Hitting the Target: Developing High-quality Evidence for Proton Beam Therapy Through Randomised Controlled Trials.

The National Health Service strategy for the delivery of proton beam therapy (PBT) in the UK provides a unique opportunity to deliver high-quality evidence for PBT through randomised controlled trials (RCTs). We present a summary of three UK PBT RCTs in progress, including consideration of their key design characteristics and outcome assessments, to inform and support future PBT trial development. The first three UK multicentre phase III PBT RCTs (TORPEdO, PARABLE and APPROACH), will compare PBT with photon radiotherapy for oropharyngeal squamous cell carcinoma, breast cancer and oligodendroglioma, respectively. All three studies were designed by multidisciplinary teams, which combined expertise from clinicians, clinical trialists and scientists with strong patient advocacy and guidance from national radiotherapy research networks and international collaborators. Consistent across all three studies is a focus on the reduction of long-term radiotherapy-related toxicities and an evaluation of patient-reported outcomes and health-related quality of life, which will address key uncertainties regarding the clinical benefits of PBT. Innovative translational components will provide insights into mechanisms of toxicity and help to frame the key future research questions regarding PBT. The UK radiotherapy research community is developing and delivering an internationally impactful PBT research portfolio. The combination of data from RCTs with prospectively collected data from a national PBT outcomes registry will provide an innovative, high-quality repository for PBT research and the platform to design and deliver future trials of PBT.

A Randomised Phase II Clinical Trial Comparing the Deliverability and Acute Toxicity of Wide Tangent versus Volumetric Modulated Arc Therapy to the Breast and Internal Mammary Chain.

AIMS: Inclusion of the internal mammary chain in the radiotherapy target volume (IMC-RT) improves disease-free and overall survival in higher risk breast cancer patients, but increases radiation doses to heart and lungs. Dosimetric data show that either modified wide-tangential fields (WT) or volumetric modulated arc therapy (VMAT) together with [AQ1]voluntary deep inspiration breath hold (vDIBH) keep mean heart doses below 4 Gy in most patients. However, the impact on departmental resources has not yet been documented. This phase II clinical trial compared the time taken to deliver IMC-RT using either WT and vDIBH or VMAT and vDIBH, together with planning time, dosimetry, set-up reproducibility and toxicity. MATERIALS AND METHODS: Left-sided breast cancer patients requiring IMC-RT were randomised to receive either WT(vDIBH) or VMAT radiotherapy. The primary outcome was treatment time, powered to detect a minimum difference of 75 min (5 min/fraction) between techniques. The population mean displacement, systematic error and random error for cone beam computed tomography chest wall matches in three directions of movement were calculated. Target volume and organ at risk doses were compared between groups. Side-effects, including skin (Radiation Therapy Oncology Group), lung and oesophageal toxicity (Common Terminology Criteria for Adverse Events v 4.03) rates, were compared between the groups over 3 months. Patient-reported outcome measures, including shoulder toxicity at baseline, 6 months and 1 year, were compared. RESULTS: Twenty-one patients were recruited from a single UK centre between February 2017 and January 2018. The mean (standard deviation) total treatment time per fraction for VMAT treatments was 13.2 min (1.7 min) compared with 28.1 min (3.3 min) for WT(vDIBH). There were no statistically significant differences in patient set-up errors in between groups. The average mean heart dose for WT(vDIBH) was 2.6 Gy compared with 3.4 Gy for VMAT(vDIBH) (P = 0.13). The mean ipsilateral lung V17Gy was 32.8% in the WT(vDIBH) group versus 34.4% in the VMAT group (P = 0.2). The humeral head (mean dose 16.8 Gy versus 2.8 Gy), oesophagus (maximum dose 37.3 Gy versus 20.1 Gy) and thyroid (mean dose 22.0 Gy versus 11.2 Gy) all received a statistically significantly higher dose in the VMAT group. There were no statistically significant differences in skin, lung or oesophageal toxicity within 3 months of treatment. Patient-reported outcomes of shoulder toxicity, pain, fatigue, breathlessness and breast symptoms were similar between groups at 1 year. CONCLUSION: VMAT(vDIBH) and WT(vDIBH) are feasible options for locoregional breast radiotherapy including the IMC. VMAT improves nodal coverage and delivers treatment more quickly, resulting in less breath holds for the patient. This is at the cost of increased dose to some non-target tissues. The latter does not appear to translate into increased toxicity in this small study.

