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..

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PURPOSE: We estimated the cost-effectiveness of 4 radiotherapy modalities to treat early breast cancer in the UK. In a subgroup of patients eligible for all modalities, we compared whole-breast (WB) and partial breast (PB) radiotherapy delivered in either 15 (WB15F, PB15F) or 5 fractions (WB5F, PB5F). In a subgroup ineligible for PB radiotherapy, we compared WB15F to WB5F. METHODS: We developed a Markov cohort model to simulate lifetime healthcare costs and quality-adjusted life years (QALYs) for each modality. This was informed by the clinical analysis of two non-inferiority trials (FAST Forward and IMPORT LOW) and supplemented with external literature. The primary analysis assumed that radiotherapy modality influences health only through its impact on locoregional recurrence and radiotherapy-related adverse events. RESULTS: In the primary analysis, PB5F had the least cost and greatest expected QALYs. WB5F had the least cost and the greatest expected QALYs in those only eligible for WB radiotherapy. Applying a cost-effectiveness threshold of £15,000/QALY, there was a 62% chance that PB5F was the cost-effective alternative in the PB eligible group, and there was a 100% chance that WB5F was cost-effective in the subgroup ineligible for PB radiotherapy. CONCLUSIONS: Hypofractionation to 5 fractions and partial breast radiotherapy modalities offer potentially important benefits to the UK health system..

INTRODUCTION: The optimal combination of radiotherapy and breast reconstruction has not yet been defined. Post-mastectomy radiotherapy (PMRT) has deleterious effects on breast reconstruction, leading to caution amongst surgeons. Pre-operative radiotherapy (PRT) is a growing area of interest, is demonstrated to be safe, and spares autologous flaps from radiotherapy. This study evaluates the aesthetic outcome of PRT and deep inferior epigastric artery perforator (DIEP) flap reconstruction within the Pre-operative Radiotherapy And Deep Inferior Epigastric artery Perforator (DIEP) flAp (PRADA) cohort. METHODS: PRADA was an observational cohort study designed to evaluate the feasibility and safety of PRT for women undergoing neoadjuvant chemotherapy and DIEP reconstruction. Panel evaluation of 3D surface images (3D-SIs) and patient-reported outcome measures (BREAST-Q) for a subset of women in the study were compared with those of a DIEP-PMRT cohort who had undergone DIEP reconstruction and PMRT. RESULTS: Seventeen out of 33 women from the PRADA study participated in this planned substudy. Twenty-eight women formed the DIEP-PMRT cohort (median follow-up 23 months). The median (inter-quartile range [IQR]) 'satisfaction with breasts' score at 12 months for the PRADA cohort was significantly better than the DIEP-PMRT cohort (77 [72-87] versus 64 [54-71], respectively), p=0.01). Median [IQR] panel evaluation (5-point scale) was also significantly better for the PRADA cohort than for the DIEP-PMRT cohort (4.3 [3.9-4.6] versus 3.6 [2.8-4] p=0.003). CONCLUSIONS: Aesthetic outcome for the PRADA cohort was reported to be 'good' or 'excellent' in 93% of cases using a bespoke panel assessment with robust methodology. Patient satisfaction at one year is encouraging and superior to DIEP-PMRT at 23 months. Switching surgery-radiotherapy sequencing leads to similar breast aesthetic outcomes and warrants further large-scale, multi-centre evaluation in a randomised trial..

Research in the field of local and locoregional breast cancer radiotherapy aims to maintain excellent oncological outcomes while reducing treatment-related toxicity. Adaptive radiotherapy (ART) considers variations in target and organs at risk (OARs) anatomy occurring during the treatment course and integrates these in re-optimized treatment plans. Exploiting ART routinely in clinic may result in smaller target volumes and better OAR sparing, which may lead to reduction of acute as well as late toxicities. In this review MR-guided and CT-guided ART for breast cancer patients according to different clinical scenarios (neoadjuvant and adjuvant partial breast irradiation, whole breast, chest wall and regional nodal irradiation) are reviewed and their advantages as well as challenging aspects discussed..

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Given that most local relapses of breast cancer occur proximal to the original location of the primary, the delivery of additional radiation dose to breast tissue that contained the original primary cancer (known as a "boost") has been a standard of care for some decades. In the context of falling relapse rates, however, it is an appropriate time to re-evaluate the role of the boost. This article reviews the evolution of the radiotherapy boost in breast cancer, discussing who to boost and how to boost in the 2020s, and arguing that, in both cases, less is more..

PURPOSE: The COVID-19 pandemic has profoundly affected cancer care worldwide, including radiation therapy (RT) for breast cancer (BC), because of risk-based resource allocation. We report the evolution of international breast RT practices during the beginning of the pandemic, focusing on differences in treatment recommendations between countries. MATERIALS AND METHODS: Between July and November 2020, a 58-question survey was distributed to radiation oncologists (ROs) through international professional societies. Changes in RT decision making during the first surge of the pandemic were evaluated across six hypothetical scenarios, including the management of ductal carcinoma in situ (DCIS), early-stage, locally advanced, and metastatic BC. The significance of changes in responses before and during the pandemic was examined using chi-square and McNemar-Bowker tests. RESULTS: One thousand one hundred three ROs from 54 countries completed the survey. Incomplete responses (254) were excluded from the analysis. Most respondents were from the United States (285), Japan (117), Italy (63), Canada (58), and Brazil (56). Twenty-one percent (230) of respondents reported treating at least one patient with BC who was COVID-19-positive. Approximately 60% of respondents reported no change in treatment recommendation during the pandemic, except for patients with metastatic disease, for which 57.7% (636/1,103; P < .0005) changed their palliative practice. Among respondents who noted a change in their recommendation during the first surge of the pandemic, omitting, delaying, and adopting short-course RT were the most frequent changes, with most transitioning to moderate hypofractionation for DCIS and early-stage BC. CONCLUSION: Early in the COVID-19 pandemic, significant changes in global RT practice patterns for BC were introduced. The impact of published results from the FAST FORWARD trial supporting ultrahypofractionation likely confounded the interpretation of the pandemic's independent influence on RT delivery..

The cyclin-dependent kinase 4 and 6 inhibitors (CDK4/6i) have become the standard of care for hormone receptor-positive (HR + ) and human epidermal growth factor receptor 2-negative (HER2-) metastatic breast cancer, improving survival outcomes compared to endocrine therapy alone. Abemaciclib and ribociclib, in combination with endocrine therapy, have demonstrated significant benefits in invasive disease-free survival for high-risk HR+/HER2- early breast cancer patients. Each CDK4/6i-palbociclib, ribociclib, and abemaciclib-exhibits distinct toxicity profiles. Radiation therapy (RT) can be delivered with a palliative or ablative intent, particularly using stereotactic body radiation therapy for oligometastatic or oligoprogressive disease. However, pivotal randomized trials lack information on concomitant CDK4/6i and RT, and existing preclinical and clinical data on the potential combined toxicities are limited and conflicting. As part of a broader effort to establish international consensus recommendations for integrating RT and targeted agents in breast cancer treatment, we conducted a systematic review and meta-analysis to evaluate the safety profile of combining CDK4/6i with palliative and ablative RT in both metastatic and early breast cancer settings..

AIMS: For patients with locally advanced primary/recurrent breast cancer, radiotherapy is an effective treatment for locoregional control. 36 Gy in 6 Gy once-weekly fractions is a commonly used schedule, but there are no data comparing local control and toxicity between 36 Gy delivered once-weekly versus accelerated schedules of multiple 6 Gy fractions per week. This retrospective study compared local control rates and acute and late toxicity in patients undergoing 30-36 Gy in 6 Gy fractions over 6 weeks versus more accelerated schedules over 2-3 weeks for an unresected breast cancer. MATERIALS AND METHODS: Patients who received 30-36 Gy in 6 Gy fractions to an unresected breast cancer ± involved lymph nodes between December 2011 and August 2020 were identified. Patients were grouped into once-weekly versus accelerated fractionation schedules. Response rates, local control and toxicity data were analysed. RESULTS: In total, 109 patients were identified. The median follow-up duration was 46 months. Forty-seven patients (43%) received once-weekly fractions and 62 patients (57%) received accelerated fractionation schedules. There were no significant differences in baseline tumour characteristics between the groups. Eighty-seven per cent of patients had an objective (complete or partial) response (81% in the once-weekly group; 91% in the accelerated group). The median time to local progression was 23.5 months overall (95% confidence interval 17.8-29.2); 23.5 months (95% confidence interval 18.8-28.1) in the once-weekly group and 19.0 months (95% confidence interval 7.0-31.1) in the accelerated group (P = 0.99). Acute toxicity of any grade occurred in 75% of patients (76% in the once-weekly group; 74% in the accelerated group) and grade 3 toxicity occurred in 7% of patients (7% in the once-weekly group; 8% in the accelerated group). There were no associations between the groups and acute or late toxicity grade (P = 0.78 and P = 0.26, respectively), although one grade 4 late toxicity (skin radionecrosis) occurred in a patient who received five fractions a week and therefore this regimen is not recommended. Study limitations included a lack of statistical power analysis, the necessary grouping of all accelerated patients for analysis and a high rate of censored data. CONCLUSION: There were no apparent differences in response rate, time to local progression or toxicity between patients who received 30-36 Gy in 6 Gy fractions once-weekly compared with twice-weekly as palliative treatment for locally advanced breast cancer. This regimen appears to be a safe alternative and may be preferred by patients..

BACKGROUND: FAST-Forward aimed to identify a 5-fraction schedule of adjuvant radiotherapy delivered in 1 week that was non-inferior in terms of local cancer control and as safe as the standard 15-fraction regimen after primary surgery for early breast cancer. Published acute toxicity and 5-year results are presented here with other aspects of the trial. DESIGN: Multicentre phase III non-inferiority trial. Patients with invasive carcinoma of the breast (pT1-3pN0-1M0) after breast conservation surgery or mastectomy randomised (1 : 1 : 1) to 40 Gy in 15 fractions (3 weeks), 27 Gy or 26 Gy in 5 fractions (1 week) whole breast/chest wall (Main Trial). Primary endpoint was ipsilateral breast tumour relapse; assuming 2% 5-year incidence for 40 Gy, non-inferiority pre-defined as < 1.6% excess for 5-fraction schedules (critical hazard ratio = 1.81). Normal tissue effects were assessed independently by clinicians, patients and photographs. SUB-STUDIES: Two acute skin toxicity sub-studies were undertaken to confirm safety of the test schedules. Primary endpoint was proportion of patients with grade ≥ 3 acute breast skin toxicity at any time from the start of radiotherapy to 4 weeks after completion. Nodal Sub-Study patients had breast/chest wall plus axillary radiotherapy testing the same three schedules, reduced to the 40 and 26 Gy groups on amendment, with the primary endpoint of 5-year patient-reported arm/hand swelling. LIMITATIONS: A sequential hypofractionated or simultaneous integrated boost has not been studied. PARTICIPANTS: Ninety-seven UK centres recruited 4096 patients (1361:40 Gy, 1367:27 Gy, 1368:26 Gy) into the Main Trial from November 2011 to June 2014. The Nodal Sub-Study recruited an additional 469 patients from 50 UK centres. One hundred and ninety and 162 Main Trial patients were included in the acute toxicity sub-studies. RESULTS: Acute toxicity sub-studies evaluable patients: (1) acute grade 3 Radiation Therapy Oncology Group toxicity reported in 40 Gy/15 fractions 6/44 (13.6%); 27 Gy/5 fractions 5/51 (9.8%); 26 Gy/5 fractions 3/52 (5.8%). (2) Grade 3 common toxicity criteria for adverse effects toxicity reported for one patient. At 71-month median follow-up in the Main Trial, 79 ipsilateral breast tumour relapse events (40 Gy: 31, 27 Gy: 27, 26 Gy: 21); hazard ratios (95% confidence interval) versus 40 Gy were 27 Gy: 0.86 (0.51 to 1.44), 26 Gy: 0.67 (0.38 to 1.16). With 2.1% (1.4 to 3.1) 5-year incidence ipsilateral breast tumour relapse after 40 Gy, estimated absolute differences versus 40 Gy (non-inferiority test) were -0.3% (-1.0-0.9) for 27 Gy (p = 0.0022) and -0.7% (-1.3-0.3) for 26 Gy (p = 0.00019). Five-year prevalence of any clinician-assessed moderate/marked breast normal tissue effects was 40 Gy: 98/986 (9.9%), 27 Gy: 155/1005 (15.4%), 26 Gy: 121/1020 (11.9%). Across all clinician assessments from 1 to 5 years, odds ratios versus 40 Gy were 1.55 (1.32 to 1.83; p < 0.0001) for 27 Gy and 1.12 (0.94-1.34; p = 0.20) for 26 Gy. Patient and photographic assessments showed higher normal tissue effects risk for 27 Gy versus 40 Gy but not for 26 Gy. Nodal Sub-Study reported no arm/hand swelling in 80% and 77% in 40 Gy and 26 Gy at baseline, and 73% and 76% at 24 months. The prevalence of moderate/marked arm/hand swelling at 24 months was 10% versus 7% for 40 Gy compared with 26 Gy. INTERPRETATION: Five-year local tumour incidence and normal tissue effects prevalence show 26 Gy in 5 fractions in 1 week is a safe and effective alternative to 40 Gy in 15 fractions for patients prescribed adjuvant local radiotherapy after primary surgery for early-stage breast cancer. FUTURE WORK: Ten-year Main Trial follow-up is essential. Inclusion in hypofractionation meta-analysis ongoing. A future hypofractionated boost trial is strongly supported. TRIAL REGISTRATION: FAST-Forward was sponsored by The Institute of Cancer Research and was registered as ISRCTN19906132. FUNDING: This award was funded by the National Institute for Health and Care Research (NIHR) Health Technology Assessment programme (NIHR award ref: 09/01/47) and is published in full in Health Technology Assessment; Vol. 27, No. 25. See the NIHR Funding and Awards website for further award information..

