P = 0.03–0.07). Moderate-severe DWI-artefacts were observed in 11/25 (44%) cases. Agreement tended to be lower in these cases. Conclusion Overall interobserver agreement for anal cancer GTV delineation on MRI is good for both radiologists and radiation oncologists, regardless of experience level. Use of DWI did not improve agreement. DWI artefacts affecting GTV delineation occurred in almost half of the patients, which may severely limit the use of DWI for radiotherapy planning if no steps are undertaken to avoid them

Outcomes and potential impact of a virtual hands-on training program on MRI staging confidence and performance in rectal cancer

Objectives: To explore the potential impact of a dedicated virtual training course on MRI staging confidence and performance in rectal cancer. // Methods: Forty-two radiologists completed a stepwise virtual training course on rectal cancer MRI staging composed of a pre-course (baseline) test with 7 test cases (5 staging, 2 restaging), a 1-day online workshop, 1 month of individual case readings (n = 70 cases with online feedback), a live online feedback session supervised by two expert faculty members, and a post-course test. The ESGAR structured reporting templates for (re)staging were used throughout the course. Results of the pre-course and post-course test were compared in terms of group interobserver agreement (Krippendorf’s alpha), staging confidence (perceived staging difficulty), and diagnostic accuracy (using an expert reference standard). // Results: Though results were largely not statistically significant, the majority of staging variables showed a mild increase in diagnostic accuracy after the course, ranging between + 2% and + 17%. A similar trend was observed for IOA which improved for nearly all variables when comparing the pre- and post-course. There was a significant decrease in the perceived difficulty level (p = 0.03), indicating an improved diagnostic confidence after completion of the course. // Conclusions: Though exploratory in nature, our study results suggest that use of a dedicated virtual training course and web platform has potential to enhance staging performance, confidence, and interobserver agreement to assess rectal cancer on MRI virtual training and could thus be a good alternative (or addition) to in-person training. // Clinical relevance statement: Rectal cancer MRI reporting quality is highly dependent on radiologists’ expertise, stressing the need for dedicated training/teaching. This study shows promising results for a virtual web-based training program, which could be a good alternative (or addition) to in-person training. // Key Points: • Rectal cancer MRI reporting quality is highly dependent on radiologists’ expertise, stressing the need for dedicated training and teaching. • Using a dedicated virtual training course and web-based platform, encouraging first results were achieved to improve staging accuracy, diagnostic confidence, and interobserver agreement. • These exploratory results suggest that virtual training could thus be a good alternative (or addition) to in-person training

Adaptive radiotherapy for long course neo-adjuvant treatment of rectal cancer.

To quantify the potential margin reduction with adaptive radiotherapy (ART) during neo-adjuvant treatment of locally-advanced rectal cancer. Repeat CT scans were acquired for 28 patients treated with 25×2 Gy, daily during the first week, and followed by weekly scans. The CTV was delineated on all scans, and shape variation was estimated. Five ART strategies were tested, consisting of an average CTV over the planning CT and one to five repeat CTs. Required PTV margins were calculated for adapted and non-adapted treatment. The strategy with the least PTV volume over the whole treatment was selected and bowel area dose reduction was estimated. Substantial systematic and random shape variation demanded for a PTV margin up to 2.4 cm at the upper-anterior part of the CTV. Plan adaptation after fraction 4 resulted in a maximum 0.7 cm margin reduction and a significant PTV reduction from 1185 to 1023 cc (p <0.0001). The bowel area volume receiving 15, 45, and 50 Gy was reduced from 436 to 402 cc, 111 to 81 cc, and 49 to 29 cc, respectively (p <0.0001). With adaptive radiotherapy, maximum required PTV margins can be reduced from 2.4 to 1.7 cm, resulting in significantly less dose to the bowel are

Pre-clinical experience of an adaptive plan library strategy in radiotherapy of rectal cancer: An inter-observer study