Five-fraction Radiotherapy for Breast Cancer: FAST-Forward to Implementation.

INTRODUCTION: The phase 3 FAST-Forward trial reported outcomes for 26 and 27 Gy schedules delivered in 5 fractions over 1 week versus 40 Gy in 15 fractions over 3 weeks in 4000 patients. We discuss concerns raised by the radiotherapy community in relation to implementing this schedule. IPSILATERAL BREAST TUMOUR RELAPSE (IBTR): Published estimated 5-year IBTR with 95% CI after 40 Gy in 15 fractions was 2.1% (95% CI 1.4-3.1), 1.7% (1.2-1.6) after 27 Gy and 1.4% (0.2-2.2) after 26 Gy, emphatically showing non-inferiority of the 5-fraction regimens. Subgroup analyses comparing IBTR in 26 Gy versus 40 Gy show no evidence of differential effect regarding age, grade, pathological tumour size, nodal status, tumour bed boost, adjuvant chemotherapy, HER2 status and triple negative status. The number of events in these analyses is small and results should be interpreted with caution. There was only 1 IBTR event post-mastectomy. NORMAL TISSUE EFFECTS: The 26 Gy schedule, on the basis of similar NTE to 40 Gy in 15 fractions, is the recommended regimen for clinical implementation. There is a low absolute rate of moderate/marked NTE, these are predominantly moderate not severe change. Subgroup analyses comparing clinician-assessed moderate or marked adverse effect for 26 Gy versus 40 Gy show no evidence of differential effects according to age, breast size, surgical deficit, tumour bed boost, or adjuvant chemotherapy. RADIOBIOLOGICAL CONSIDERATIONS: The design of the FAST-Forward trial does not control for time-related effects, and the ability to interpret clinical outcomes in terms of underlying biology is limited. There could conceivably be a time-effect for tumour control. A slight reduction in α/ß estimate for the late normal tissue effects of test regimens might be a chance effect, but if real could reflect fewer consequential late effects due to lower rates of moist desquamation. CONCLUSION: The 26 Gy 5-fraction daily regimen for breast radiotherapy can be implemented now.

Women's Free-text Comments on their Quality of Life: An Exploratory Analysis from the UK Standardisation of Breast Radiotherapy (START) Trials for Early Breast Cancer.

AIMS: Exploratory analysis of patients' unsolicited written comments in the first 2 years of the Standardisation of Breast Radiotherapy (START) trial quality of life study highlighted a potential effect of non-treatment-related problems on the ratings and interpretation of patient self-reported questionnaires. At 5 years of follow-up all eligible subjects were invited to write comments to further explore these findings. MATERIALS AND METHODS: Using inductive qualitative methods informed by the exploratory analysis, comments were allocated to relevant themes. Key patient-reported outcome measures (PROMs), clinical and demographic factors were collated for patients who did and did not comment at 5 years and comparisons between the groups explored. RESULTS: Of 2208 women completing baseline PROMs, 482 proffered comments from 0 to 24 months, forming nine distinct themes, including chronic conditions, life events and psychosocial concerns. At 5 years, 1041/1727 (60.3%) women contributed comments, of whom 500 randomly selected participants formed the sample for analysis. Findings revealed comorbidity, impaired physical functioning and psychosocial problems as key themes, with prevalent adverse effects from local and systemic treatments. Eight new themes emerged at 5 years, including ageing, concerns about future cancer and positive aspects of care. Women commenting were better educated, slightly older and more likely to have had chemotherapy compared with non-commenters. They had significantly worse PROM scores for global health and key quality of life domains relevant to the difficulties they revealed. CONCLUSIONS: Difficult personal circumstances and other health concerns affected many women's PROM ratings at 5 years of follow-up, in addition to ongoing cancer treatment effects. Greater attention to multiple sources of distress and adversity could facilitate personalised care and aid interpretation of PROMs.