AIMS: The benefit of stereotactic body radiotherapy (SBRT) in metachronous oligometastatic breast cancer (OMBC) has previously been described and its use in current clinical practice is established. The role of SBRT in the management of synchronous OMBC remains uncertain. The aim of this study was to compare outcomes of SBRT-treated synchronous OMBC with those of SBRT-treated metachronous OMBC. MATERIALS AND METHODS: This was a retrospective analysis of consecutive extracranial OMBC patients treated with SBRT at a single institution between 2011 and 2022. Kaplan-Meier methods were used to calculate progression-free survival (PFS), overall survival, local control and distant control. Log-rank tests were used to test any differences. Cox regression was used for univariate and multivariate analyses to identify predictive factors. Toxicity was assessed using Common Terminology Criteria for Adverse Events (CTCAE) version 5. RESULTS: In total, 74 OMBC patients with 113 lesions were analysed. The median follow-up was 20 months (range 0-98). Seventy per cent of patients presented metachronously and 30% synchronously. 30 Gy in three fractions was most commonly prescribed, resulting in a median biologically effective dose (BED at α/β = 10) of 60 Gy (range 35.7-112.5 Gy). Forty-nine per cent of patients switched systemic therapy post-SBRT (median time to switch: 14 months, range 0-79). Two patients (2%) experienced grade 3 acute toxicities with no grade ≥4 toxicities. At 2 years overall survival was 92.4% and PFS 39.0%, local control 85.9% and distant control 37.0%. For metachronous and synchronous disease, respectively, 2-year local control rates were 86.5% and 85.8% and PFS rates were 35.3% and 48.3%. The median PFS of metachronous and synchronous disease were 18 months and 17 months, respectively (P = 0.86). Predictive factors on multivariate analysis were treated site for overall survival, change in systemic therapy post-SBRT for PFS and BED for local control. CONCLUSION: Our data confirm SBRT as a well-tolerated treatment for OMBC with excellent local control rates regardless of metachronous or synchronous presentation. There is no suggestion that survival outcomes are inferior for synchronous disease. Further prospective studies are required to validate this finding..

PURPOSE: Adjuvant proton beam therapy (PBT) is increasingly available to patients with breast cancer. It achieves better planned dose distributions than standard photon radiation therapy and therefore may reduce the risks. However, clinical evidence is lacking. METHODS AND MATERIALS: A systematic review of clinical outcomes from studies of adjuvant PBT for early breast cancer published in 2000 to 2022 was undertaken. Early breast cancer was defined as when all detected invasive cancer cells are in the breast or nearby lymph nodes and can be removed surgically. Adverse outcomes were summarized quantitatively, and the prevalence of the most common ones were estimated using meta-analysis. RESULTS: Thirty-two studies (1452 patients) reported clinical outcomes after adjuvant PBT for early breast cancer. Median follow-up ranged from 2 to 59 months. There were no published randomized trials comparing PBT with photon radiation therapy. Scattering PBT was delivered in 7 studies (258 patients) starting 2003 to 2015 and scanning PBT in 22 studies (1041 patients) starting 2000 to 2019. Two studies (123 patients) starting 2011 used both PBT types. For 1 study (30 patients), PBT type was unspecified. Adverse events were less severe after scanning than after scattering PBT. They also varied by clinical target. For partial breast PBT, 498 adverse events were reported (8 studies, 358 patients). None were categorized as severe after scanning PBT. For whole breast or chest wall ± regional lymph nodes PBT, 1344 adverse events were reported (19 studies, 933 patients). After scanning PBT, 4% (44/1026) of events were severe. The most prevalent severe outcome after scanning PBT was dermatitis, which occurred in 5.7% (95% confidence interval, 4.2-7.6) of patients. Other severe adverse outcomes included infection, pain, and pneumonitis (each ≤1%). Of the 141 reconstruction events reported (13 studies, 459 patients), the most prevalent after scanning PBT was prosthetic implant removal (34/181, 19%). CONCLUSIONS: This is a quantitative summary of all published clinical outcomes after adjuvant PBT for early breast cancer. Ongoing randomized trials will provide information on its longer-term safety compared with standard photon radiation therapy..

BACKGROUND: A tumour-bed boost delivered after whole-breast radiotherapy increases local cancer-control rates but requires more patient visits and can increase breast hardness. IMPORT HIGH tested simultaneous integrated boost against sequential boost with the aim of reducing treatment duration while maintaining excellent local control and similar or reduced toxicity. METHODS: IMPORT HIGH is a phase 3, non-inferiority, open-label, randomised controlled trial that recruited women after breast-conserving surgery for pT1-3pN0-3aM0 invasive carcinoma from radiotherapy and referral centres in the UK. Patients were randomly allocated to receive one of three treatments in a 1:1:1 ratio, with computer-generated random permuted blocks used to stratify patients by centre. The control group received 40 Gy in 15 fractions to the whole breast and 16 Gy in 8 fractions sequential photon tumour-bed boost. Test group 1 received 36 Gy in 15 fractions to the whole breast, 40 Gy in 15 fractions to the partial breast, and 48 Gy in 15 fractions concomitant photon boost to the tumour-bed volume. Test group 2 received 36 Gy in 15 fractions to the whole breast, 40 Gy in 15 fractions to the partial breast, and 53 Gy in 15 fractions concomitant photon boost to the tumour-bed volume. The boost clinical target volume was the clip-defined tumour bed. Patients and clinicians were not masked to treatment allocation. The primary endpoint was ipsilateral breast tumour relapse (IBTR) analysed by intention to treat; assuming 5% 5-year incidence with the control group, non-inferiority was predefined as 3% or less absolute excess in the test groups (upper limit of two-sided 95% CI). Adverse events were assessed by clinicians, patients, and photographs. This trial is registered with the ISRCTN registry, ISRCTN47437448, and is closed to new participants. FINDINGS: Between March 4, 2009, and Sept 16, 2015, 2617 patients were recruited. 871 individuals were assigned to the control group, 874 to test group 1, and 872 to test group 2. Median boost clinical target volume was 13 cm3 (IQR 7 to 22). At a median follow-up of 74 months there were 76 IBTR events (20 for the control group, 21 for test group 1, and 35 for test group 2). 5-year IBTR incidence was 1·9% (95% CI 1·2 to 3·1) for the control group, 2·0% (1·2 to 3·2) for test group 1, and 3·2% (2·2 to 4·7) for test group 2. The estimated absolute differences versus the control group were 0·1% (-0·8 to 1·7) for test group 1 and 1·4% (0·03 to 3·8) for test group 2. The upper confidence limit for test group 1 versus the control group indicated non-inferiority for 48 Gy. Cumulative 5-year incidence of clinician-reported moderate or marked breast induration was 11·5% for the control group, 10·6% for test group 1 (p=0·40 vs control group), and 15·5% for test group 2 (p=0·015 vs control group). INTERPRETATION: In all groups 5-year IBTR incidence was lower than the 5% originally expected regardless of boost sequencing. Dose-escalation is not advantageous. 5-year moderate or marked adverse event rates were low using small boost volumes. Simultaneous integrated boost in IMPORT HIGH was safe and reduced patient visits. FUNDING: Cancer Research UK..

There is a sound empirical basis for hypofractionation in radiotherapy for breast cancer. This article reviews the radiobiological implications of hypofractionation in breast cancer derived from a series of clinical trials that began when 50 Gy in 25 fractions over 5 weeks was commonplace. These trials led first to 40 Gy in 15 fractions over 3 weeks and, subsequently, to 26 Gy in five fractions over 1 week being adopted as standards of care for many patients prescribed whole- or partial-breast radiotherapy after primary surgery..

Hypofractionated radical radiotherapy is now an accepted standard of care for tumour sites such as prostate and breast cancer. Much research effort is being directed towards more profoundly hypofractionated (ultrahypofractionated) schedules, with some reaching UK standard of care (e.g. adjuvant breast). Hypofractionation exerts varying influences on each of the major clinical end points of radiotherapy studies: acute toxicity, late toxicity and local control. This review will discuss these effects from the viewpoint of the traditional 5 Rs of radiobiology, before considering non-canonical radiobiological effects that may be relevant to ultrahypofractionated radiotherapy. The principles outlined here may assist the reader in their interpretation of the wealth of clinical data presented in the tumour site-specific articles in this special issue..

BACKGROUND: Radiotherapy before mastectomy and autologous free-flap breast reconstruction can avoid adverse radiation effects on healthy donor tissues and delays to adjuvant radiotherapy. However, evidence for this treatment sequence is sparse. We aimed to explore the feasibility of preoperative radiotherapy followed by skin-sparing mastectomy and deep inferior epigastric perforator (DIEP) flap reconstruction in patients with breast cancer requiring mastectomy. METHODS: We conducted a prospective, non-randomised, feasibility study at two National Health Service trusts in the UK. Eligible patients were women aged older than 18 years with a laboratory diagnosis of primary breast cancer requiring mastectomy and post-mastectomy radiotherapy, who were suitable for DIEP flap reconstruction. Preoperative radiotherapy started 3-4 weeks after neoadjuvant chemotherapy and was delivered to the breast, plus regional nodes as required, at 40 Gy in 15 fractions (over 3 weeks) or 42·72 Gy in 16 fractions (over 3·2 weeks). Adverse skin radiation toxicity was assessed preoperatively using the Radiation Therapy Oncology Group toxicity grading system. Skin-sparing mastectomy and DIEP flap reconstruction were planned for 2-6 weeks after completion of preoperative radiotherapy. The primary endpoint was the proportion of open breast wounds greater than 1 cm width requiring a dressing at 4 weeks after surgery, assessed in all participants. This study is registered with ClinicalTrials.gov, NCT02771938, and is closed to recruitment. FINDINGS: Between Jan 25, 2016, and Dec 11, 2017, 33 patients were enrolled. At 4 weeks after surgery, four (12·1%, 95% CI 3·4-28·2) of 33 patients had an open breast wound greater than 1 cm. One (3%) patient had confluent moist desquamation (grade 3). There were no serious treatment-related adverse events and no treatment-related deaths. INTERPRETATION: Preoperative radiotherapy followed by skin-sparing mastectomy and immediate DIEP flap reconstruction is feasible and technically safe, with rates of breast open wounds similar to those reported with post-mastectomy radiotherapy. A randomised trial comparing preoperative radiotherapy with post-mastectomy radiotherapy is required to precisely determine and compare surgical, oncological, and breast reconstruction outcomes, including quality of life. FUNDING: Cancer Research UK, National Institute for Health Research..

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..

AIMS: To develop quality indicators (QIs) for the evaluation of the prevention and management of cancer therapy-related cardiovascular toxicity. METHODS AND RESULTS: We followed the European Society of Cardiology (ESC) methodology for QI development which comprises (i) identifying the key domains of care for the prevention and management of cancer therapy-related cardiovascular toxicity in patients on cancer treatment, (ii) performing a systematic review of the literature to develop candidate QIs, and (iii) selecting of the final set of QIs using a modified Delphi process. Work was undertaken in parallel with the writing of the 2022 ESC Guidelines on Cardio-Oncology and in collaboration with the European Haematology Association, the European Society for Therapeutic Radiology and Oncology and the International Cardio-Oncology Society. In total, 5 main and 9 secondary QIs were selected across five domains of care: (i) Structural framework, (ii) Baseline cardiovascular risk assessment, (iii) Cancer therapy related cardiovascular toxicity, (iv) Predictors of outcomes, and (v) Monitoring of cardiovascular complications during cancer therapy. CONCLUSION: We present the ESC Cardio-Oncology QIs with their development process and provide an overview of the scientific rationale for their selection. These indicators are aimed at quantifying and improving the adherence to guideline-recommended clinical practice and improving patient outcomes..

