Good intentions and ICH-GCP: Trial conduct training needs to go beyond the ICH-GCP document and include the intention-to-treat principle.

BACKGROUND: It is assumed investigators and statisticians fully understand the importance of avoiding missing outcomes and the intention-to-treat principle during design and analysis phases of a randomised controlled trial in order to obtain the most valuable and reliable results. However, many personnel undertaking day-to-day trial conduct and data collection commonly rely exclusively for guidance on the widely implemented, indeed regulated, International Conference on Harmonisation-Good Clinical Practice document as the guideline and standard for trial conduct. PURPOSE: This article describes adverse consequences of omission of intention-to-treat principles from training for trial personnel and explores the need for training in addition to the International Conference on Harmonisation-Good Clinical Practice guideline document. METHODS: Data from the Breast Boost Study were used to illustrate a comparison of actual results, where vigilant senior investigators re-enforced intention-to-treat requirements throughout all aspects of trial conduct with results that could easily have occurred if study personnel did not understand the importance of intention-to-treat principles. Experience as a co-ordinating centre for an international trial (Trans-Tasman Radiation Oncology Group 08.06 Breast STARS) acted as an audit of data-management culture regarding intention-to-treat in Australia and New Zealand. RESULTS: Despite the Breast Boost Study exceeding planned accrual, it was demonstrated that the study, which found a statistically significant result, could have reported a negative or inconclusive result under the scenario of trial conduct personnel having lack of understanding of the importance of avoiding losses to follow-up. Trans-Tasman Radiation Oncology 08.06 co-ordination experience verified that data-management culture in Australia and New Zealand does not adequately recognise intention-to-treat principles, and this is reflected in trial conduct. LIMITATIONS: Trial data described are limited to two trials and in the Australian and New Zealand setting. CONCLUSION: To be both scientifically and ethically valid, guidelines for trial conduct should include and stress the importance of the intention-to-treat principle and in particular avoiding missing outcomes. Our discussion highlights the vitally important role played by personnel involved in day-to-day trial conduct. Inclusion of scientific principles in guideline documents and/or training which goes beyond International Conference on Harmonisation-Good Clinical Practice to include intention-to-treat is essential to achieve robust research results. Related aspects of randomised trial consent and ethics are discussed.

SABR for Early Non-Small Cell Lung Cancer: Changes in Pulmonary Function, Dyspnea, and Quality of Life.

PURPOSE: The aim of this study was to report pulmonary function tests (PFTs) and clinician-reported and patient-reported quality-of-life (QoL) outcomes on a cohort of patients with non-small cell lung cancer (NSCLC) treated with SABR. METHODS AND MATERIALS: A total of 119 patients with NSCLC were treated with SABR in the prospective cohort SSBROC study of patients with T1-T2N0M0 NSCLC. PFTs and QoL measures were obtained at baseline pretreatment and at 6-month intervals. Here we report on the 6- to 18-month time points. Analysis of covariance (ANCOVA) methods adjusting for baseline analyzed potential predictors on outcomes of PFTs and patient-reported dyspnea at 18 months. RESULTS: The only statistically significant decline in PFTs was seen in forced expiratory volume in 1 second (FEV1) at 18 months post-SABR, with a decline of -0.11 L (P = .0087; 95% CI, -0.18 to -0.02). Of potential predictors of decline, only a 1-unit increase in smoking pack-years resulted in a -0.12 change in diffusing capacity for carbon monoxide (P = .026; 95% CI, -0.02 to -0.23) and a 0.003 decrease in FEV1 (P = .026; 95% CI, -0.006 to -0.0004). For patient-reported outcomes, statistically significant worsening in both the European Organisation for Research and Treatment of Cancer Quality of Life Core Questionnaire (QLQ-C30 Version 3) and the lung module (QLQ-LC13) dyspnea scores occurred at the 18-month time point, but not earlier. No potential predictors of worsening dyspnea were statistically significant. There was no statistically significant decline in clinician-reported outcomes or global QoL scores. CONCLUSIONS: We found a statistically significant decline in FEV1 at 18 months posttreatment. Smoking pack-years was a predictor for decline in diffusing capacity for carbon monoxide and FEV1 at 18 months. Worsening of patient-reported dyspnea scores was observed, consistent with the expected progression of lung comorbid disease.

