Association between radiotherapy protocol variations and outcome in the CONVERT trial.

Background: Radiotherapy quality assurance (QA) is integral to radiotherapy delivery. Here we report comprehensive contouring, dosimetry, and treatment delivery QA, describe protocol compliance, and detail the impact of protocol variations on acute grade ≥3 toxicity, progression free survival (PFS), and overall survival (OS) in the phase III CONVERT trial. Materials/Methods: Radiotherapy planning data from one hundred randomly selected patients were requested. Members of the CONVERT Trial Management Group (TMG) recontoured the heart, lung, and spinal cord organs at risk (OAR) according to the trial guideline. The existing radiotherapy plan were re-applied to the new structures and the new dosimetric data were recollected. Compliance with radiotherapy QA components were recorded and radiotherapy QA components were pooled into protocol variations: acceptable, acceptable variation, and unacceptable variation. Univariable analysis with a Cox proportional hazards model established the relationship between protocol variations and patient outcome. Results: Ninety-three cases were submitted for retrospective radiotherapy QA review. Demographics of the radiotherapy QA cohort (n=93) matched the non-QA (n=450) cohort. 97.8% of gross tumour volume (GTV) contours were protocol compliant. OAR contours were non-compliant in 79.6% instances of the heart, 37.6% lung, and 75.3% spinal cord. Of the non-compliant heart contours, 86.5% and 2.7% had contours caudal and cranial to the protocol-defined heart borders. 10.8% did not include the pericardial sac and 2.7% did not include the anterior aspect of the pericardium. Eleven (11.8%) submissions exceeded protocol-defined dosimetric heart constraints; six of which were only noted on the application of protocol-compliant contours. Unacceptable variations were not associated with an increase in grade 3 toxicity (p=0.808), PFS (p=0.232), or OS (p=0.743). Conclusion: Non-protocol compliant heart contours were associated with increased dose delivered to the heart OAR, with 11.8 % of submitted heart structures exceeding protocol-defined constraints. In this QA cohort of patients with small cell lung cancer, unacceptable variations were not associated with acute grade ≥3 toxicity, PFS, or OS. Radiotherapy QA remains the cornerstone of high-quality radiotherapy delivery and should be embedded into clinical trial and non-clinical trial practice; clinical trials should report standardised radiotherapy QA parameters alongside trial outcomes.

Automatic evaluation of contours in radiotherapy planning utilising conformity indices and machine learning.

BACKGROUND AND PURPOSE: Peer-review of Target Volume (TV) and Organ at Risk (OAR) contours in radiotherapy planning are typically conducted visually; this can be time consuming and subject to interobserver variation. This study investigated automatic evaluation of contouring using conformity indices and supervised machine learning. METHODS: A total of 393 contours from 253 Stereotactic Ablative Body Radiotherapy (SABR) benchmark cases (adrenal gland, liver, pelvic lymph node and spine), delineated by 132 clinicians from 25 centres, were visually evaluated for conformity against gold standard contours. Contours were scored as "pass" or "fail" on visual peer review and six Conformity Indices (CIs) were applied. CI values were mapped to pass/fail scores for each contour and used to train supervised machine learning models. A 5-fold cross validation method was employed to determine the predictive accuracies of each model. RESULTS: The stomach structure produced models with the highest predictive accuracy overall (96% using Support Vector Machine and Ensemble models), whilst the liver GTV produced models with the lowest predictive accuracy (76% using Logistic Regression). Predictive accuracies across all models ranged from 68-96% (68-87% for TV and 71-96% for OARs). CONCLUSIONS: Although a final visual review by an experienced clinician is still required, the automatic contour evaluation method could reduce the time for benchmark case reviews by identifying gross contouring errors. This method could be successfully implemented to support departmental training and the continuous assessment of outlining for clinical staff in the peer-review process, to reduce interobserver variability in contouring and improve interpretation of radiological anatomy.

Organ at risk delineation for radiation therapy clinical trials: Global Harmonization Group consensus guidelines.

BACKGROUND AND PURPOSE: The Global Quality Assurance of Radiation Therapy Clinical Trials Harmonization Group (GHG) is a collaborative group of Radiation Therapy Quality Assurance (RTQA) Groups harmonizing and improving RTQA for multi-institutional clinical trials. The objective of the GHG OAR Working Group was to unify OAR contouring guidance across RTQA groups by compiling a single reference list of OARs in line with AAPM TG 263 and ASTRO, together with peer-reviewed, anatomically defined contouring guidance for integration into clinical trial protocols independent of the radiation therapy delivery technique. MATERIALS AND METHODS: The GHG OAR Working Group comprised of 22 multi-professional members from 6 international RTQA Groups and affiliated organizations conducted the work in 3 stages: (1) Clinical trial documentation review and identification of structures of interest (2) Review of existing contouring guidance and survey of proposed OAR contouring guidance (3) Review of survey feedback with recommendations for contouring guidance with standardized OAR nomenclature. RESULTS: 157 clinical trials were examined; 222 OAR structures were identified. Duplicates, non-anatomical, non-specific, structures with more specific alternative nomenclature, and structures identified by one RTQA group were excluded leaving 58 structures of interest. 6 OAR descriptions were accepted with no amendments, 41 required minor amendments, 6 major amendments, 20 developed as a result of feedback, and 5 structures excluded in response to feedback. The final GHG consensus guidance includes 73 OARs with peer-reviewed descriptions (Appendix A). CONCLUSION: We provide OAR descriptions with standardized nomenclature for use in clinical trials. A more uniform dataset supports the delivery of clinically relevant and valid conclusions from clinical trials.

Mycophenolate mofetil alongside high-dose corticosteroids: optimizing the management of combination immune checkpoint inhibitor-induced colitis.

Immune checkpoint inhibitor (IO) induced colitis is primarily managed with corticosteroids. Most patients have a rapid resolution of symptoms and do not require additional immunosuppressants. Many patients, however, require prolonged corticosteroid courses to maintain control of toxicity. Mycophenolate mofetil (MMF) is the prodrug of mycophenolic acid; which in turn directly inhibits activated T and B lymphocytes. MMF, in addition to corticosteroids, may enable reduction of corticosteroids without precipitating resurgence of colitis. Metastatic melanoma patients between 1 January 2017 and 31 December 2017 with combination IO-induced colitis were managed with a novel treatment algorithm: upfront oral enteric-coated MMF alongside high-dose corticosteroids. Outcome measures included incidence of colitis flare, time to grade 1 colitis, time to patient-reported normal bowel habit and overall cumulative corticosteroid exposure. Thirteen patients developed high-grade combination IO-induced colitis; 11 were managed with the combination of high-dose corticosteroid and MMF. Median patient age was 59 (range: 28-73) years. Four (36%) developed flare of colitis; flares occurred at a median of 11 (interquartile range: 4.5-16.75) days. All colitis flares responded fully to infliximab (5 mg/kg). The remaining seven patients did not develop colitis flare during corticosteroid wean. All patients were successfully weaned from corticosteroids and none had a resurgence of colitis at 8 weeks following discontinuation of MMF. Concomitant enteric-coated MMF alongside high-dose corticosteroids may hasten the improvement of high-grade colitis to normal bowel habit and reduce the incidence of colitis flare.