BACKGROUND: Deep-inspiration breath-hold (DIBH) reduces radiation dose to the heart in patients undergoing locoregional breast radiotherapy. In the context of tangential irradiation of the breast/ chest wall, a voluntary breath hold (vDIBH) technique has been shown to be as reproducible as a machine-assisted breath hold technique using the active breathing co-ordinator (ABC™, Elekta, Crawley, UK, ABC_DIBH). This study compares set-up reproducibility for vDIBH versus ABC_DIBH in patients undergoing volumetric-modulated arc radiotherapy (VMAT) for breast cancer, both with and without wax bolus. METHOD: Patients with breast cancer requiring pan regional lymph node VMAT +/- wax bolus in breath-hold were CT scanned in vDIBH and ABC_DIBH. Patients were randomised to receive one technique for fractions 1-7 and the other for fractions 8-15. Daily cone beam computed tomography (CBCT) was performed and registered to planning-CT using bony anatomy. Within-patient comparisons of mean daily chest wall position were made using a paired t-test. Population, systematic (∑) and random errors (α) were estimated. Intrafraction reproducibility was assessed by comparing chest wall position and diaphragm movement between consecutive breath holds on CBCT. RESULTS: 16 patients were recruited. All completed treatment with both techniques (9 patients with wax bolus, 7 patients without). CBCT derived ∑ were 2.1-6.4 mm (ABC_DIBH) and 2.1-4.9 mm (vDIBH), α were 1.7-2.6 mm (ABC_DIBH) and 2.2-2.7 mm (vDIBH) and mean daily chest wall displacements (MD) were 0.0-1.5 mm (ABC_DIBH) and -0.1-1.6 vDIBH (all p non-significant). Chest wall and diaphragm position was equivalent between consecutive breath holds in ABC and vDIBH (median difference 1.0 mm and 0.8 mm respectively, non p significant) demonstrating equivalent intrafraction reproducibility. CONCLUSION: This study demonstrates that a simple voluntary breath hold technique is feasible in combination with VMAT (+/- bolus) and is as reproducible as ABC_DIBH with VMAT for the irradiation of the breast and axillary and IMC lymph nodes in breast cancer patients..

BACKGROUND AND PURPOSE: Adjuvant radiotherapy of internal mammary nodes (IMN) improves survival in high-risk early breast cancer patients but inevitably leads to more dose to heart and lung. Target coverage is often compromised to meet heart/lung dose constraints. We estimate heart and lung dose when target coverage is not compromised in consecutive patients. These estimates are used to guide the choice of selection criteria for the randomised Danish Breast Cancer Group (DBCG) Proton Trial. MATERIALS AND METHODS: 179 breast cancer patients already treated with loco-regional IMN radiotherapy from 18 European departments were included. If the clinically delivered treatment plan did not comply with defined target coverage requirements, the plan was modified retrospectively until sufficient coverage was reached. The choice of selection criteria was based on the estimated number of eligible patients for different heart and lung dose thresholds in combination with proton therapy capacity limitations and dose-response relationships for heart and lung. RESULTS: Median mean heart dose was 3.0 Gy (range, 1.1-8.2 Gy) for left-sided and 1.4 Gy (0.4-11.5 Gy) for right-sided treatment plans. Median V17Gy/V20Gy (hypofractionated/normofractionated plans) for ipsilateral lung was 31% (9-57%). The DBCG Radiotherapy Committee chose mean heart dose ≥ 4 Gy and/or lung V17Gy/V20Gy ≥ 37% as thresholds for inclusion in the randomised trial. Using these thresholds, we estimate that 22% of patients requiring loco-regional IMN radiotherapy will be eligible for the trial. CONCLUSION: The patient selection criteria for the DBCG Proton Trial are mean heart dose ≥ 4 Gy and/or lung V17Gy/V20Gy ≥ 37%..

In the care of patients with operable breast cancer, there has been a shift toward increasing use of neoadjuvant therapy. There are benefits to neoadjuvant therapy, such as monitoring for response, as well as an increased rate of breast conservation and reduction of potential morbidity associated with breast surgery, including axillary management. Among patients with highly proliferative tumors, such as HER2-positive or triple-negative breast cancer, those with residual disease are at higher risk of recurrence, which informs the recommended systemic therapy in the adjuvant setting. For instance, in patients with residual disease after neoadjuvant chemotherapy and HER2-targeted therapy, there is a role for adjuvant trastuzumab emtansine for those with residual disease at the time of surgery. The same holds true regarding the role of adjuvant capecitabine in patients with residual disease after neoadjuvant chemotherapy. With the added complexities of treating patients in the era of the COVID-19 outbreak, additional considerations are critical, including initiation of surgery within an appropriate time from completion of neoadjuvant therapy. National consensus guidelines on time to surgery must be developed to improve measurement and comparison across systems. In addition, there is emerging radiation treatment management research addressing a number of factors, including hypofractionation, role of proton beam therapy, safe omission of radiotherapy, and preoperative radiotherapy with or without drug combination. In this article, the multidisciplinary approach of treating patients with operable breast cancer is highlighted, with updates and future considerations described..

AIMS: Moderately hypofractionated breast irradiation has been evaluated in several prospective studies, resulting in wide acceptance of shorter treatment protocols for postoperative breast irradiation. Reimbursement for radiation therapy varies between private and public systems and between countries, impacting variably financial considerations in the use of hypofractionation. The aim of this study was to evaluate the financial impact of moderately hypofractionated breast irradiation by reimbursement system in different countries. MATERIALS AND METHODS: The study was designed by an international group of radiation oncologists. A web-questionnaire was distributed to representatives from each country. The participants were asked to involve the financial consultant at their institution. RESULTS: Data from 13 countries from all populated continents were collected (Europe: Denmark, France, Italy, the Netherlands, Spain, UK; North America: Canada, USA; South America: Brazil; Africa: South Africa; Oceania: Australia; Asia: Israel, Taiwan). Clinicians and/or departments in most of the countries surveyed (77%) receive remuneration based on the number of fractions delivered to the patient. The financial loss per patient estimated resulting from applying moderately hypofractionated breast irradiation instead of conventional fractionation ranged from 5-10% to 30-40%, depending on the healthcare provider. CONCLUSION: Although a generalised adoption of moderately hypofractionated breast irradiation would allow for a considerable reduction in social and economic burden, the financial loss for the healthcare providers induced by fee-for-service remuneration may be a factor in the slow uptake of these regimens. Therefore, fee-for-service reimbursement may not be preferable for radiation oncology. We propose that an alternative system of remuneration, such as bundled payments based on stage and diagnosis, may provide more value for all stakeholders..

• Survey of European radiotherapy department heads after 1 year of Covid-pandemic. • A decrease in patient volume was reported in 53%. • Enrollment in clinical studies was decreased in 58%. • Concerns were expressed related to well-being of staff in 76% of the departments..

PURPOSE: Post mastectomy radiation therapy (PMRT) reduces locoregional recurrence (LRR) and breast cancer mortality for selected patients. Bolus overcomes the skin-sparing effect of external-beam radiotherapy, ensuring adequate dose to superficial regions at risk of local recurrence (LR). This systematic review summarizes the current evidence regarding the impact of bolus on LR and acute toxicity in the setting of PMRT. RESULTS: 27 studies were included. The use of bolus led to higher rates of acute grade 3 radiation dermatitis (pooled rates of 9.6% with bolus vs. 1.2% without). Pooled crude LR rates from thirteen studies (n = 3756) were similar with (3.5%) and without (3.6%) bolus. CONCLUSIONS: Bolus may be indicated in cases with a high risk of LR in the skin, but seems not to be necessary for all patients. Further work is needed to define the role of bolus in PMRT..

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/β 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..

Bolus serves as a tissue equivalent material that shifts the 95-100% isodose line towards the skin and subcutaneous tissue. The need for bolus for all breast cancer patients planned for postmastectomy radiation therapy (PMRT) has been questioned. The work was initiated by the faculty of the European SocieTy for Radiotherapy & Oncology (ESTRO) breast cancer courses and represents a multidisciplinary international breast cancer expert collaboration to optimize PMRT. Due to the lack of randomised trials evaluating the benefits of bolus, we designed a stepwise project to evaluate the existing evidence about the use of bolus in the setting of PMRT to achieve an international consensus for the indications of bolus in PMRT, based on the Delphi method..

AIMS: Exposure of the heart to radiation increases the risk of ischaemic heart disease, proportionate to the mean heart dose (MHD). Radiotherapy techniques including proton beam therapy (PBT) can reduce MHD. The aims of this study were to quantify the MHD reduction achievable by PBT compared with volumetric modulated arc therapy in breath hold (VMAT-BH) in patients with pectus excavatum (PEx), to identify an anatomical metric from a computed tomography scan that might indicate which patients will achieve the greatest MHD reductions from PBT. MATERIALS AND METHODS: Sixteen patients with PEx (Haller Index ≥2.7) were identified from radiotherapy planning computed tomography images. Left breast/chest wall, axilla (I-IV) and internal mammary node (IMN) volumes were delineated. VMAT and PBT plans were prepared, all satisfying target coverage constraints. Signed-rank comparisons of techniques were undertaken for the mean dose to the heart, ipsilateral lung and contralateral breast. Spearman's rho correlations were calculated for anatomical metrics against MHD reduction achieved by PBT. RESULTS: The mean MHD for VMAT-BH plans was 4.1 Gy compared with 0.7 Gy for PBT plans. PBT reduced MHD by an average of 3.4 Gy (range 2.8-4.4 Gy) compared with VMAT-BH (P < 0.001). PBT significantly reduced the mean dose to the ipsilateral lung (4.7 Gy, P < 0.001) and contralateral breast (2.7 Gy, P < 0.001). The distance (mm) at the most inferomedial extent of IMN volume (IMN to heart distance) negatively correlated with MHD reduction achieved by PBT (Spearman's rho -0.88 (95% confidence interval -0.96 to -0.67, P < 0.001)). CONCLUSION: For patients with PEx requiring left-sided breast and IMN radiotherapy, a clinically significant MHD reduction is achievable using PBT, compared with the optimal photon technique (VMAT-BH). This is a patient group in whom PBT could have the greatest benefit..

BACKGROUND: For patients with early breast cancer considered at very-low risk of local relapse, risks of radiotherapy may outweigh the benefits. Decisions regarding treatment omission can lead to patient uncertainty (decisional conflict), which may be lessened with patient decision aids (PDA). PRIMETIME (ISRCTN 41579286) is a UK-led biomarker-directed study evaluating omission of adjuvant radiotherapy in breast cancer; an embedded Study Within A Trial (SWAT) investigated whether PDA reduces decisional conflict using a cluster stepped-wedge trial design. METHODS: PDA diagrams and a video explaining risks and benefits of radiotherapy were developed in close collaboration between patient advocates and PRIMETIME trialists. The SWAT used a cluster stepped-wedge trial design, where each cluster represented the radiotherapy centre and referring peripheral centres. All clusters began in the standard information group (patient information and diagrams) and were randomised to cross-over to the enhanced information group (standard information plus video) at 2, 4 or 6 months. Primary endpoint was the decisional conflict scale (0-100, higher scores indicating greater conflict) which was assessed on an individual participant level. Multilevel mixed effects models used a random effect for cluster and a fixed effect for each step to adjust for calendar time and clustering. Robust standard errors were also adjusted for the clustering effect. RESULTS: Five hundred twenty-one evaluable questionnaires were returned from 809 eligible patients (64%) in 24 clusters between April 2018 and October 2019. Mean decisional conflict scores in the standard group (N = 184) were 10.88 (SD 11.82) and 8.99 (SD 11.82) in the enhanced group (N = 337), with no statistically significant difference [mean difference - 1.78, 95%CI - 3.82-0.25, p = 0.09]. Compliance with patient information and diagrams was high in both groups although in the enhanced group only 121/337 (36%) reported watching the video. CONCLUSION: The low levels of decisional conflict in PRIMETIME are reassuring and may reflect the high-quality information provision, such that not everyone required the video. This reinforces the importance of working with patients as partners in clinical trials especially in the development of patient-centred information and decision aids..