The UK HeartSpare Study (Stage II): Multicentre Evaluation of a Voluntary Breath-hold Technique in Patients Receiving Breast Radiotherapy.

AIMS: To evaluate the feasibility and heart-sparing ability of the voluntary breath-hold (VBH) technique in a multicentre setting. MATERIALS AND METHODS: Patients were recruited from 10 UK centres. Following surgery for early left breast cancer, patients with any heart inside the 50% isodose from a standard free-breathing tangential field treatment plan underwent a second planning computed tomography (CT) scan using the VBH technique. A separate treatment plan was prepared on the VBH CT scan and used for treatment. The mean heart, left anterior descending coronary artery (LAD) and lung doses were calculated. Daily electronic portal imaging (EPI) was carried out and scanning/treatment times were recorded. The primary end point was the percentage of patients achieving a reduction in mean heart dose with VBH. Population systematic (Σ) and random errors (σ) were estimated. Within-patient comparisons between techniques used Wilcoxon signed-rank tests. RESULTS: In total, 101 patients were recruited during 2014. Primary end point data were available for 93 patients, 88 (95%) of whom achieved a reduction in mean heart dose with VBH. Mean cardiac doses (Gy) for free-breathing and VBH techniques, respectively, were: heart 1.8 and 1.1, LAD 12.1 and 5.4, maximum LAD 35.4 and 24.1 (all P<0.001). Population EPI-based displacement data showed Σ =+1.3-1.9 mm and σ=1.4-1.8 mm. Median CT and treatment session times were 21 and 22 min, respectively. CONCLUSIONS: The VBH technique is confirmed as effective in sparing heart tissue and is feasible in a multicentre setting.

Do Patient-reported Outcome Measures Agree with Clinical and Photographic Assessments of Normal Tissue Effects after Breast Radiotherapy? The Experience of the Standardisation of Breast Radiotherapy (START) Trials in Early Breast Cancer.

AIMS: In radiotherapy trials, normal tissue effects (NTE) are important end points and it is pertinent to ask whether patient-reported outcome measures (PROMs) could replace clinical and/or photographic assessments. Data from the Standardisation of Breast Radiotherapy (START) trials are examined. MATERIALS AND METHODS: NTEs in the treated breast were recorded by (i) annual clinical assessments, (ii) photographs at 2 and 5 years, (iii) PROMs at 6 months, 1, 2 and 5 years after radiotherapy. Hazard ratios for the radiotherapy schedules were compared. Measures of agreement of assessments at 2 and 5 years tested concordance. RESULTS: PROMs were available at 2 and/or 5 years for 1939 women, of whom 1870 had clinical and 1444 had photographic assessments. All methods were sensitive to the dose difference between schedules. Patients reported a higher prevalence for all NTE end points than clinicians or photographs (P < 0.001 for most NTEs). Concordance was generally poor; weighted kappa at 2 years ranged from 0.05 (telangiectasia) to 0.21 (shrinkage and oedema). The percentage agreement was lowest between PROMs and photographic assessments of change in breast appearance (38%). CONCLUSIONS: All three methods produced similar conclusions for the comparison of trial schedules, despite low concordance between the methods on an individual patient basis. Careful consideration should be given to the different contributions of the measures of NTE in future radiotherapy trials.

NMR-based metabolomics and breath studies show lipid and protein catabolism during low dose chronic T(1)AM treatment.