Tumour Stroma Ratio Assessment Using Digital Image Analysis Predicts Survival in Triple Negative and Luminal Breast Cancer.

We aimed to determine the clinical significance of tumour stroma ratio (TSR) in luminal and triple negative breast cancer (TNBC) using digital image analysis and machine learning algorithms. Automated image analysis using QuPath software was applied to a cohort of 647 breast cancer patients (403 luminal and 244 TNBC) using digital H&E images of tissue microarrays (TMAs). Kaplan-Meier and Cox proportional hazards were used to ascertain relationships with overall survival (OS) and breast cancer specific survival (BCSS). For TNBC, low TSR (high stroma) was associated with poor prognosis for both OS (HR 1.9, CI 1.1-3.3, p = 0.021) and BCSS (HR 2.6, HR 1.3-5.4, p = 0.007) in multivariate models, independent of age, size, grade, sTILs, lymph nodal status and chemotherapy. However, for luminal tumours, low TSR (high stroma) was associated with a favourable prognosis in MVA for OS (HR 0.6, CI 0.4-0.8, p = 0.001) but not for BCSS. TSR is a prognostic factor of most significance in TNBC, but also in luminal breast cancer, and can be reliably assessed using quantitative image analysis of TMAs. Further investigation into the contribution of tumour subtype stromal phenotype may further refine these findings.

Collaborative implementation of stereotactic ablative body radiotherapy: A model for the safe implementation of complex radiotherapy techniques in Australia.

INTRODUCTION: Stereotactic ablative radiotherapy (SABR) for lung cancer is a modality of treatment that has improved outcomes for lung cancer patients. However, radiotherapy for lung cancer is underutilized and fewer than half of elderly patients with non-small cell lung cancer (NSCLC) receive active treatment. The purpose of this study is to report on a collaboration in implementing an NSCLC SABR (stereotactic ablative body radiation) program safely, efficiently, and uniformly across several centers, including regional sites. The first aim of this paper is to detail the collaboration and implementation that started in 2013 and is ongoing. The second aim of this paper is to document early toxicities and quality of life outcomes. METHOD: A tripartite approach was used to develop the protocol and networks required for the implementation of SABR across multiple sites in NSW. Departments starting the programmes were supported and physics credentialing with central site submission was required before commencing the treatment. Additional ongoing support was available via an email discussion group involving all members of the collaboration. RESULTS: Between July 22, 2013 and February 22, 2016, 41 patients were enrolled with 34 patients in active follow up. The toxicity profile so far is similar to those of published studies with no appreciable effect on quality of life outcomes. CONCLUSION: The collaboration formed an effective framework in facilitating the implementation of SABR across several sites in NSW and could be used as a model for the safe and uniform implementation of new technologies in Australia.

Breast irradiation causes pallor in the nipple-areolar complex in women with Celtic skin type (result from the St. George and Wollongong randomised breast boost trial).

INTRODUCTION: The nipple-areolar complex (NAC) has special histological properties with higher melanocyte concentration than breast skin. To date, there are no data describing the late effects on the NAC following breast-conserving therapy (BCT). This study evaluated colour changes in the NAC in patients treated with breast-conserving surgery and adjuvant radiotherapy after 5 years. METHODS: Digital photographs obtained at 5 years following breast irradiation from the St. George and Wollongong (SGW) trial (NCT00138814) were evaluated by five experts using an iPad® (Apple Inc., Cupertino, CA, USA) application specifically created for this study. The SGW trial randomised 688 patients with Tis-2, N0-1, M0 carcinoma to the control arm of 50 Gy in 25 fractions and boost arm of 45 Gy in 25 fractions and 16 Gy in 8 fractions electron boost. RESULTS: A total of 141/372 (38%) patients had altered NAC (86% lighter, 10% darker). Patients with Celtic skin type had increased likelihood of having an altered NAC (odds ratio (OR), 1.75 (CI 1.1-2.7, P = 0.011)). On subgroup analysis, those with Celtic skin type receiving biologically equivalent dose (BED) Gy3 ≥ 80 Gy had OR of 3.03 (95% CI 1.2-7.5, P = 0.016) for having altered colour. There was a dose response with more profound changes seen in the NAC compared with irradiated breast skin if BED Gy3 ≥ 80 Gy with OR of 2.42 (95% CI 1.1-5.6, P = 0.036). CONCLUSION: In this Caucasian BCT population, over 30% of patients developed lighter NAC and more commonly in women with Celtic skin type. The degree of this effect increased with higher radiation dose.