PURPOSE: High-field magnetic resonance-linear accelerators (MR-Linacs), linear accelerators combined with a diagnostic magnetic resonance imaging (MRI) scanner and online adaptive workflow, potentially give rise to novel online anatomic and response adaptive radiation therapy paradigms. The first high-field (1.5T) MR-Linac received regulatory approval in late 2018, and little is known about clinical use, patient tolerability of daily high-field MRI, and toxicity of treatments. Herein we report the initial experience within the MOMENTUM Study (NCT04075305), a prospective international registry of the MR-Linac Consortium. METHODS AND MATERIALS: Patients were included between February 2019 and October 2020 at 7 institutions in 4 countries. We used descriptive statistics to describe the patterns of care, tolerability (the percentage of patients discontinuing their course early), and safety (grade 3-5 Common Terminology Criteria for Adverse Events v.5 acute toxicity within 3 months after the end of treatment). RESULTS: A total 943 patients participated in the MOMENTUM Study, 702 of whom had complete baseline data at the time of this analysis. Patients were primarily male (79%) with a median age of 68 years (range, 22-93) and were treated for 39 different indications. The most frequent indications were prostate (40%), oligometastatic lymph node (17%), brain (12%), and rectal (10%) cancers. The median number of fractions was 5 (range, 1-35). Six patients discontinued MR-Linac treatments, but none due to an inability to tolerate repeated high-field MRI. Of the 415 patients with complete data on acute toxicity at 3-month follow-up, 18 (4%) patients experienced grade 3 acute toxicity related to radiation. No grade 4 or 5 acute toxicity related to radiation was observed. CONCLUSIONS: In the first 21 months of our study, patterns of care were diverse with respect to clinical utilization, body sites, and radiation prescriptions. No patient discontinued treatment due to inability to tolerate daily high-field MRI scans, and the acute radiation toxicity experience was encouraging..

INTRODUCTION: Over half of women with surgically managed breast cancer in the UK undergo breast-conserving treatment (BCT). While photographs are shown prior to reconstructive surgery or complex oncoplastic procedures, standard practice prior to breast conservation is to simply describe the likely aesthetic changes. Patients have expressed the desire for more personalized information about likely appearance after surgery. The hypothesis was that viewing a three-dimensional (3D) simulation improves patients' confidence in knowing their likely aesthetic outcome after surgery. METHODS: A randomized, controlled trial of 117 women planning unilateral BCT was undertaken. The randomization was three-way: standard of care (verbal description alone, control group), viewing two-dimensional (2D) photographs, or viewing a 3D simulation before surgery. The primary endpoint was the comparison between groups' median answer on a visual analogue scale (VAS) for the question administered before surgery: 'How confident are you that you know how your breasts are likely to look after treatment?' RESULTS: The median VAS in the control group was 5.2 (i.q.r. 2.6-7.8); 8.0 (i.q.r. 5.7-8.7) for 2D photography, and 8.9 (i.q.r. 8.2-9.5) for 3D simulation. There was a significant difference between groups (P < 0.010) with post-hoc pairwise comparisons demonstrating a statistically significant difference between 3D simulation and both standard care and viewing 2D photographs (P < 0.010 and P = 0.012, respectively). CONCLUSION: This RCT has demonstrated that women who viewed an individualized 3D simulation of likely aesthetic outcome for BCT were more confident going into surgery than those who received standard care or who were shown 2D photographs of other women. The impact on longer-term satisfaction with outcome remains to be determined.Registration number: NCT03250260 (http://www.clinicaltrials.gov)..

INTRODUCTION: This paper presents the results of a survey of the routine use of permanent marks for radiotherapy in the UK. This was undertaken to provide an overview of current practice. Permanent marks are a somewhat invasive procedure, and should be subject to scrutiny and judicious application. METHOD: The authors reviewed the literature on international radiotherapy permanent marking practice. Common themes that emerged were the psychology of permanent marking and ink-type considerations, current practice and training, and safety. These were used to develop a questionnaire in order to form an overview of the use of marks nationally, and to identify any recurrent issues. The questionnaire also sought information regarding locations and numbers of permanent marks used for common treatment sites. The survey was sent to 71 departments in the UK using email. RESULTS: 70% of departments responded. 62% of departments reported patients who had refused permanent marks. The reasons for refusal varied. India or drawing ink was used in 49 of the 51 departments (96%). The most common teaching method of tattooing involved combined observation and verbal coaching. Most departments had a written procedure for tattooing, but some did not. Although sharps injuries were rare, they were documented. CONCLUSION: Most departments in the UK had encountered patient refusal of permanent marks, with breast patients representing the largest group which declined. There is variation in practice throughout the UK, and the equipment used is not specialised for tattooing purposes. Sharps injuries, although rare, do occur, and training methods are not consistent. IMPLICATIONS FOR PRACTICE: The requirement for national guidelines is posited. Further investigation into the need for permanent marks in an era of state-of-the-art imaging technology is also required..

Breast cancer is the leading cause of brain metastases in women. Large randomized clinical trials that have evaluated local therapies in patients with brain metastases include patients with brain metastases from a variety of cancer types. The incidence of brain metastases in the breast cancer population continues to grow, which is, aside from the rising breast cancer incidence, mainly attributable to improvements in systemic therapies leading to more durable control of extracranial metastatic disease and prolonged survival. The management of breast cancer brain metastases remains challenging, even more so with the continued advancement of local and highly effective systemic therapies. For most patients, a metastases-directed initial approach (i.e., radiation, surgery) represents the most appropriate initial therapy. Treatment should be based on multidisciplinary team discussions and a shared decision with the patients taking into account the risks and benefits of each therapeutic modality with the goal of prolonging survival while maintaining quality of life. In this narrative review, a multidisciplinary group of experts will address challenging questions in the context of current scientific literature and propose a therapeutic algorithm for breast cancer patients with brain metastases..

BACKGROUND: Two-thirds of patients with early breast cancer undergo breast-conserving treatment (BCT). Aesthetic outcome is important and has long term implications for psychosocial wellbeing. The aesthetic goal of BCT is symmetry for which there is no gold-standard measure. Panel scoring is the most widely adopted assessment but has well-described limitations. This paper describes a model to objectively report aesthetic outcome using measures derived from 3-dimensional surface images (3D-SI). METHOD: Objective measures and panel assessment were undertaken independently for 3D-SI of women who underwent BCT 1-5 years previously. Univariate analysis was used to test for association between measures and panel score. A forward stepwise multiple linear regression model was fitted to identify 3D measurements that jointly predicted the mean panel score. The fitted model coefficients were used to predict mean panel scores for an independent validation set then compared to the mean observed panel score. RESULTS: Very good intra-panel reliability was observed for the training and validation sets (wκ = 0.87, wκ = 0.84). Six 3D-measures were used in the multivariate model. There was a good correlation between the predicted and mean observed panel score in the training (n = 190) and validation (n = 100) sets (r = 0.68, r = 0.65). The 3D model tended to predict scores towards the median. The model was calibrated which improved the distribution of predicted scores. CONCLUSION: A six-variable objective aesthetic outcome model for BCT has been described and validated. This can predict and could replace panel assessment, facilitating the independent and unbiased evaluation of aesthetic outcome to communicate and compare results, benchmark practice, and raise standards..

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PURPOSE: To assess the pathologic and radiologic response in patients with low-risk breast cancer treated with magnetic resonance (MR) guided neoadjuvant partial breast irradiation (NA-PBI) and to evaluate toxicity and patient-reported outcomes (PROs). METHODS AND MATERIALS: For this single-arm prospective trial, women with unifocal, non-lobular tumors with a maximum diameter of 20 mm (age, 50-70 years) or 30 mm (age, ≥70 years) and tumor-negative sentinel node(s) were eligible. Patients were treated with a single ablative dose of NA-PBI followed by breast-conserving surgery after an interval of 6 to 8 months. Target volumes were defined on radiation therapy planning computed tomography scan and additional magnetic resonance imaging. Prescribed doses to gross tumor volume and clinical target volume (gross tumor volume plus 20 mm margin) were 20 Gy and 15 Gy, respectively. Primary outcome was pathologic complete response (pCR). Secondary outcomes were radiologic response (on magnetic resonance imaging), toxicity (Common Terminology Criteria for Adverse Events), PROs (European Organisation for Research and Treatment of Cancer QLQ-BR23, Hospital Anxiety and Depression Scale), and cosmesis (assessed by patient, radiation oncologist, and BCCT.core software). RESULTS: Thirty-six patients were treated with NA-PBI, and pCR was reported in 15 patients (42%; 95% confidence interval, 26%-59%). Radiologic complete response was observed in 15 patients, 10 of whom had pCR (positive predictive value, 67%; 95% confidence interval, 39%-87%). After a median follow-up of 21 months (range, 12-41), all patients experienced grade 1 fibrosis in the treated breast volume. Transient grade 2 and 3 toxicity was observed in 31% and 3% of patients, respectively. Local recurrences were absent. No deterioration in PROs or cosmetic results was observed. CONCLUSIONS: NA-PBI has the potential to induce pCR in a substantial proportion of patients, with acceptable toxicity. This treatment seems a feasible alternative to standard postoperative irradiation and could even result in postponement or omission of surgery if pCR can be accurately predicted in selected low-risk patients..

PURPOSE: Hydrogen peroxide (H2O2) plays a vital role in normal cellular processes but at supraphysiological concentrations causes oxidative stress and cytotoxicity, a property that is potentially exploitable for the treatment of cancer in combination with radiation therapy (RT). We report the first phase 1 trial testing the safety and tolerability of intratumoral H2O2 + external beam RT as a novel combination in patients with breast cancer and exploratory plasma marker analyses investigating possible mechanisms of action. METHODS AND MATERIALS: Twelve patients with breast tumors ≥3 cm (surgically or medically inoperable) received intratumoral H2O2 with either 36 Gy in 6 twice-weekly fractions (n = 6) or 49.5 Gy in 18 daily fractions (n = 6) to the whole breast ± locoregional lymph nodes in a single-center, nonrandomized study. H2O2 was mixed in 1% sodium hyaluronate gel (final H2O2 concentration 0.5%) before administration to slow drug release and minimize local discomfort. The mixture was injected intratumorally under ultrasound guidance twice weekly 1 hour before RT. The primary endpoint was patient-reported maximum intratumoral pain intensity before and 24 hours postinjection. Secondary endpoints included grade ≥3 skin toxicity and tumor response by ultrasound. Blood samples were collected before, during, and at the end of treatment for cell-death and immune marker analysis. RESULTS: Compliance with H2O2 and RT was 100%. Five of 12 patients reported moderate pain after injection (grade 2 Common Terminology Criteria for Adverse Events v4.02) with median duration 60 minutes (interquartile range, 20-120 minutes). Skin toxicity was comparable to RT alone, with maintained partial/complete tumor response relative to baseline in 11 of 12 patients at last follow-up (median 12 months). Blood marker analysis highlighted significant associations of TRAIL, IL-1β, IL-4, and MIP-1α with tumor response. CONCLUSIONS: Intratumoral H2O2 with RT is well tolerated with no additional toxicity compared with RT alone. If efficacy is confirmed in a randomized phase 2 trial, the approach has potential as a cost-effective radiation response enhancer in multiple cancer types in which locoregional control after RT alone remains poor..

BACKGROUND: We aimed to identify a five-fraction schedule of adjuvant radiotherapy (radiation therapy) delivered in 1 week that is non-inferior in terms of local cancer control and is as safe as an international standard 15-fraction regimen after primary surgery for early breast cancer. Here, we present 5-year results of the FAST-Forward trial. METHODS: FAST-Forward is a multicentre, phase 3, randomised, non-inferiority trial done at 97 hospitals (47 radiotherapy centres and 50 referring hospitals) in the UK. Patients aged at least 18 years with invasive carcinoma of the breast (pT1-3, pN0-1, M0) after breast conservation surgery or mastectomy were eligible. We randomly allocated patients to either 40 Gy in 15 fractions (over 3 weeks), 27 Gy in five fractions (over 1 week), or 26 Gy in five fractions (over 1 week) to the whole breast or chest wall. Allocation was not masked because of the nature of the intervention. The primary endpoint was ipsilateral breast tumour relapse; assuming a 2% 5-year incidence for 40 Gy, non-inferiority was predefined as ≤1·6% excess for five-fraction schedules (critical hazard ratio [HR] of 1·81). Normal tissue effects were assessed by clinicians, patients, and from photographs. This trial is registered at isrctn.com, ISRCTN19906132. FINDINGS: Between Nov 24, 2011, and June 19, 2014, we recruited and obtained consent from 4096 patients from 97 UK centres, of whom 1361 were assigned to the 40 Gy schedule, 1367 to the 27 Gy schedule, and 1368 to the 26 Gy schedule. At a median follow-up of 71·5 months (IQR 71·3 to 71·7), the primary endpoint event occurred in 79 patients (31 in the 40 Gy group, 27 in the 27 Gy group, and 21 in the 26 Gy group); HRs versus 40 Gy in 15 fractions were 0·86 (95% CI 0·51 to 1·44) for 27 Gy in five fractions and 0·67 (0·38 to 1·16) for 26 Gy in five fractions. 5-year incidence of ipsilateral breast tumour relapse after 40 Gy was 2·1% (1·4 to 3·1); estimated absolute differences versus 40 Gy in 15 fractions were -0·3% (-1·0 to 0·9) for 27 Gy in five fractions (probability of incorrectly accepting an inferior five-fraction schedule: p=0·0022 vs 40 Gy in 15 fractions) and -0·7% (-1·3 to 0·3) for 26 Gy in five fractions (p=0·00019 vs 40 Gy in 15 fractions). At 5 years, any moderate or marked clinician-assessed normal tissue effects in the breast or chest wall was reported for 98 of 986 (9·9%) 40 Gy patients, 155 (15·4%) of 1005 27 Gy patients, and 121 of 1020 (11·9%) 26 Gy patients. Across all clinician assessments from 1-5 years, odds ratios versus 40 Gy in 15 fractions were 1·55 (95% CI 1·32 to 1·83, p<0·0001) for 27 Gy in five fractions and 1·12 (0·94 to 1·34, p=0·20) for 26 Gy in five fractions. Patient and photographic assessments showed higher normal tissue effect risk for 27 Gy versus 40 Gy but not for 26 Gy versus 40 Gy. INTERPRETATION: 26 Gy in five fractions over 1 week is non-inferior to the standard of 40 Gy in 15 fractions over 3 weeks for local tumour control, and is as safe in terms of normal tissue effects up to 5 years for patients prescribed adjuvant local radiotherapy after primary surgery for early-stage breast cancer. FUNDING: National Institute for Health Research Health Technology Assessment Programme..