OBJECTIVE: 3-Iodothyronamine (T1 AM), an analog of thyroid hormone, is a recently discovered fast-acting endogenous metabolite. Single high-dose treatments of T1 AM have produced rapid short-term effects, including a reduction of body temperature, bradycardia, and hyperglycemia in mice. DESIGN AND METHODS: The effect of daily low doses of T1 AM (10 mg/kg) for 8 days on weight loss and metabolism in spontaneously overweight mice was monitored. The experiments were repeated twice (n = 4). Nuclear magnetic resonance (NMR) spectroscopy of plasma and real-time analysis of exhaled (13) CO2 in breath by cavity ring down spectroscopy (CRDS) were used to detect T1 AM-induced lipolysis. RESULTS: CRDS detected increased lipolysis in breath shortly after T1 AM administration that was associated with a significant weight loss but independent of food consumption. NMR spectroscopy revealed alterations in key metabolites in serum: valine, glycine, and 3-hydroxybutyrate, suggesting that the subchronic effects of T1 AM include both lipolysis and protein breakdown. After discontinuation of T1 AM treatment, mice regained only 1.8% of the lost weight in the following 2 weeks, indicating lasting effects of T1 AM on weight maintenance. CONCLUSIONS: CRDS in combination with NMR and (13) C-metabolic tracing constitute a powerful method of investigation in obesity studies for identifying in vivo biochemical pathway shifts and unanticipated debilitating side effects.

Integration of patient-reported outcome measures with key clinical outcomes after immediate latissimus dorsi breast reconstruction and adjuvant treatment.

BACKGROUND: Clinical evidence on patient-reported outcome measures (PROMS) in breast reconstruction is lacking. The aim of this study was to evaluate PROMs in implant-assisted latissimus dorsi (LDI) or tissue-only autologous latissimus dorsi (ALD) flap reconstruction in relation to complications and adjuvant treatments. METHODS: This was a prospective cohort study involving six UK centres. Eligible patients had primary early-stage breast cancer. The European Organization for Research and Treatment of Cancer quality-of-life questionnaire (QLQ)-C30 and QLQ-BR23, Functional Assessment of Cancer Therapy-Breast Cancer scale (FACT-B), Body Image Scale, and Hospital Anxiety and Depression Scale were completed before operation and at 3, 6 and 12 months after surgery. RESULTS: A total of 182 patients (82 LDI and 100 ALD) were recruited between 2007 and 2010 with symptomatic (59·9 per cent) or screen-detected (39·6 per cent) cancers. Some 64·3 per cent had lymph node-negative disease; 30 per cent of the LDI group had radiotherapy, compared with 53·0 per cent in the ALD group (P = 0·004). Early complications up to 3 months after surgery were reported in 66 and 51·0 per cent of patients in the LDI and ALD groups respectively (P = 0·062) and long-term complications (4-12 months) in 48 and 45·0 per cent (P = 0·845). Role functioning and pain (P = 0·002 for both) were adversely affected in the ALD group compared with results in the LDI group, with no significant effects of radiotherapy on any health-related quality of life (HRQL). Chemotherapy and early complications adversely affected HRQL, which improved between 3 and 12 months after surgery (P < 0·010 for all). CONCLUSION: There is evidence of similar HRQL between types of latissimus dorsi breast reconstruction for up to a year after surgery. There appear to be no overarching effects for radiotherapy after mastectomy on the specific HRQL domains studied in the short term. The identification of variables that affect HRQL is important, including their integration into the analysis of PROMs.

Coping response and survival in breast cancer patients: a new analysis.

PURPOSE: The purpose of this study was to analyse the impact of coping response on survival of breast cancer by using a new method of assessing coping. METHOD: Adjustment to cancer was assessed using a revised measure in a large cohort of breast cancer patients (N = 578) followed up over a period of 10 years. Impact of coping response measured early in the disease process (<4 months from primary diagnosis of early-stage breast cancer) was assessed, and survival analyses were undertaken including known clinical staging data and cancer treatment details. RESULTS: After 5 years of follow-up from primary diagnosis, the effect of prior 'negative adjustment' was statistically significantly linked to increased risk of death and relapse of breast cancer, and for the 10-year analysis, this result remained for both risk of death and relapse. There was no statistically significant effect on survival of the novel 'positive adjustment' response. CONCLUSIONS: Coping with cancer was assessed using a new methodology and is linked to an adverse impact of negative adjustment on overall survival. Positive adjustment was unrelated to survival. The current study strengthens previous evidence that there is a link between survival and coping response. The question remains of how coping response might affect physical outcome. It is considered that coping response likely impacts survival through the mediating effects on lifestyle and health behaviour that may contribute to an adverse prognosis.

