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.

The impact of breast cosmetic and functional outcomes on quality of life: long-term results from the St. George and Wollongong randomized breast boost trial.

The aims of this study were to evaluate the impact of cosmetic and functional outcomes after breast-conserving surgery (BCS) and radiation on quality of life (QOL). In this exploratory analysis; baseline, 5 and 10 years data of patient's assessment of breast cosmesis, arm swelling/pain, limitation of movement, loss of feeling in fingers and breast sensitivity/tenderness were dichotomized and their impact on QOL (QLQ-C30) were assessed. Multivariable modelling was also performed to assess associations with QOL. The St. George and Wollongong randomized trial randomized 688 patients into the boost and no boost arms. 609, 580, and 428 patients had baseline, 5 and 10 years cosmetic data available, respectively. Similar numbers had the various functional assessments in the corresponding period. By univariate analysis, cosmesis and a number of functional outcomes were highly associated with QOL. Adjusted multivariate modelling showed that cosmesis remained associated with QOL at 5 and 10 years. Breast sensitivity, arm pain, breast separation, age and any distant cancer event were also associated with QOL on multivariate modelling at 10 years. This study highlights the importance of maintaining favorable cosmetic and functional outcomes following BCS. In addition, the clinically and statistically significant relationship between functional outcomes and QOL shows the importance for clinicians and allied health professionals in identifying, discussing, managing, and limiting these effects in women with breast cancer in order to maintain QOL.

hist2RNA: An Efficient Deep Learning Architecture to Predict Gene Expression from Breast Cancer Histopathology Images.

Gene expression can be used to subtype breast cancer with improved prediction of risk of recurrence and treatment responsiveness over that obtained using routine immunohistochemistry (IHC). However, in the clinic, molecular profiling is primarily used for ER+ breast cancer, which is costly, tissue destructive, requires specialised platforms, and takes several weeks to obtain a result. Deep learning algorithms can effectively extract morphological patterns in digital histopathology images to predict molecular phenotypes quickly and cost-effectively. We propose a new, computationally efficient approach called hist2RNA inspired by bulk RNA sequencing techniques to predict the expression of 138 genes (incorporated from 6 commercially available molecular profiling tests), including luminal PAM50 subtype, from hematoxylin and eosin (H&E)-stained whole slide images (WSIs). The training phase involves the aggregation of extracted features for each patient from a pretrained model to predict gene expression at the patient level using annotated H&E images from The Cancer Genome Atlas (TCGA, n = 335). We demonstrate successful gene prediction on a held-out test set (n = 160, corr = 0.82 across patients, corr = 0.29 across genes) and perform exploratory analysis on an external tissue microarray (TMA) dataset (n = 498) with known IHC and survival information. Our model is able to predict gene expression and luminal PAM50 subtype (Luminal A versus Luminal B) on the TMA dataset with prognostic significance for overall survival in univariate analysis (c-index = 0.56, hazard ratio = 2.16 (95% CI 1.12-3.06), p < 5 × 10-3), and independent significance in multivariate analysis incorporating standard clinicopathological variables (c-index = 0.65, hazard ratio = 1.87 (95% CI 1.30-2.68), p < 5 × 10-3). The proposed strategy achieves superior performance while requiring less training time, resulting in less energy consumption and computational cost compared to patch-based models. Additionally, hist2RNA predicts gene expression that has potential to determine luminal molecular subtypes which correlates with overall survival, without the need for expensive molecular testing.

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.

External validation of the American Joint Committee on Cancer melanoma staging system eighth edition using the surveillance, epidemiology, and end results program.

AIM: The American Joint Committee on Cancer (AJCC) melanoma staging system eighth edition (AJCC-8) was recently released to provide accurate staging reflecting advances in the treatment of melanoma. Using population registry data, this study independently validates and compares the prognostic performance of AJCC-8 to the seventh edition (AJCC-7). METHODS: We extracted patient-, tumor-related, and survival data from the SEER-18 registry between 2010 and 2015. To assess overall survival (OS) and cancer-specific survival (CSS) for AJCC-7 and AJCC-8, we performed Kaplan-Meier analysis and computed cumulative hazard functions using Nelson-Aalen function. RESULTS: Of 126,408 individuals, 59,989 (47%) and 60,411 (48%) had available data for pathological and clinical-stage OS analysis, respectively. The 3-year OS for AJCC-7 among pathologically staged patients was: stage IA 97%, stage IB 95%, stage IIA 87%, stage IIB 76%, stage IIC 57%, stage IIIA 86%, stage IIIB 69%, stage IIIC 50%, and stage IV 24%. The 3-year OS for AJCC-8 patients was similar but was 56% for stage IIIC and 30% for stage IIID. Stage IV individuals with an elevated LDH had worse OS and CSS at all measured time-points up to 60 months compared to those with a normal LDH. CONCLUSION: The discriminatory ability of AJCC-8 and AJCC-7 appear comparable. Changes in AJCC-8 identified stage IIID as a poor prognostic subgroup among stage III patients and elevated LDH in stage IV. However, patients with advanced T-stage, node-negative tumors experienced worse survival compared to those with earlier T-stage, node-positive tumors, and the results of ongoing trials should inform adjuvant therapy in this subset of patients.