PURPOSE: Our purpose was to present and evaluate expert consensus on contouring primary breast tumors on magnetic resonance imaging (MRI) in the setting of neoadjuvant partial breast irradiation in trials. METHODS AND MATERIALS: Expert consensus on contouring guidelines for target definition of primary breast tumors on contrast-enhanced MRI in trials was developed by an international team of experienced breast radiation oncologists and a dedicated breast radiologist during 3 meetings. At the first meeting, draft guidelines were developed through discussing and contouring 2 cases. At the second meeting 6 breast radiation oncologists delineated gross tumor volume (GTV) in 10 patients with early-stage breast cancer (cT1N0) according to draft guidelines. GTV was expanded isotropically (20 mm) to generate clinical target volume (CTV), excluding skin and chest wall. Delineations were reviewed for disagreement and guidelines were clarified accordingly. At the third meeting 5 radiation oncologists redelineated 6 cases using consensus-based guidelines. Interobserver variation of GTV and CTV was assessed using generalized conformity index (CI). CI was calculated as the sum of volumes each pair of observers agreed upon, divided by the sum of encompassing volumes for each pair of observers. RESULTS: For the 2 delineation sessions combined, mean GTV ranged between 0.19 and 2.44 cm3, CI for GTV ranged between 0.28 and 0.77, and CI for CTV between 0.77 and 0.94. The largest interobserver variation in GTV delineations was observed in cases with extended tumor spiculae, blood vessels near or markers within the tumor, or with increased enhancement of glandular breast tissue. Consensus-based guidelines stated to delineate all visible tumors on contrast enhanced-MRI scan 1 to 2 minutes after contrast injection and if a marker was inserted in the tumor to include this. CONCLUSIONS: Expert-based consensus on contouring primary breast tumors on MRI in trials has been reached. This resulted in low interobserver variation for CTV in the context of a uniform 20 mm GTV to CTV expansion margin..

Current research in radiotherapy (RT) for breast cancer is evaluating neoadjuvant as opposed to adjuvant partial breast irradiation (PBI) with the aim of reducing the volume of breast tissue irradiated and therefore the risk of late treatment-related toxicity. The development of magnetic resonance (MR)-guided RT, including dedicated MR-guided RT systems [hybrid machines combining an MR scanner with a linear accelerator (MR-linac) or 60Co sources], could potentially reduce the irradiated volume even further by improving tumour visibility before and during each RT treatment. In this position paper, we discuss MR guidance in relation to each step of the breast RT planning and treatment pathway, focusing on the application of MR-guided RT to neoadjuvant PBI..

Purpose: MR-guided Radiation Therapy (MRgRT) allows for high-precision radiotherapy under real-time MR visualization. This enables margin reduction and subsequent dose escalation which may lead to higher tumor control and less toxicity. The Unity MR-linac (Elekta AB, Stockholm, Sweden) integrates a linear accelerator with a 1.5T diagnostic quality MRI and an online adaptive workflow. A prospective international registry was established to facilitate the evidence-based implementation of the Unity MR-linac into clinical practice, to systemically evaluate long-term outcomes, and to aid further technical development of MR-linac-based MRgRT. Methods and Results: In February 2019, the Multi-OutcoMe EvaluatioN of radiation Therapy Using the MR-linac study (MOMENTUM) started within the MR-linac Consortium. The MOMENTUM study is an international academic-industrial partnership between several hospitals and industry partner Elekta. All patients treated on the MR-linac are eligible for inclusion in MOMENTUM. For participants, we collect clinical patient data (e.g., patient, tumor, and treatment characteristics) and technical patient data which is defined as information generated on the MR-linac during treatment. The data are captured, pseudonymized, and stored in an international registry at set time intervals up to two years after treatment. Patients can choose to provide patient-reported outcomes and consent to additional MRI scans acquired on the MR-linac. This registry will serve as a data platform that supports multicenter research investigating the MR-linac. Rules and regulations on data sharing, data access, and intellectual property rights are summarized in an academic-industrial collaboration agreement. Data access rules ensure secure data handling and research integrity for investigators and institutions. Separate data access rules exist for academic and industry partners. This study is registered at ClinicalTrials.gov with ID: NCT04075305 (https://clinicaltrials.gov/ct2/show/NCT04075305). Conclusion: The multi-institutional MOMENTUM study has been set up to collect clinical and technical patient data to advance technical development, and facilitate evidenced-based implementation of MR-linac technology with the ultimate purpose to improve tumor control, survival, and quality of life of patients with cancer..

PURPOSE: IMPORT LOW demonstrated noninferiority of partial-breast and reduced-dose radiotherapy versus whole-breast radiotherapy for local relapse and similar or reduced toxicity at 5 years. Comprehensive patient-reported outcome measures collected at serial time points are now reported. PATIENTS AND METHODS: IMPORT LOW recruited women with low-risk breast cancer after breast-conserving surgery. Patients were randomly assigned to 40 Gy whole-breast radiotherapy (control), 36 Gy whole-breast and 40 Gy partial-breast radiotherapy (reduced-dose), or 40 Gy partial-breast radiotherapy only (partial-breast) in 15 fractions. European Organisation for Research and Treatment of Cancer Quality of Life Questionnaires Core 30 and Breast Cancer-Specific Module, Body Image Scale, protocol-specific items, and the Hospital Anxiety and Depression Scale were administered at baseline, 6 months, and 1, 2, and 5 years. Patterns of moderate/marked adverse effects (AEs) were assessed using longitudinal regression models, and baseline predictors were investigated. RESULTS: A total of 41 of 71 centers participated in the patient-reported outcome measures substudy; 1,265 (95%) of 1,333 patients consented, and 557 (58%) of 962 reported no moderate/marked AEs at 5 years. Breast appearance change was most prevalent and persisted over time (approximately 20% at each time point). Prevalence of breast hardness, pain, oversensitivity, edema, and skin changes reduced over time ( P < .001 for each), whereas breast shrinkage increased ( P < .001). Analysis by treatment group showed average number of AEs per person was lower in partial-breast (incidence rate ratio, 0.77; 95% CI, 0.71 to 0.84; P < .001) and reduced-dose (incidence rate ratio, 0.83; 95% CI, 0.76 to 0.90; P < .001) versus whole-breast group and decreased over time in all groups. Younger age, larger breast size/surgical deficit, lymph node positivity, and higher levels of anxiety/depression were baseline predictors of subsequent AE reporting. CONCLUSION: Most AEs reduced over time, with fewer AEs in the partial-breast and reduced-dose groups. Baseline predictors for AE reporting were identified. These findings will facilitate informed discussion and shared decision making for future patients receiving moderately hypofractionated breast radiotherapy..

AIMS: Irradiation of the internal mammary chain (IMC) is increasing following recently published data, but the need for formal delineation of lymph node volumes is slowing implementation in some healthcare settings. A field-placement algorithm for irradiating locoregional lymph nodes including the IMC could reduce the resource impact of introducing irradiation of the IMC. This study describes the development and evaluation of such an algorithm. MATERIALS AND METHODS: An algorithm was developed in which six points representing lymph node clinical target volume borders (based on European Society for Radiotherapy and Oncology consensus nodal contouring guidelines) were placed on computed tomography-defined anatomical landmarks and used to place tangential and nodal fields. Single-centre testing in 20 cases assessed the success of the algorithm in covering planning target volumes (PTVs) and adequately sparing organs at risk. Plans derived using the points algorithm were also compared with plans generated following formal delineation of nodal PTVs, using the Wilcoxon signed rank test. Timing data for point placement were collected. Multicentre testing using the same methods was then carried out to establish whether the technique was transferable to other centres. RESULTS: Single-centre testing showed that 95% of cases met the nodal PTV coverage dose constraints (binomial probability confidence interval 75.1-99.9%) with no statistically significant reduction in mean heart dose or ipsilateral lung V17Gy associated with formal nodal delineation. In multicentre testing, 69% of cases met nodal PTV dose constraints and there was a statistically significant difference in IMC PTV coverage using the points algorithm when compared with formally delineated nodal volumes (P < 0.01). However, there was no difference in axillary level 1-4 PTV coverage (P = 0.11) with all cases meeting target volume constraints. CONCLUSIONS: The optimal strategy for breast and locoregional lymph node radiotherapy is target volume delineation. However, use of this novel points-based field-placement algorithm results in dosimetrically acceptable plans without the need for formal lymph node contouring in a single-centre setting and for the breast and level 1-4 axilla in a multicentre setting. Further quality assurance measures are needed to enable implementation of the algorithm for irradiation of the IMC in a multicentre setting..

BACKGROUND: In an era of low local relapse rates after adjuvant breast radiotherapy, risks of late normal-tissue effects (NTE) need to be balanced against risk of relapse. NTE are assessed using patient-reported outcome measures (PROMs), clinician-reported outcomes (CRO) and photographs. This analysis investigates whether PROMs can be used as primary NTE endpoints in breast radiotherapy trials. METHODS: Analyses were conducted within IMPORT LOW (ISRCTN12852634) at 2 and 5 years. NTE were recorded by CRO, photographs and PROMs. Measures of agreement tested concordance, risk ratios for radiotherapy groups were compared, and influence of baseline characteristics on concordance investigated. RESULTS: In 1095 patients who consented to PROMS and photographs, PROMs were available at 2 and/or 5 years for 976 patients, of whom 909 had CRO and 844 had photographs. Few patients had moderate/marked NTE, irrespective of method used (eg. 19% patients and 9% clinicians reported breast shrinkage at year-5). Patients reported more NTE than assessed from CRO or photographs (p < 0.001 for most NTE). Concordance between assessments was poor on an individual patient level; eg. for year-5 breast shrinkage, % agreement = 48% and weighted kappa = 0.17. Risk ratios comparing radiotherapy schedules were consistent between PROMs and CRO or photographs. CONCLUSIONS: Few patients had moderate/marked NTE irrespective of method used. Patients reported more NTE than CRO and photographs, therefore NTE may be underestimated if PROMs are not used. Despite poor concordance between methods, effect sizes from PROMs were consistent with CRO and photographs, suggesting PROMs can be used as primary NTE endpoints in breast radiotherapy trials..

AIMS: In patients undergoing locoregional radiotherapy (RT) for breast cancer including the internal mammary chain (IMC), VMAT has been shown to be superior to tangential-field radiotherapy in terms of target coverage and minimising dose to heart and lungs. In this study we describe and validate organ motion-based robust optimisation for generating breast and locoregional lymph node VMAT plans that are robust to inter-fractional changes. MATERIALS AND METHODS: In this retrospective study of five patients with left-sided breast cancer requiring locoregional breast radiotherapy including the IMC, non-robust plans were generated in the nominal scenario (planning-CT) and corresponding robust plans were created by optimising over a range of simulated CTs representing worst-case scenario shape changes to the breast. Both plans were re-calculated on CBCT images (n = 67) acquired prior to RT to generate estimates of delivered fractional dose. Plan robustness to inter-fractional changes was assessed in terms of the estimated target coverage and OAR dose. RESULTS: Organ motion-based robust optimisation was able to generate clinically acceptable treatment plans in the nominal scenario on the planning CT with no significant differences to OAR dose between the robust and non-robust planning techniques. All plans (robust and non-robust) achieved the mandatory target coverage requirements. Estimates of delivered dose demonstrated a significant improvement in breast target coverage for the robust plans compared to non-robust plans. For the breast CTV, 92% of the robust plans achieved the optimal D98% > 95% clinical goal as compared to 71% of the non-robust plans (p < 0.01). 94% of robust plans achieved acceptable superficial breast coverage, as compared to 55% for the non-robust technique. CONCLUSIONS: Organ motion-based robust optimisation VMAT is able to produce clinically acceptable organ-at-risk sparing plans for locoregional breast radiotherapy (including the IMC) that are robust to inter-fractional changes, therefore reducing the likelihood of reactive adaptive re-planning..