Background and purpose: The clinical target volume (CTV) in radiotherapy of rectal cancer is subject to large deformations. With a plan library strategy, the treatment may be adapted to these deformations. The purpose of this study was to determine feasibility and consistency in plan selection for a plan library strategy in radiotherapy of rectal cancer. Material and methods: Thirty rectal cancer patients were included in this retrospective study with in total 150 CBCT scans. A library of CTVs was constructed with in-house built software using population statistics on daily rectal deformations. The library consisted of five plans based on: the original CTV, two larger, and two smaller CTVs. An inter-observer study (study-I) was performed to test the consistency in plan choices between four observers (all RTTs). After five months the observers were asked to re-evaluate (study-II) the same set of scans based on refined guidelines. Results: In study-I the observers reached accordance with the majority choice in 69% of cases. This improved to 87% in study-II. The consensus meeting revealed that inconsistency in choices mainly arose from inadequate instructions, which were later clarified and formulated more accurately. Conclusion: Plan selection based on daily CBCT scans for rectal cancer patients is feasible, and can be performed consistently by well-trained RTTs. Keywords: Plan library, Rectum, Adaptive radiotherapy, Inter-observer stud

A phase Ia/Ib trial of the DNA-dependent protein kinase inhibitor (DNA-PKi) M3814 in combination with radiotherapy in patients with advanced solid tumors

e14048 Background: DNA-PK, with its protein subunits, Ku70 and Ku80, regulates one of the major pathways responsible for repair of double-strand breaks in DNA that are induced by radiotherapy (RT) and some chemotherapeutic agents (CT). Therefore, the combined strategy of RT with a DNA-PKi is promising. The purpose of this phase I trial is to explore the safety, tolerability, pharmacokinetic (PK) profile, and clinical activity of M3814 administered together with RT and chemo-RT (CRT). Methods: Patients (pts) with tumors or metastasis in the head and neck region or thorax in need of palliative RT (10 x 3 Gy) are eligible for the dose escalation part Ia, with a starting dose of 100 mg once daily. Dose escalation decisions are aided by the Bayesian logistic regression model with overdose control. Dose-limiting toxicity (DLT) is evaluated up to 3 weeks after RT. Rich PK sampling is taken during treatment. Tumor evaluation is performed every 6 weeks up to 6 months and every third month thereafter. Results: As of January 2017, 7 pts had been enrolled into the part Ia dose escalation arm and treated with 100 mg daily. The most frequent adverse events (AEs) were fatigue, constipation, decreased appetite, dry mouth, dysphagia, headache, oral pain, radiation skin injury, and mucositis in more than 1 pt (20%). No pts discontinued due to AE. Two episodes of grade 3 mucositis lasting > 7 days were reported; one of these was classified as a DLT, and both pts recovered without sequelae. Two of 7 pts enrolled had local tumor control at +300 days. PK analysis demonstrated high exposure variability. Conclusions: M3814 at the 100 mg daily dose was tolerable as palliative treatment and dose escalation is currently at 200 mg. In part Ib of the study, two separate dose escalation arms will enroll pts with either head and neck squamous cell carcinoma (SCCHN; US only) or non-small cell lung cancer (EU and US) to receive CRT 2 Gy x 30-35 over 6-7 weeks with curative intent; the SCCHN cohort is now open for enrollment. For these two cohorts, the DLT window will be 12 weeks. Clinical trial information: NCT02516813

Defining near-complete response following (chemo)radiotherapy for rectal cancer: systematic review

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

Identification and immunolocalization of superoxide dismutase isoenzymes of olive pollen