Patterns of complementary and alternative medicine use among patients undergoing cancer treatment.

This study aimed to assess the prevalence of complementary and alternative medicine (CAM) use in a representative cancer population prior to and within 6 months of diagnosis. A total of 304 newly diagnosed cancer patients from two UK cancer centres completed a postal survey. Of them, 100 patients (32.9%) used CAM before their cancer diagnosis, 59 of these CAM users continued post diagnosis. Twenty-nine individuals who had not used CAM before began to use it after their cancer diagnosis, creating a total of 88 (28.9%) CAM users in this sample. Reasons for not using CAM included lack of interest, lack of information or endorsement from professionals and satisfaction with conventional care. For those using CAM before diagnosis but not afterwards, the most common reason was a lack of expert guidance on what was safe to use. The use of CAM medicines bought from health food and other retail outlets was high. Complementary and alternative medicine use in cancer patients is common and demonstrates a complex pattern, but CAM use is not significantly greater than in the general population. Some patients purchase CAM medicines without seeking medical advice, thus risking drug interactions. Research to generate information on safety and efficacy of CAM is required.

Menopausal hot flushes after breast cancer.

The study aimed to improve understanding of the natural history and impact of hot flushes after breast cancer. Data were collected from women participating in an RCT of relaxation to reduce the incidence of flushes from breast cancer follow-up clinics from two hospitals in South-East England. Repondents were 150 women experiencing hot flushes following completion of primary treatment for breast cancer. This study utilized a flush diary, the Hot Flushes and Night Sweats Questionnaire (HFNSQ), Functional Assessment of Cancer Therapy with Endocrine Subscale (FACT-ES) and Spielberger State/Trait Anxiety Index (STAI) as the main outcome measures. The study found that in this sample, 51 (34%) women experienced flushes more than five years after diagnosis and 75 (50%) more than 5 years after menopause. Sleep disruption occurred in 90 women (72% of those that returned diaries), affecting half of the nights they recorded. The mean problem rating on the HFNSQ was 4.85 out of 10. A peak incidence of flushes was apparent around 10 a.m. in women taking tamoxifen. It was concluded that hot flushes after breast cancer may be long-lasting and cause sleeping difficulties for many women. Tamoxifen may affect the diurnal pattern of flushes. After breast cancer, the duration of flushes, potential distress and disruption to women's lives should not be underestimated and appropriate interventions should be offered.

Acute toxicity and 2-year adverse effects of 30 Gy in five fractions over 15 days to whole breast after local excision of early breast cancer.

AIMS: A pilot study was undertaken with the aim of documenting acute skin reactions and 2-year late adverse effects of a five-fraction course of adjuvant whole breast radiotherapy delivered over 15 days after local tumour excision of early breast cancer. MATERIALS AND METHODS: Thirty women with early invasive breast cancer aged>or=50 years with a pathological tumour size<3 cm, complete microscopic resection, negative axillary node status and no requirement for cytotoxic therapy were prescribed 30 Gy in five fractions over 15 days to the whole breast using tangential 6-10 MV X-ray beams and three-dimensional dose compensation with written informed consent. Post-surgical baseline photographs of the breasts were taken, and acute skin erythema and moist desquamation were each scored weekly for 7 weeks using four-point graded scales (grade 0=none, 1=mild, 2=moderate, 3=severe). This was followed by an annual clinical assessment, including repeat photographs at 2 years. RESULTS: Nine patients (30%, 95% confidence interval 14.7-49.4%) developed grade 2 erythema, with the remaining 21 patients developing milder degrees of reaction. Four (13.3%, 95% confidence interval 3.7-30.7) patients developed moist desquamation, grade 1 in three women and grade 2 in the fourth. At 2 years after treatment, 23/30 (77%) patients scored no change in photographic breast appearance compared with the pre-treatment baseline; seven (23%, 95% confidence interval 9.9-42.3) scored a mild change in breast appearance, and none developed a marked change. After a mean follow-up of 3.1 years (standard deviation 0.37, range 2.1-3.9 years) there have been no ipsilateral local tumour relapses. CONCLUSIONS: Further evaluation of a five-fraction regimen of adjuvant whole breast radiotherapy in a phase III randomised trial is justified, including a regimen delivered in a total of 5 days.