BACKGROUND: Seroma describes a collection of serous fluid within a cavity, occurring following surgery. Seroma is associated with normal tissue effects (NTE) following breast radiotherapy, as reported by clinicians and on photographs. This study investigates the association between seroma and the NTE breast appearance change collected using patient-reported outcome measures (PROMs) in IMPORT HIGH, as well as investigating the association between breast appearance change and patient/tumour/treatment factors. METHODS: Case-control methodology was used for seroma analysis within IMPORT HIGH. Cases were patients reporting moderate/marked breast appearance change and controls reported none/mild changes at year-3. One control was selected at random for each case. Seromas were graded as not visible/subtle or visible/highly visible on CT radiotherapy planning scans. Logistic regression tested associations, adjusting for patient/tumour/treatment factors. RESULTS: 1078/1149 patients consented to PROMs, of whom 836 (78%) reported whether they had 3-year breast appearance change; 231 cases and 231 controls were identified. 304/462 (66%) patients received chemotherapy. Seroma prevalence was 20% (41/202) in cases and 16% (32/205) in controls, and less frequent in patients receiving adjuvant chemotherapy [10% (24/246) compared with 29% (40/138) without]. Visible seroma was not significantly associated with breast appearance change [OR 1.38 (95%CI 0.83-2.29), p = 0.219]. Larger tumour size, haematoma, current smoking and body image concerns at baseline were independent risk factors. CONCLUSIONS: Seroma was not associated with patient-reported breast appearance change, but haematoma and smoking were significant risk factors. Lack of association may be related to lower prevalence of seroma compared with previous reports, perhaps reflecting patients receiving adjuvant chemotherapy in whom seroma resolves prior to radiotherapy..

Immediate breast reconstruction (IBR) rates after mastectomy are increasing. Postmastectomy radiation therapy (PMRT) contouring guidelines for target volumes in the setting of IBR are lacking. Therefore, many patients who have had IBR receive PMRT to target volumes similar to conventional simulator-based whole breast irradiation. The aim of this paper is to describe delineation guidelines for PMRT after implant-based IBR based on a thorough understanding of the surgical procedures, disease stage, patterns of recurrence and radiation techniques. They are based on a consensus endorsed by a global multidisciplinary group of breast cancer experts..

Adjuvant radiotherapy after breast-conserving surgery has been an important component of the standard of care for early breast cancer. Improvements in breast cancer care have resulted in a substantial reduction in local relapse rates over recent decades. Although the proportional benefits of adjuvant radiotherapy are similar for different prognostic risk groups of patients, the absolute benefits depend on the risk of relapse and therefore vary considerably between prognostic groups. Radiotherapy is not without risk and for some patients at very low risk of relapse the risks of radiotherapy may outweigh the benefit, leading to potential overtreatment. Randomised controlled trial (RCT) evidence shows that omission of radiotherapy in low risk early breast cancer does not reduce overall survival or increase breast cancer mortality and local recurrences are salvageable. Despite this there has not been a change in practice regarding omission of radiotherapy. The reasons for this may include challenges in patient selection. Recent advances in immunohistochemistry and genomic profiling may improve risk stratification and the development of biomarkers to directed therapies. Several RCTs have quantified the benefit of radiotherapy in reducing local relapse. Where a treatment benefit is known but is considered to be so small not to be clinically relevant then alternatives to RCTs may be considered to answer the question of need. This is because we can assess risk against a fixed 'absolute' boundary rather than needing a randomised comparator. The prospective cohort study is an alternative to the RCT design to answer the question of need for radiotherapy. The feasibility of recruitment into biomarker-directed de-escalation studies will become apparent as more studies open. The challenge is to determine if we are able to accurately risk stratify patients and avoid unnecessary toxicity, thereby tailoring the need for adjuvant breast radiotherapy on an individual patient basis..

Voluntary inspiration breath hold (VIBH) for left breast cancer patients has been shown to be a safe and effective method of reducing radiation dose to the heart. Currently, VIBH protocol compliance is monitored visually. In this work, we establish whether it is possible to gate the delivery of radiation from an Elekta linac using the Microsoft Kinect version 2 (Kinect v2) depth sensor to measure a patient breathing signal. This would allow contactless monitoring during VMAT treatment, as an alternative to equipment-assisted methods such as active breathing control (ABC). Breathing traces were acquired from six left breast radiotherapy patients during VIBH. We developed a gating interface to an Elekta linac, using the depth signal from a Kinect v2 to control radiation delivery to a programmable motion platform following patient breathing patterns. Radiation dose to a moving phantom with gating was verified using point dose measurements and a Delta4 verification phantom. 60 breathing traces were obtained with an acquisition success rate of 100%. Point dose measurements for gated deliveries to a moving phantom agreed to within 0.5% of ungated delivery to a static phantom using both a conventional and VMAT treatment plan. Dose measurements with the verification phantom showed that there was a median dose difference of better than 0.5% and a mean (3% 3 mm) gamma index of 92.6% for gated deliveries when using static phantom data as a reference. It is possible to use a Kinect v2 device to monitor voluntary breath hold protocol compliance in a cohort of left breast radiotherapy patients. Furthermore, it is possible to use the signal from a Kinect v2 to gate an Elekta linac to deliver radiation only during the peak inhale VIBH phase..

The American Society of Radiation Oncology has recently updated its guidelines on the role of accelerated partial breast irradiation in the management of breast cancer. This commentary discusses the new recommendations and how we might advise patients in the light of existing data..

AIMS: Radiotherapy target volumes in early breast cancer treatment increasingly include the internal mammary chain (IMC). In order to maximise survival benefits of IMC radiotherapy, doses to the heart and lung should be minimised. This dosimetry study compared the ability of three-dimensional conformal radiotherapy, arc therapy and proton beam therapy (PBT) techniques with and without breath-hold to achieve target volume constraints while minimising dose to organs at risk (OARs). MATERIALS AND METHODS: In 14 patients' datasets, seven IMC radiotherapy techniques were compared: wide tangent (WT) three-dimensional conformal radiotherapy, volumetric-modulated arc therapy (VMAT) and PBT, each in voluntary deep inspiratory breath-hold (vDIBH) and free breathing (FB), and tomotherapy in FB only. Target volume coverage and OAR doses were measured for each technique. These were compared using a one-way ANOVA with all pairwise comparisons tested using Bonferroni's multiple comparisons test, with adjusted P-values ≤ 0.05 indicating statistical significance. RESULTS: One hundred per cent of WT(vDIBH), 43% of WT(FB), 100% of VMAT(vDIBH), 86% of VMAT(FB), 100% of tomotherapy FB and 100% of PBT plans in vDIBH and FB passed all mandatory constraints. However, coverage of the IMC with 90% of the prescribed dose was significantly better than all other techniques using VMAT(vDIBH), PBT(vDIBH) and PBT(FB) (mean IMC coverage ± 1 standard deviation = 96.0% ± 4.3, 99.8% ± 0.3 and 99.0% ± 0.2, respectively). The mean heart dose was significantly reduced in vDIBH compared with FB for both the WT (P < 0.0001) and VMAT (P < 0.0001) techniques. There was no advantage in target volume coverage or OAR doses for PBT(vDIBH) compared with PBT(FB). CONCLUSIONS: Simple WT radiotherapy delivered in vDIBH achieves satisfactory coverage of the IMC while meeting heart and lung dose constraints. However, where higher isodose coverage is required, VMAT(vDIBH) is the optimal photon technique. The lowest OAR doses are achieved by PBT, in which the use of vDIBH does not improve dose statistics..

BACKGROUND: The authors investigated aesthetic outcome and patient satisfaction in women who have undergone deep inferior epigastric artery perforator (DIEP) flap reconstruction in the setting of postmastectomy radiotherapy. Patients who underwent DIEP flap reconstruction without postmastectomy radiotherapy were the control group. METHODS: Participants who had undergone DIEP flap reconstruction between September 1, 2009, and September 1, 2014, were recruited, answered the BREAST-Q, and underwent three-dimensional surface-imaging. A panel assessed the aesthetic outcome by reviewing these images. RESULTS: One hundred sixty-seven women participated. Eighty women (48 percent) underwent immediate DIEP flap reconstruction and no postmastectomy radiotherapy; 28 (17 percent) underwent immediate DIEP flap reconstruction with postmastectomy radiotherapy; 38 (23 percent) underwent simple mastectomy, postmastectomy radiotherapy, and DIEP flap reconstruction; and 21 (13 percent) underwent mastectomy with temporizing implant, postmastectomy radiotherapy, and DIEP flap reconstruction. Median satisfaction scores were significantly different among the groups (p < 0.05). Post hoc comparison demonstrated that women who had an immediate DIEP flap reconstruction were significantly less satisfied if they had postmastectomy radiotherapy. In women requiring radiotherapy, those undergoing delayed reconstruction after a simple mastectomy were most satisfied, but there was no significant difference between the immediate DIEP flap and temporizing implant groups. Median panel scores differed among groups, being significantly higher if the immediate reconstruction was not subjected to radiotherapy. There was no significant difference in panel assessment among the three groups of women who had received radiotherapy. CONCLUSIONS: Patients who avoid having their immediate DIEP flap reconstruction irradiated are more satisfied and have better aesthetic outcome than those who undergo postmastectomy radiotherapy. In women requiring radiotherapy and who wish to have an immediate or "delayed-immediate" reconstruction, there were no significant differences in panel or patient satisfaction. Therefore, immediate DIEP flap reconstruction or mastectomy with temporizing implant then DIEP flap surgery are acceptable treatment pathways in the context of post-mastectomy radiotherapy..

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OBJECTIVES: To reduce treatment planning times while maintaining plan quality through the introduction of semi-automated planning techniques for breast radiotherapy. METHODS: Automatic critical structure delineation was examined using the Smart Probabilistic Image Contouring Engine (SPICE) commercial autosegmentation software (Philips Radiation Oncology Systems, Fitchburg, WI) for a cohort of ten patients. Semiautomated planning was investigated by employing scripting in the treatment planning system to automate segment creation for breast step-and-shoot planning and create objectives for segment weight optimization; considerations were made for three different multileaf collimator (MLC) configurations. Forty patients were retrospectively planned using the script and a planning time comparison performed. RESULTS: The SPICE heart and lung outlines agreed closely with clinician-defined outlines (median Dice Similarity Coefficient > 0.9); median difference in mean heart dose was 0.0 cGy (range -10.8 to 5.4 cGy). Scripted treatment plans demonstrated equivalence with their clinical counterparts. No statistically significant differences were found for target parameters. Minimal ipsilateral lung dose increases were also observed. Statistically significant (P < 0.01) time reductions were achievable for MLCi and Agility MLC (Elekta Ltd, Crawley, UK) plans (median 4.9 and 5.9 min, respectively). CONCLUSIONS: The use of commercial autosegmentation software enables breast plan adjustment based on doses to organs at risk. Semi-automated techniques for breast radiotherapy planning offer modest reductions in planning times. However, in the context of a typical department's breast radiotherapy workload, minor savings per plan translate into greater efficiencies overall..

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..

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PURPOSE: To establish whether objective measurements of symmetry of volume and shape using three-dimensional surface imaging (3D-SI) can be used as surrogate markers of aesthetic outcome in patients who have undergone breast conserving therapy (BCT). METHODS: Women who had undergone unilateral BCT in the preceding 1-6 years were invited to participate. Participants completed a satisfaction questionnaire (BREAST-Q) and underwent 3D-SI. Volume and surface symmetry were measured on the images. Assessment of aesthetic outcome was undertaken by a panel of clinicians. The Kruskal-Wallis test was used to assess the relationship between volume and shape symmetry measurements with the panel score. Spearman's rho correlations were used to assess the relationship between the measurements and patient satisfaction. RESULTS: 200 women participated. Median volume symmetry was 87% (IQR 78-93) and shape symmetry was 5.9 mm (IQR 4.2-8.0). The participants were grouped according to panel assessment of aesthetic outcome (poor, fair, good, excellent) and the median volume and shape symmetry was calculated for each group. Volume symmetry significantly differed between the groups. Post hoc pairwise comparisons demonstrated that these differences existed between panel scores of fair versus good and good versus excellent. Median shape symmetry also differed according to patient panel groups with four significant pairwise comparisons between poor versus good, poor versus excellent, fair versus good and fair versus excellent. There was a significant but weak correlation of both volume symmetry and surface asymmetry with BREAST-Q scores (correlation coefficients 0.187 and -0.229, respectively). CONCLUSION: Breast volume and shape symmetry are both associated with panel assessment scores and patient satisfaction. The objective volume and shape symmetry measures were strongly associated with panel assessment scores, such that a 3D-SI tool could replace panel assessment as a faster and more objective method of evaluating aesthetic outcomes..