Survival prediction in triple negative breast cancer using multiple instance learning of histopathological images.

Computational pathology is a rapidly expanding area for research due to the current global transformation of histopathology through the adoption of digital workflows. Survival prediction of breast cancer patients is an important task that currently depends on histopathology assessment of cancer morphological features, immunohistochemical biomarker expression and patient clinical findings. To facilitate the manual process of survival risk prediction, we developed a computational pathology framework for survival prediction using digitally scanned haematoxylin and eosin-stained tissue microarray images of clinically aggressive triple negative breast cancer. Our results show that the model can produce an average concordance index of 0.616. Our model predictions are analysed for independent prognostic significance in univariate analysis (hazard ratio = 3.12, 95% confidence interval [1.69,5.75], p < 0.005) and multivariate analysis using clinicopathological data (hazard ratio = 2.68, 95% confidence interval [1.44,4.99], p < 0.005). Through qualitative analysis of heatmaps generated from our model, an expert pathologist is able to associate tissue features highlighted in the attention heatmaps of high-risk predictions with morphological features associated with more aggressive behaviour such as low levels of tumour infiltrating lymphocytes, stroma rich tissues and high-grade invasive carcinoma, providing explainability of our method for triple negative breast cancer.

Multiplexed immunofluorescence identifies high stromal CD68+PD-L1+ macrophages as a predictor of improved survival in triple negative breast cancer.

Triple negative breast cancer (TNBC) comprises 10-15% of all breast cancers and has a poor prognosis with a high risk of recurrence within 5 years. PD-L1 is an important biomarker for patient selection for immunotherapy but its cellular expression and co-localization within the tumour immune microenvironment and associated prognostic value is not well defined. We aimed to characterise the phenotypes of immune cells expressing PD-L1 and determine their association with overall survival (OS) and breast cancer-specific survival (BCSS). Using tissue microarrays from a retrospective cohort of TNBC patients from St George Hospital, Sydney (n = 244), multiplexed immunofluorescence (mIF) was used to assess staining for CD3, CD8, CD20, CD68, PD-1, PD-L1, FOXP3 and pan-cytokeratin on the Vectra Polaris™ platform and analysed using QuPath. Cox multivariate analyses showed high CD68+PD-L1+ stromal cell counts were associated with improved prognosis for OS (HR 0.56, 95% CI 0.33-0.95, p = 0.030) and BCSS (HR 0.47, 95% CI 0.25-0.88, p = 0.018) in the whole cohort and in patients receiving chemotherapy, improving incrementally upon the predictive value of PD-L1+ alone for BCSS. These data suggest that CD68+PD-L1+ status can provide clinically useful prognostic information to identify sub-groups of patients with good or poor prognosis and guide treatment decisions in TNBC.

What women in the United States Virgin Islands still want and need to know about HPV, cervical cancer, and condom use.

Cervical cancer is an infection-related cancer caused primarily by the human papilloma virus. Sexual behavior is a primary risk factor for contracting the genital type of the HPV. While studies have shown that vertical transmission, horizontal transmission, and transmission of the HPV following contact with infected secretions without sexual intercourse are possible, they are not common. The incidence of cervical cancer in the Caribbean is the third highest in the world. This report describes the outcomes of a cross-sectional, mixed methods, exploratory study undertaken to examine questions and concerns about HPV transmission, physical examination, cervical cancer screening, and HPV/cervical cancer risk management among a targeted group of single, unmarried women in the U.S. Virgin Islands. Analysis of the data revealed that the women had many questions and concerns about the origin of HPV infection and cervical cancer, HPV and cervical cancer risk factors, HPV and cervical cancer screening, and HPV and cervical cancer prevention and risk management. Results of the study are used to suggest opportunities for nurses to respond to the questions and concerns posed by the women through the University of the Virgin Islands and within community-based settings.

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.

TILs Immunophenotype in Breast Cancer Predicts Local Failure and Overall Survival: Analysis in a Large Radiotherapy Trial with Long-Term Follow-Up.