Evaluation of a method for grading late photographic change in breast appearance after radiotherapy for early breast cancer.

AIMS: Serial photographs have been collected prospectively to evaluate the effect of radiotherapy on normal tissues in the breast. The aim of this study was to compare two methods of scoring radiation-induced changes. MATERIALS AND METHODS: Five-year photographs of 400 patients randomised to receive either 42.9 or 39 Gy in 13 fractions to the whole breast after tumour excision of early breast cancer were compared with a post-surgery baseline and scored for change in breast appearance on a three-point graded scale. Two alternative methods of scoring using three observers were compared: (a) scores allocated independently, with independent resolution of discrepancies, and (b) scores allocated by consensus. RESULTS: Treatment effects estimated from the consensus and independent scores were very similar (odds ratio 1.89, 95% confidence interval 1.21-2.96 vs 2.28, 95% confidence interval 1.50-3.47, respectively). Agreement between the scores obtained from each method was reasonable, and the repeatability of the consensus method was good. CONCLUSIONS: The consensus method of scoring photographic change in breast appearance seems to be no less sensitive to randomised dose as the independent method of assessment, but is much quicker to administer. The consensus method has been used to score over 3000 sets of photographs in the National Cancer Research Institute Standardisation of Breast Radiotherapy trial.

The UK Standardisation of Breast Radiotherapy (START) Trial B of radiotherapy hypofractionation for treatment of early breast cancer: a randomised trial.

BACKGROUND: The international standard radiotherapy schedule for early breast cancer delivers 50 Gy in 25 fractions of 2.0 Gy over 5 weeks, but there is a long history of non-standard regimens delivering a lower total dose using fewer, larger fractions (hypofractionation). We aimed to test the benefits of radiotherapy schedules using fraction sizes larger than 2.0 Gy in terms of local-regional tumour control, normal tissue responses, quality of life, and economic consequences in women prescribed post-operative radiotherapy. METHODS: Between 1999 and 2001, 2215 women with early breast cancer (pT1-3a pN0-1 M0) at 23 centres in the UK were randomly assigned after primary surgery to receive 50 Gy in 25 fractions of 2.0 Gy over 5 weeks or 40 Gy in 15 fractions of 2.67 Gy over 3 weeks. Women were eligible for the trial if they were aged over 18 years, did not have an immediate reconstruction, and were available for follow-up. Randomisation method was computer generated and was not blinded. The protocol-specified principal endpoints were local-regional tumour relapse, defined as reappearance of cancer at irradiated sites, late normal tissue effects, and quality of life. Analysis was by intention to treat. This study is registered as an International Standard Randomised Controlled Trial, number ISRCTN59368779. FINDINGS: 1105 women were assigned to the 50 Gy group and 1110 to the 40 Gy group. After a median follow up of 6.0 years (IQR 5.0-6.2) the rate of local-regional tumour relapse at 5 years was 2.2% (95% CI 1.3-3.1) in the 40 Gy group and 3.3% (95% CI 2.2 to 4.5) in the 50 Gy group, representing an absolute difference of -0.7% (95% CI -1.7% to 0.9%)--ie, the absolute difference in local-regional relapse could be up to 1.7% better and at most 1% worse after 40 Gy than after 50 Gy. Photographic and patient self-assessments indicated lower rates of late adverse effects after 40 Gy than after 50 Gy. INTERPRETATION: A radiation schedule delivering 40 Gy in 15 fractions seems to offer rates of local-regional tumour relapse and late adverse effects at least as favourable as the standard schedule of 50 Gy in 25 fractions.