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BACKGROUND: Local cancer relapse risk after breast conservation surgery followed by radiotherapy has fallen sharply in many countries, and is influenced by patient age and clinicopathological factors. We hypothesise that partial-breast radiotherapy restricted to the vicinity of the original tumour in women at lower than average risk of local relapse will improve the balance of beneficial versus adverse effects compared with whole-breast radiotherapy. METHODS: IMPORT LOW is a multicentre, randomised, controlled, phase 3, non-inferiority trial done in 30 radiotherapy centres in the UK. Women aged 50 years or older who had undergone breast-conserving surgery for unifocal invasive ductal adenocarcinoma of grade 1-3, with a tumour size of 3 cm or less (pT1-2), none to three positive axillary nodes (pN0-1), and minimum microscopic margins of non-cancerous tissue of 2 mm or more, were recruited. Patients were randomly assigned (1:1:1) to receive 40 Gy whole-breast radiotherapy (control), 36 Gy whole-breast radiotherapy and 40 Gy to the partial breast (reduced-dose group), or 40 Gy to the partial breast only (partial-breast group) in 15 daily treatment fractions. Computer-generated random permuted blocks (mixed sizes of six and nine) were used to assign patients to groups, stratifying patients by radiotherapy treatment centre. Patients and clinicians were not masked to treatment allocation. Field-in-field intensity-modulated radiotherapy was delivered using standard tangential beams that were simply reduced in length for the partial-breast group. The primary endpoint was ipsilateral local relapse (80% power to exclude a 2·5% increase [non-inferiority margin] at 5 years for each experimental group; non-inferiority was shown if the upper limit of the two-sided 95% CI for the local relapse hazard ratio [HR] was less than 2·03), analysed by intention to treat. Safety analyses were done in all patients for whom data was available (ie, a modified intention-to-treat population). This study is registered in the ISRCTN registry, number ISRCTN12852634. FINDINGS: Between May 3, 2007, and Oct 5, 2010, 2018 women were recruited. Two women withdrew consent for use of their data in the analysis. 674 patients were analysed in the whole-breast radiotherapy (control) group, 673 in the reduced-dose group, and 669 in the partial-breast group. Median follow-up was 72·2 months (IQR 61·7-83·2), and 5-year estimates of local relapse cumulative incidence were 1·1% (95% CI 0·5-2·3) of patients in the control group, 0·2% (0·02-1·2) in the reduced-dose group, and 0·5% (0·2-1·4) in the partial-breast group. Estimated 5-year absolute differences in local relapse compared with the control group were -0·73% (-0·99 to 0·22) for the reduced-dose and -0·38% (-0·84 to 0·90) for the partial-breast groups. Non-inferiority can be claimed for both reduced-dose and partial-breast radiotherapy, and was confirmed by the test against the critical HR being more than 2·03 (p=0·003 for the reduced-dose group and p=0·016 for the partial-breast group, compared with the whole-breast radiotherapy group). Photographic, patient, and clinical assessments recorded similar adverse effects after reduced-dose or partial-breast radiotherapy, including two patient domains achieving statistically significantly lower adverse effects (change in breast appearance [p=0·007 for partial-breast] and breast harder or firmer [p=0·002 for reduced-dose and p<0·0001 for partial-breast]) compared with whole-breast radiotherapy. INTERPRETATION: We showed non-inferiority of partial-breast and reduced-dose radiotherapy compared with the standard whole-breast radiotherapy in terms of local relapse in a cohort of patients with early breast cancer, and equivalent or fewer late normal-tissue adverse effects were seen. This simple radiotherapy technique is implementable in radiotherapy centres worldwide. FUNDING: Cancer Research UK..

PURPOSE: The most recently developed module of the BREAST-Q, a validated patient outcome measure, is for patients who have undergone breast-conserving therapy (BCT) for cancer. This aim of this study was to assess patient satisfaction and quality of life after BCT using BREAST-Q, investigate clinical risk factors for lower satisfaction and explore the relationship between patient satisfaction with the appearance of their breasts and the other domains of the BREAST-Q. METHODS: Women who had undergone unilateral BCT in the preceding 1-6 years were invited to participate at the time of their annual surveillance mammogram. Clinicopathological data were collected from an electronic database. Linear regression was used to evaluate risk factors for lower satisfaction. Spearman's rho correlation coefficients were calculated to evaluate the relationship between domains. RESULTS: 200 women completed the questionnaire. Mean age was 60 years (SD 11.1). Time from surgery was 35.5 months (SD 17.8). Median score for 'Satisfaction with breasts' was 68 (interquartile range 55-80). Lowest scores were for 'sexual wellbeing' (57, IQR 45-66). On multivariate analysis, BMI at the time of surgery (p = 0.002), delayed wound healing (p = 0.001) and axillary surgery (p = 0.003) were independent risk factors for lower satisfaction. There was significant correlation between 'Satisfaction with breasts' and all other BREAST-Q domains. CONCLUSION: High BMI, delayed wound healing and axillary surgery are risk factors for lower patient satisfaction. This first publication reporting the whole dataset for the BREAST-Q BCT will serve as a benchmark for future studies of patient satisfaction following BCT..

OBJECTIVE: The purpose of the work was to estimate the dose received by the heart throughout a course of breath-holding breast radiotherapy. METHODS: 113 cone-beam CT (CBCT) scans were acquired for 20 patients treated within the HeartSpare 1A study, in which both an active breathing control (ABC) device and a voluntary breath-hold (VBH) method were used. Predicted mean heart doses were obtained from treatment plans. CBCT scans were imported into a treatment planning system, heart outlines defined, images registered to the CT planning scan and mean heart dose recorded. Two observers outlined two cases three times each to assess interobserver and intraobserver variation. RESULTS: There were no statistically significant differences between ABC and VBH heart dose data from CT planning scans, or in the CBCT-based estimates of heart dose, and no effect from the order of the breath-hold method. Variation in mean heart dose per fraction over the three imaged fractions was <6 cGy without setup correction, decreasing to 3.3 cGy with setup correction. If scaled to 15 fractions, all differences between predicted and estimated mean heart doses were <0.5 Gy and in 80% of cases, they were <0.25 Gy. CONCLUSION: Variation in mean heart dose was at an acceptable level over the duration of breath-holding radiotherapy and was well predicted by the planning system. Advances in knowledge: Mean heart dose was not adversely affected by fraction-to-fraction variations throughout a course of heart-sparing radiotherapy using two well-established breath-holding methods..

OBJECTIVE: The purpose of this UK study was to evaluate interfraction reproducibility and body image score when using ultraviolet (UV) tattoos (not visible in ambient lighting) for external references during breast/chest wall radiotherapy and compare with conventional dark ink. METHODS: In this non-blinded, single-centre, parallel group, randomized control trial, patients were allocated to receive either conventional dark ink or UV ink tattoos using computer-generated random blocks. Participant assignment was not masked. Systematic (∑) and random (σ) setup errors were determined using electronic portal images. Body image questionnaires were completed at pre-treatment, 1 month and 6 months to determine the impact of tattoo type on body image. The primary end point was to determine that UV tattoo random error (σsetup) was no less accurate than with conventional dark ink tattoos, i.e. <2.8 mm. RESULTS: 46 patients were randomized to receive conventional dark or UV ink tattoos. 45 patients completed treatment (UV: n = 23, dark: n = 22). σsetup for the UV tattoo group was <2.8 mm in the u and v directions (p = 0.001 and p = 0.009, respectively). A larger proportion of patients reported improvement in body image score in the UV tattoo group compared with the dark ink group at 1 month [56% (13/23) vs 14% (3/22), respectively] and 6 months [52% (11/21) vs 38% (8/21), respectively]. CONCLUSION: UV tattoos were associated with interfraction setup reproducibility comparable with conventional dark ink. Patients reported a more favourable change in body image score up to 6 months following treatment. Advances in knowledge: This study is the first to evaluate UV tattoo external references in a randomized control trial..

OBJECTIVE: To determine if subsets of patients may benefit from smaller or larger margins when using laser setup and bony anatomy verification of breast tumour bed (TB) boost radiotherapy (RT). METHODS: Verification imaging data acquired using cone-beam CT, megavoltage CT or two-dimensional kilovoltage imaging on 218 patients were used (1574 images). TB setup errors for laser-only setup (dlaser) and for bony anatomy verification (dbone) were determined using clips implanted into the TB as a gold standard for the TB position. Cases were grouped by centre-, patient- and treatment-related factors, including breast volume, TB position, seroma visibility and surgical technique. Systematic (Σ) and random (σ) TB setup errors were compared between groups, and TB planning target volume margins (MTB) were calculated. RESULTS: For the study population, Σlaser was between 2.8 and 3.4 mm, and Σbone was between 2.2 and 2.6 mm, respectively. Females with larger breasts (p = 0.03), easily visible seroma (p ≤ 0.02) and open surgical technique (p ≤ 0.04) had larger Σlaser. Σbone was larger for females with larger breasts (p = 0.02) and lateral tumours (p = 0.04). Females with medial tumours (p < 0.01) had smaller Σbone. CONCLUSION: If clips are not used, margins should be 8 and 10 mm for bony anatomy verification and laser setup, respectively. Individualization of TB margins may be considered based on breast volume, TB and seroma visibility. ADVANCES IN KNOWLEDGE: Setup accuracy using lasers and bony anatomy is influenced by patient and treatment factors. Some patients may benefit from clip-based image guidance more than others..

PURPOSE: To compare mean heart and left anterior descending coronary artery (LAD) doses (NTDmean) and positional reproducibility in larger-breasted women receiving left breast radiotherapy using supine voluntary deep-inspiratory breath-hold (VBH) and free-breathing prone techniques. MATERIALS AND METHODS: Following surgery for early breast cancer, patients with estimated breast volumes >750 cm(3) underwent planning-CT scans in supine VBH and free-breathing prone positions. Radiotherapy treatment plans were prepared, and mean heart and LAD doses were calculated. Patients were randomised to receive one technique for fractions 1-7, before switching techniques for fractions 8-15 (40 Gy/15 fractions total). Daily electronic portal imaging and alternate-day cone-beam CT (CBCT) imaging were performed. The primary endpoint was the difference in mean LAD NTDmean between techniques. Population systematic (Σ) and random errors (σ) were estimated. Within-patient comparisons between techniques used Wilcoxon signed-rank tests. RESULTS: 34 patients were recruited, with complete dosimetric data available for 28. Mean heart and LAD NTDmean doses for VBH and prone treatments respectively were 0.4 and 0.7 (p<0.001) and 2.9 and 7.8 (p<0.001). Clip-based CBCT errors for VBH and prone respectively were ⩽3.0 mm and ⩽6.5 mm (Σ) and ⩽3.5 mm and ⩽5.4 mm (σ). CONCLUSIONS: In larger-breasted women, supine VBH provided superior cardiac sparing and reproducibility than a free-breathing prone position..

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Following early results of recent studies of intraoperative radiotherapy (IORT) in the adjuvant treatment of patients with early breast cancer, the clinical utility of IORT is a subject of much recent debate within the breast oncology community. This review describes the intraoperative techniques available, the potential indications and the evidence to date pertaining to local control and toxicity. We also discuss any implications for current practice and future research..

OBJECTIVE: To evaluate breath-hold stability and constancy for a voluntary breath-hold (VBH) technique in a retrospective analysis. METHODS: Movie loop sequences of electronic portal image data from multiple breath holds in a cohort of 19 patients were used to assess within and between breath-hold stability. In vivo dosimetry data based on electronic portal imaging (EPI) were analysed for 31 VBH patients plus a cohort of free-breathing (FB) patients to provide a reference. A phantom experiment simulated the impact on dose of FB, breath hold and unplanned release of breath hold. RESULTS: 165/174 (93%) movie loop data sets had no detectable displacement. For the remaining 12, median displacement = 1.5 mm and maximum displacement = 3 mm (one patient on one fraction). In vivo dosimetry data analysis showed a median dose difference measured to planned of -0.2% (VBH) and -0.1% (FB). Dose distribution evaluation (γ) pass rates were 84% (VBH) and 91% (FB) including the lung region; 93% and 96% with a lung override. Unplanned release of phantom breath-hold position changed median dose by ≤1% and degraded γ pass rates to 79-62%. Failing regions were mostly in the periphery of the treated volume. CONCLUSION: The data confirmed that multiple VBHs using visual monitoring are stable; in vivo dose verification via EPI was within expected and acceptable levels. ADVANCES IN KNOWLEDGE: These data provide further reassurance that VBH is a safe technique for cardiac sparing breast radiotherapy and support its rapid, widespread implementation..