AIM: To determine the prognostic significance of the immunophenotype of tumour-infiltrating lymphocytes (TILs) within a cohort of breast cancer patients with long-term follow-up. METHODS: Multiplexed immunofluorescence and automated image analysis were used to assess the expression of CD3, CD8, CD20, CD68, Fox P3, PD-1 and PD-L1 in a clinical trial of local excision and radiotherapy randomised to a cavity boost or not (n = 485, median follow-up 16 years). Kaplan-Meier and Cox multivariate analysis (MVA) methodology were used to ascertain relationships with local recurrence (LR), overall survival (OS) and disease-free survival (DFS). NanoString BC360 gene expression panel was applied to a subset of luminal patients to identify pathways associated with LR. RESULTS: LR was predicted by low CD8 in MVA in the whole cohort (HR 2.34, CI 1.4-4.02, p = 0.002) and luminal tumours (HR 2.19, CI 1.23-3.92, p = 0.008) with associations with increased stromal components, decreased Tregs (FoxP3), inflammatory chemokines and SOX2. Poor OS was associated with low CD20 in the whole cohort (HR 1.73, CI 1.2-2.4, p = 0.002) and luminal tumours on MVA and low PD-L1 in triple-negative cancer (HR 3.44, CI 1.5-7, p = 0.003). CONCLUSIONS: Immunophenotype adds further prognostic data to help further stratify risk of LR and OS even in TILs low-luminal tumours.

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.

Proposal for a gold standard for cosmetic evaluation after breast conserving therapy: Results from the St George and Wollongong Breast Boost trial.

INTRODUCTION: Breast cosmesis is an important endpoint of breast conserving therapy (BCT), but a gold standard method of its evaluation is not yet established. The St. George and Wollongong Randomised Breast Boost trial used five different methods of cosmetic assessment, including both subjective and objective, to comprehensively evaluate the cosmetic outcome of the trial patients. This current study analyses the level of concordance between these methods in an attempt to determine a possible standard in the evaluation of breast cosmesis. METHODS: Patients attending follow-up clinic reviews at 5 years post breast radiotherapy were evaluated. Patients completed a cosmesis and functional assessment questionnaire, assessing clinicians completed an EORTC (European Organization for Research and Treatment of Cancer) cosmetic rating questionnaire and photographs were obtained. The photographs were later assessed by a panel of five experts, as well as analysed using the objective pBRA (relative Breast Retraction Assessment) and the BCCT.core (Breast Cancer Conservative Treatment.cosmetic results) computer software. Scores were dichotomised to excellent/good and fair/poor. Pairwise comparisons between all methods, except pBRA, were carried out using overall agreement calculations and kappa scores. pBRA scores were compared on a continuous scale with each of the other dichotomised scores obtained by the other four methods. RESULTS: Of 513 St George patients alive at 5 years, 385 (75%) attended St George for follow-up and consented to photography. Results showed that assessment by physicians in clinic and patient self-assessment were more favourable regarding overall cosmetic outcome than evaluation of photographs by the panel or the BCCT.core software. Excellent/good scores by clinician-live and patient self-assessments were 93% and 94% respectively (agreement 89%), as compared to 75% and 74% only by BCCT.core and panel assessments respectively (agreement 83%, kappa 0.57). For the pBRA measurements, there was a statistically significant difference (P <0.001) between scores for excellent/good versus fair/poor cosmesis by all four methods. The range of median pBRA measurements for fair/poor scores was 13.4-14.8 and for excellent/good scores was 8.0-9.4. CONCLUSION: Incorporating both BCCT.core assessment and patient self-assessment could potentially provide the basis of a gold standard method of breast cosmetic evaluation. BCCT.core represents an easy, time efficient, reproducible, cost effective and reliable method, however, it lacks the functional and psychosocial elements of cosmesis that only patient self-reported outcomes can provide.

The risk of second malignancies after 125I prostate brachytherapy as monotherapy in a single Australian institution.