5 páginas, 3 figuras.-- The definitive version is available at www3.interscience.wiley.comGametophytic tissues of plants are an area largely neglected in the broad literature on free radical processes in plants. In order to study the mechanisms of protection against oxidative stress in pollen, the presence of the key antioxidative enzyme superoxide dismutase (SOD; EC 1.15.1.1) was investigated. Crude extracts of olive tree (Olea europaea L.) pollen were subjected to native PAGE in 10% polyacrylamide gels. The SOD activity staining of gels showed the presence of four isoenzymes. All the SODS were completely inhibited by 2 mM KCN and 5 mM H2O2, and therefore belong to the family of CuZn-SODS. Isoelectric focusing (pH 3.5-7) of crude extracts and further detection of SOD activity allowed determination of isoelectric points for the four isoforms, namely 4.60, 4.78, 5.08 and 5.22. The cross-reactivity of pollen extracts with a polyclonal antibody to cytosolic CuZn-SOD from spinach leaves was assayed by western blotting. After SDS-PAGE and immunoblotting, a major polypeptide band of about 16.5 kDa was detected, which is characteristic of the subunit of most CuZn-SODS. Immunocytochemical studies at TEM level using the same antiserum showed that CuZn-SOD was localized in the cytoplasm of both vegetative and generative cells, and also in material adhered to the pollen wall. The olive pollen CuZn-SODS could function in the protection against oxidative stress during pollen development.This work was supported by Project FMBI-CT95-0470 from the European Commission, and by the Junta de Andalucía (research groups CVI 0192 and AGR 160), Spain.Peer reviewe

Repeat CT assessed CTV variation and PTV margins for short- and long-course pre-operative RT of rectal cancer.

To quantify the inter-fraction shape variation of the CTV in rectal-cancer patients treated with 5 × 5 (SCRT) and 25 × 2 Gy (LCRT) and derive PTV margins. Thirty-three SCRT with daily repeat CT scans and 30 LCRT patients with daily scans during the first week followed by weekly scans were included. The CTV was delineated on all scans and local shape variation was calculated with respect to the planning CT. Margin estimation was done using the local shape variation to assure 95% minimum dose for at least 90% of patients. Using 482 CT scans, systematic and random CTV shape variation was heterogeneous, ranging from 0.2 cm close to bony structures up to 1.0 cm SD at the upper-anterior CTV region. A significant reduction in rectal volume during LCRT resulted in an average 0.5 cm posterior shift of the upper-anterior CTV. Required margins ranged from 0.7 cm close to bony structures up to 3.1 and 2.3 cm in the upper-anterior region for SCRT and LCRT, respectively. Heterogeneous shape variation demands anisotropic PTV margins. Required margins were substantially larger in the anterior direction compared to current clinical margins. These larger margins were, however, based on strict delineated CTVs, resulting in smaller PTVs compared to current practic

Improved pharmacodynamic (PD) assessment of low dose PARP inhibitor PD activity for radiotherapy and chemotherapy combination trials

Background: PARP inhibitors are currently evaluated in combination with radiotherapy and/or chemotherapy. As sensitizers, PARP inhibitors are active at very low concentrations therefore requiring highly sensitive pharmacodynamic (PD) assays. Current clinical PD-assays partly fail to provide such sensitivities. The aim of our study was to enable sensitive PD evaluation of PARP inhibitors for clinical sensitizer development. Material and methods: PBMCs of healthy individuals and of olaparib and radiotherapy treated lung cancer patients were collected for ELISA-based PD-assays. Results: PAR-signal amplification by ex vivo irradiation enabled an extended quantification range for PARP inhibitory activities after ex vivo treatment with inhibitors. This “radiation-enhanced-PAR” (REP) assay provided accurate IC50 values thereby also revealing differences among healthy individuals. Implemented in clinical radiotherapy combination Phase I trials, the REP-assay showed sensitive detection of PARP inhibition in patients treated with olaparib and establishes strong PARP inhibitory activities at low daily doses. Conclusions: Combination trials of radiotherapy and novel targeted agent(s) often require different and more sensitive PD assessments than in the monotherapy setting. This study shows the benefit and relevance of sensitive and adapted PD-assays for such combination purposes and provides proof of clinically relevant cellular PARP inhibitory activities at low daily olaparib doses