Radiotherapy breast boost with reduced whole-breast dose is associated with improved cosmesis: the results of a comprehensive assessment from the St. George and Wollongong randomized breast boost trial.

PURPOSE: To evaluate comprehensively the effect of a radiotherapy boost on breast cosmetic outcomes after 5 years in patients treated with breast-conserving surgery. METHODS: The St. George and Wollongong trial (NCT00138814) randomized 688 patients with histologically proven Tis-2, N 0-1, M0 carcinoma to the control arm of 50 Gy in 25 fractions (342 patients) and the boost arm of 45 Gy in 25 fractions to the whole breast followed by a 16 Gy in 8 fraction electron boost (346 patients). Five-year cosmetic outcomes were assessed by a panel subjectively in 385 patients and objectively using pBRA (relative breast retraction assessment). A subset of patients also had absolute BRA measurements. Clinician assessment and patient self-assessment of overall cosmetic and specific items as well as computer BCCT.core analysis were also performed. RESULTS: The boost arm had improved cosmetic overall outcomes as scored by the panel and BCCT.core software with 79% (p = 0.016) and 81% (p = 0.004) excellent/good cosmesis respectively compared with 68% in no-boost arm. The boost arm also had lower pBRA and BRA values with a mean difference of 0.60 and 1.82 mm, respectively, but was not statistically significant. There was a very high proportion of overall excellent/good cosmetic outcome in 95% and 93% in the boost and no-boost arms using patient self-assessment. However, no difference in overall and specific items scored by clinician assessment and patient self-assessment was found. CONCLUSION: The results show the negative cosmetic effect of a 16-Gy boost is offset by a lower whole-breast dose of 45 Gy.

Digital photography as source documentation of skin toxicity: an analysis from the Trans Tasman Radiation Oncology Group (TROG) 04.01 post-mastectomy radiation skin care trial.

INTRODUCTION: This study evaluated digital photographs as a method of providing auditable source documentation for radiotherapy-induced skin toxicity and the possibility therefore of centralised, blinded scoring for a multicentre randomised controlled trial. METHODS: Digital photograph sets from the first five patients from each of 12 participating centres were audited. Minimum camera specifications and photograph requirements were protocol specified. Three readers rated photographs for four key quality items. They also scored skin reactions according to National Cancer Institute Common Terminology Criteria (CTC) v3.0 acute skin score and also for the presence of any moist desquamation. RESULTS: Five hundred fifty-two images were available. Field of view was scored as inadequate in 1-10%, focus inadequate in 0.4-4%, lighting inadequate in 0.2-3% and dividing line marking inadequate for scoring of skin reactions within sectors in 18-23% of photographs by three readers. Reader pairwise inter-observer agreement was 83-88% for CTC acute skin scores, but the kappa value ranged from 0.58 to 0.73. The percentage of image sectors not scored by readers due to difficulty in assessing was 1-10%. Moist desquamation was scored by clinicians in 8 (medial)-13% (lateral) of patients compared with 3-5% and 5-11% by readers. CONCLUSION: Photo reader inter-observer agreement is only moderate. Photo readers tended to underscore the frequency of moist desquamation, but the trend by sector parallels the clinical scorers. Photographs are useful source documents for auditing and monitoring, but not a replacement for clinical scoring.