PURPOSE: To report the incidence of second primary cancer (SPC) after 125I brachytherapy (BT) for early prostate cancer in an Australian institution. METHODS AND MATERIALS: All the patients in our cohort had a cystoscopy before the implant. Data were prospectively collected on all subsequent SPC diagnoses. Standardized incidence ratios (SIRs) were calculated to compare data with the Australian population. Kaplan-Meier analysis was used to determine the actuarial second malignancy and pelvic malignancy rates and the death from SPC and from any cause. RESULTS: A total of 889 patients were followed up for a median of 4.16 (0-13) years with 370 (42%) patients having ≥5 years of followup. Sixty patients subsequently developed an SPC of which 11 were pelvic malignancies. The 5- and 10-year cumulative incidences were 1.3% (95% confidence interval [CI]: 0.6-3) and 3.3% (95% CI: 1-7) for any pelvic malignancy and 1% (95% CI: 0.4-2) and 2.6% (1-6) for bladder cancer, respectively. The SIR was significantly higher than expected for all bladder cancers at 2.9 (95% CI: 1-6) and close to significance (SIR, 3.0; 95% CI: 0.97-7) for bladder cancers within the first 5 years of followup in the subgroup analysis. On multivariate analysis, older age was associated with increased SPC risk and older age and positive smoking status were associated with increased overall mortality, mortality due to SPC, and mortality from second malignancy (p < 0.05). CONCLUSIONS: There may be a small increased risk of bladder SPC after prostate BT. A tendency toward a higher risk of bladder SPC after BT was found within the first 5 years of followup probably reflecting screening bias.

Randomized, paired comparison of No-Sting Barrier Film versus sorbolene cream (10% glycerine) skin care during postmastectomy irradiation.

PURPOSE: Postmastectomy irradiation provides an excellent model for irradiated skin care practices because of the relatively uniform surface and radiation compared with other situations in which radiation-induced moist desquamation is common. We designed a study to test the effect of prophylactic 3M Cavilon No-Sting Barrier Film (No-Sting) on the rates of moist desquamation compared with sorbolene cream (with 10% glycerin). METHODS AND MATERIALS: The irradiated chest wall was divided into medial and lateral halves. Sixty-one women were randomized to have No-Sting applied to either the medial or lateral half, with the alternate half treated with sorbolene. RESULTS: For all patients, the skin toxicity, calculated as the area under the curve, mean No-Sting and sorbolene score was 8.1 vs. 9.2, respectively (p = 0.005, Wilcoxon signed rank test). The total number of weeks of moist desquamation for the 61 patients was 40 vs. 45, equating to a mean of 0.65 week vs. 0.74 week per patient in the No-Sting and sorbolene-treated areas, respectively. The rates of moist desquamation were 33% vs. 46% (p = 0.096, McNemar's Exact test). For 58 fully assessable patients (minimum of 7 weekly observations), the area under the curve and rates of moist desquamation were significantly different statistically (p = 0.002 and 0.049, respectively). No statistically significant differences were noted in the pain scores. The pruritus scores were significantly reduced in the No-Sting area (area under the curve, p = 0.011). CONCLUSION: No-Sting reduces the duration and frequency of radiation-induced moist desquamation.

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.

Minimal benefit of respiratory-gated radiation therapy in the management of thoracic malignancy.

BACKGROUND: Respiratory-gated radiotherapy (RGRT) is used in several centres around the world. However, there is continuing controversy regarding the benefit of this technique. The aims of this study are to quantify the dosimetric benefits and the potential predictive factors. METHODS: Thirty-four consecutive patients were planned using the RGRT and the Free Breathing (FB) approach and compared with regard to target volume coverage and normal tissue parameters. Potential predictive factors were also evaluated. RESULTS: Tumour coverage was similar 94.4% versus 95.5%. Use of RGRT was not associated with a significant reduction in spinal cord, oesophagus or cardiac dosimetric parameters. However, it did reduce the lung mean dose by 1.33 Gy (P < 0.001) and V20 by 2.2% (P < 0.001). Only superior/inferior displacement of >1 cm was predictive of a >5% reduction in lung V20 parameter, and these patients all had a gross tumour volume (GTV) of <100 cm(3). CONCLUSIONS: The dosimetric benefit of applying RGRT is small when applied in an unselected population of patients. Superior/inferior displacement of >1 cm for tumours with GTV less than 100 cm(3) may be used to select patients who may derive a >5% reduction in lung V20 parameters.

A paired, double-blind, randomized comparison of a moisturizing durable barrier cream to 10% glycerine cream in the prophylactic management of postmastectomy irradiation skin care: trans Tasman Radiation Oncology Group (TROG) 04.01.

PURPOSE: A previous, unblinded study demonstrated that an alcohol-free barrier film containing an acrylate terpolymer (ATP) was effective in reducing skin reactions compared with a 10% glycerine cream (sorbolene). The different appearances of these products precluded a blinded comparison. To test the acrylate terpolymer principle in a double-blinded manner required the use of an alternative cream formulation, a moisturizing durable barrier cream (MDBC); the study was conducted by the Trans Tasman Radiation Oncology Group (TROG) as protocol 04.01. METHODS AND MATERIALS: A total of 333 patients were randomized; 1 patient was ineligible and 14 patients withdrew or had less than 7 weeks' observations, leaving 318 for analysis. The chest wall was divided into medial and lateral compartments, and patients were randomized to have MDBC applied daily to the medial or lateral compartment and sorbolene to the other compartment. Weekly observations, photographs, and symptom scores (pain and pruritus) were collected to week 12 or resolution of skin reactions if earlier. Skin dose was confirmed by centrally calibrated thermoluminescent dosimeters. RESULTS: Rates of medial and lateral compartment Common Toxicity Criteria (CTC), version 3, greater than or equal to grade 3 skin reactions were 23% and 41%, but rates by skin care product were identical at 32%. There was no significant difference between MDBC and sorbolene in the primary endpoint of peak skin reactions or secondary endpoints of area-under-the-curve skin reaction scores. CONCLUSIONS: The MDBC did not reduce the peak skin reaction compared to sorbolene. It is possible that this is related to the difference in the formulation of the cream compared with the film formulation. Skin dosimetry verification and double blinding are essential for radiation skin care comparative studies.

Metastatic cutaneous squamous cell carcinoma to parotid nodes: the role of bolus with adjuvant radiotherapy.

INTRODUCTION: Information regarding the addition of tissue equivalent bolus to adjuvant radiotherapy (RT) for intra-parotid metastatic head and neck cutaneous squamous cell carcinoma is lacking. This study aimed to evaluate the effect of bolus versus no bolus on the patterns of regional and distant recurrence, regional control (RC), cancer-specific survival (CSS), overall survival, RT toxicity and RT interruption. METHODS: A retrospective study was performed on consecutive patients diagnosed between 1994 and 2008 with metastatic head and neck cutaneous squamous cell carcinoma who were treated with parotidectomy ± selective neck dissection and adjuvant RT ± parotid bolus. RESULTS: Seventy-five patients were identified: 64 males and 11 females, with median age of 79 years (range 40-96) of which 39 had bolus during RT. Median follow up was 48 months (range 4-177). There were 23 regional recurrences - 14 dermal, six dermal + nodal and three isolated nodal - and only two systemic recurrences. Nine patients had RT interruption >6 days due to acute skin toxicity. Bolus was associated with increased grade ≥3 radiation dermatitis (P = 0.02). RT interruption >6 days was significantly associated with inferior RC and hazard ratio, 2.83 (95% confidence interval: 1.04-7.71, P = 0.042). Lympho-vascular space invasion, positive margins and nodes >2 cm were adversely significant on CSS multivariate analysis. RC, CSS and overall survival at 5 years were 67, 66 and 52%, respectively. CONCLUSIONS: Dermal involvement dominated the pattern of regional recurrence. Bolus was associated with significantly worse skin reaction. Bolus use was not associated with a significant overall benefit on RC. This analysis does not support the use of bolus as applied in this cohort.

Metastatic Cutaneous Squamous Cell Carcinoma to the Axilla: A Review of Patient Outcomes and Implications for Future Practice.

BACKGROUND: Nodal metastasis from cutaneous SCC carries a high morbidity and mortality. Limited direct evidence is available as to the impact of radiotherapy on the outcome of patients with metastatic axillary SCC. The purpose of this study was to report on the outcomes of patients with metastatic cutaneous SCC to the axilla treated with radiotherapy. METHODS: A retrospective review of patients treated with radiotherapy between 1993 and 2010 for metastatic cutaneous SCC to the axilla was undertaken at St George Hospital, Sydney. RESULTS: Radiotherapy was administered to 36 patients, 30 with curative intent (4 definitive, 26 adjuvant) and 6 with palliative intent, 27/36 (75%) were male, 22/36 (61%) had a previous diagnosis of cutaneous SCC, and 1/36 (3%) was immunosuppressed. Mean age was 74.6 years. Mean radiotherapy dose (BEDGy10) was 61Gy10 (range 39-85 Gy10), 20/36 (56%) patients experienced recurrence, including 16 local failures and 4 isolated distant failures. Median survival for the curative and palliative groups was 3 years and 1 month, respectively. Relapse free survival (n = 36) at 2 and 5 years was 46% and 35%, respectively (curative 52% and 39%). Only 1 failure achieved complete salvage. CONCLUSION: Despite current best practice (surgery and radiotherapy), the predominant pattern of failure in these patients with metastatic axillary cSCC was locoregional. The difficulty in successfully salvaging patients after locoregional nodal relapse suggests a need for treatment intensification.

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.