Breast cancer radiotherapy reduces the risk of cancer recurrence and death. However, it usually involves some radiation exposure of the heart and analyses of randomised trials have shown that it can increase the risk of heart disease. Estimates of the absolute risks of radiation-related heart disease are needed to help oncologists plan each individual woman's treatment. The risk for an individual woman varies according to her estimated cardiac radiation dose and her background risk of ischaemic heart disease in the absence of radiotherapy. When it is known, this risk can then be compared with the absolute benefit of the radiotherapy. At present, many UK cancer centres are already giving radiotherapy with mean heart doses of less than 3 Gy and for most women the benefits of the radiotherapy will probably far outweigh the risks. Technical approaches to minimising heart dose in breast cancer radiotherapy include optimisation of beam angles, use of multileaf collimator shielding, intensity-modulated radiotherapy, treatment in a prone position, treatment in deep inspiration (including the use of breath-hold and gating techniques), proton therapy and partial breast irradiation. The multileaf collimator is suitable for many women with upper pole left breast cancers, but for women with central or lower pole cancers, breath-holding techniques are now recommended in national UK guidelines. Ongoing work aims to identify ways of irradiating pan-regional lymph nodes that are effective, involve minimal exposure of organs at risk and are feasible to plan, deliver and verify. These will probably include wide tangent-based field-in-field intensity-modulated radiotherapy or arc radiotherapy techniques in combination with deep inspiratory breath-hold, and proton beam irradiation for women who have a high predicted heart dose from intensity-modulated radiotherapy..

OBJECTIVE: IMPORT HIGH is a multicentre randomized UK trial testing dose-escalated intensity-modulated radiotherapy (IMRT) after tumour excision in females with early breast cancer and higher than average local recurrence risk. A survey was carried out to investigate the impact of this trial on the adoption of advanced breast radiotherapy (RT) techniques in the UK. METHODS: A questionnaire was sent to all 26 IMPORT HIGH recruiting RT centres to determine whether the trial has influenced non-trial breast RT techniques in terms of volume delineation, dosimetry, treatment delivery and verification. In order to compare the clinical practice of breast RT between IMPORT HIGH and non-IMPORT HIGH centres, parts of the Royal College of Radiologists (RCR) breast RT audit result were used in this study. RESULTS: 26/26 participating centres completed the questionnaire. After joining the trial, the number of centres routinely using tumour bed clips to guide whole-breast RT rose from 5 (19%) to 21 (81%). 20/26 (77%) centres now contour target volumes and organs at risk (OARs) in some or all patients compared with 14 (54%) before the trial. 14/26 (54%) centres offer inverse-planned IMRT for selected non-trial patients with breast cancer, and 10/14 (71%) have adopted the IMPORT HIGH trial protocol for target volume and OARs dose constraints. Only 2/26 (8%) centres used clip information routinely for breast treatment verification prior to IMPORT HIGH, a minority that has since risen to 7/26 (27%). Data on 1386 patients was included from the RCR audit. This suggested that more cases from IMPORT HIGH centres had surgical clips implanted (83 vs 67%), were treated using CT guided planning with full three-dimensional dose compensation (100 vs 75%), and were treated with photon boost RT (30 vs 8%). CONCLUSION: The study suggests that participation in the IMPORT HIGH trial has played an important part in providing the guidance and support networks needed for the safe integration of advanced RT techniques, where appropriate, as a standard of care for breast cancer patients treated at participating cancer centres. ADVANCES IN KNOWLEDGE: We investigated the impact of the IMPORT HIGH trial on the adoption of advanced breast RT techniques in the UK and the trial has influenced non-trial breast RT techniques in terms of volume delineation, dosimetry, treatment delivery and verification..

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Breath-holding techniques reduce the amount of radiation received by cardiac structures during tangential-field left breast radiotherapy. With these techniques, patients hold their breath while radiotherapy is delivered, pushing the heart down and away from the radiotherapy field. Despite clear dosimetric benefits, these techniques are not yet in widespread use. One reason for this is that commercially available solutions require specialist equipment, necessitating not only significant capital investment, but often also incurring ongoing costs such as a need for daily disposable mouthpieces. The voluntary breath-hold technique described here does not require any additional specialist equipment. All breath-holding techniques require a surrogate to monitor breath-hold consistency and whether breath-hold is maintained. Voluntary breath-hold uses the distance moved by the anterior and lateral reference marks (tattoos) away from the treatment room lasers in breath-hold to monitor consistency at CT-planning and treatment setup. Light fields are then used to monitor breath-hold consistency prior to and during radiotherapy delivery..

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AIMS: To determine the effect of image-guided radiotherapy on the dose distributions in breast boost treatments. MATERIALS AND METHODS: Computed tomography images from a cohort of 60 patients treated within the IMPORT HIGH trial (CRUK/06/003) were used to create sequential and concomitant boost treatment plans (30 cases each). Two treatment plans were created for each case using tumour bed planning target volume (PTV) margins of 5 mm (achieved with image-guided radiotherapy) and 8 mm (required for bony anatomy verification). Dose data were collected for breast, lung and heart; differences with margin size were tested for statistical significance. RESULTS: A median decrease of 29 cm(3) (range 11-193 cm(3)) of breast tissue receiving 95% of the prescribed dose was observed where image-guided radiotherapy margins were used. Decreases in doses to lungs, contralateral breast and heart were modest, but statistically significant (P < 0.01). Plan quality was compromised with the 8 mm PTV margin in one in eight sequential boost plans and one third of concomitant boost plans. Tumour bed PTV coverage was <95% (>91%) of the prescribed dose in 12 cases; in addition, the required partial breast median dose was exceeded in nine concomitant boost cases by 0.5-3.7 Gy. CONCLUSIONS: The use of image guidance and, hence, a reduced tumour bed PTV margin, in breast boost radiotherapy resulted in a modest reduction in radiation dose to breast, lung and heart tissues. Reduced margins enabled by image guidance were necessary to discriminate between dose levels to multiple PTVs in the concomitant breast boost plans investigated..

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PURPOSE: International consensus has not been reached regarding the optimal number of implanted tumour bed (TB) markers for partial breast/breast boost radiotherapy target volume delineation. Four common methods are: insertion of 6 clips (4 radial, 1 deep and 1 superficial), 5 clips (4 radial and 1 deep), 1 clip at the chest wall, and no clips. We compared TB volumes delineated using 6, 5, 1 and 0 clips in women who have undergone wide-local excision (WLE) of breast cancer (BC) with full-thickness closure of the excision cavity, in order to determine the additional margin required for breast boost or partial breast irradiation (PBI) when fewer than 6 clips are used. METHODS: Ten patients with invasive ductal BC who had undergone WLE followed by implantation of six fiducial markers (titanium clips) each underwent CT imaging for radiotherapy planning purposes. Retrospective processing of the DICOM image datasets was performed to remove markers and associated imaging artefacts, using an in-house software algorithm. Four observers outlined TB volumes on four different datasets for each case: (1) all markers present (CT6M); (2) the superficial marker removed (CT(5M)); (3) all but the chest wall marker removed (CTCW); (4) all markers removed (CT(0M)). For each observer, the additional margin required around each of TB(0M), TBCW, and TB(5M) in order to encompass TB(6M) was calculated. The conformity level index (CLI) and differences in centre-of-mass (COM) between observers were quantified for CT(0M), CTCW, CT(5M), CT(6M). RESULTS: The overall median additional margins required to encompass TB(6M) were 8mm (range 0-28 mm) for TB(0M), 5mm (range 1-13 mm) for TBCW, and 2mm (range 0-7 mm) for TB(5M). CLI were higher for TB volumes delineated using CT(6M) (0.31) CT(5M) (0.32) than for CTCW (0.19) and CT(0M) (0.15). CONCLUSIONS: In women who have undergone WLE of breast cancer with full-thickness closure of the excision cavity and who are proceeding to PBI or breast boost RT, target volume delineation based on 0 or 1 implanted markers is not recommended as large additional margins are required to account for uncertainty over true TB location. Five implanted markers (one deep and four radial) are likely to be adequate assuming the addition of a standard 10-15 mm TB-CTV margin. Low CLI values for all TB volumes reflect the sensitivity of low volumes to small differences in delineation and are unlikely to be clinically significant for TB(5M) and TB(6M) in the context of adequate TB-CTV margins..

PURPOSE: To determine whether voluntary deep-inspiratory breath-hold (v_DIBH) and deep-inspiratory breath-hold with the active breathing coordinator™ (ABC_DIBH) in patients undergoing left breast radiotherapy are comparable in terms of normal-tissue sparing, positional reproducibility and feasibility of delivery. METHODS: Following surgery for early breast cancer, patients underwent planning-CT scans in v_DIBH and ABC_DIBH. Patients were randomised to receive one technique for fractions 1-7 and the second technique for fractions 8-15 (40 Gy/15 fractions total). Daily electronic portal imaging (EPI) was performed and matched to digitally-reconstructed radiographs. Cone-beam CT (CBCT) images were acquired for 6/15 fractions and matched to planning-CT data. Population systematic (Σ) and random errors (σ) were estimated. Heart, left-anterior-descending coronary artery, and lung doses were calculated. Patient comfort, radiographer satisfaction and scanning/treatment times were recorded. Within-patient comparisons between the two techniques used the paired t-test or Wilcoxon signed-rank test. RESULTS: Twenty-three patients were recruited. All completed treatment with both techniques. EPI-derived Σ were ≤ 1.8mm (v_DIBH) and ≤ 2.0mm (ABC_DIBH) and σ ≤ 2.5mm (v_DIBH) and ≤ 2.2mm (ABC_DIBH) (all p non-significant). CBCT-derived Σ were ≤ 3.9 mm (v_DIBH) and ≤ 4.9 mm (ABC_DIBH) and σ ≤ 4.1mm (v_DIBH) and ≤ 3.8mm (ABC_DIBH). There was no significant difference between techniques in terms of normal-tissue doses (all p non-significant). Patients and radiographers preferred v_DIBH (p=0.007, p=0.03, respectively). Scanning/treatment setup times were shorter for v_DIBH (p=0.02, p=0.04, respectively). CONCLUSIONS: v_DIBH and ABC_DIBH are comparable in terms of positional reproducibility and normal tissue sparing. v_DIBH is preferred by patients and radiographers, takes less time to deliver, and is cheaper than ABC_DIBH..

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AIMS: To measure cardiac tissue doses in left-sided breast cancer patients receiving supine tangential field radiotherapy with multileaf collimation (MLC) cardiac shielding of the heart and to assess the effect on target volume coverage. MATERIALS AND METHODS: Sixty-seven consecutive patients who underwent adjuvant radiotherapy to the left breast (n = 48) or chest wall (n = 19) in 2009/2010 were analysed. The heart, left anterior descending coronary artery (LAD), whole breast and partial breast clinical target volumes (WBCTV and PBCTV) were outlined retrospectively (the latter only in patients who had undergone breast-conserving surgery [BCS]). The mean heart and LAD NTDmean and maximum LAD doses (LADmax) were calculated for all patients (NTDmean is a biologically weighted mean dose normalised to 2 Gy fractions using a standard linear quadratic model). Coverage of WBCTV and PBCTV by the 95% isodose was assessed (BCS patients only). RESULTS: The mean heart NTDmean (standard deviation) was 0.8 (0.3) Gy, the mean LAD NTDmean 6.7 (4.3) Gy and the mean LADmax 40.3 (10.1) Gy. Coverage of the WBCTV by 95% isodose was <90% in one in three patients and PBCTV coverage <95% (range 78-94%) in one in 10 BCS patients. CONCLUSION: The use of MLC cardiac shielding reduces doses to cardiac tissues at the expense of target tissue coverage. Formal target volume delineation in combination with an assessment of the likelihood of local relapse is recommended in order to aid decisions regarding field and MLC placement..

PURPOSE: To validate and compare the accuracy of breast tissue segmentation methods applied to computed tomography (CT) scans used for radiation therapy planning and to study the effect of tissue distribution on the segmentation accuracy for the purpose of developing models for use in adaptive breast radiation therapy. METHODS AND MATERIALS: Twenty-four patients receiving postlumpectomy radiation therapy for breast cancer underwent CT imaging in prone and supine positions. The whole-breast clinical target volume was outlined. Clinical target volumes were segmented into fibroglandular and fatty tissue using the following algorithms: physical density thresholding; interactive thresholding; fuzzy c-means with 3 classes (FCM3) and 4 classes (FCM4); and k-means. The segmentation algorithms were evaluated in 2 stages: first, an approach based on the assumption that the breast composition should be the same in both prone and supine position; and second, comparison of segmentation with tissue outlines from 3 experts using the Dice similarity coefficient (DSC). Breast datasets were grouped into nonsparse and sparse fibroglandular tissue distributions according to expert assessment and used to assess the accuracy of the segmentation methods and the agreement between experts. RESULTS: Prone and supine breast composition analysis showed differences between the methods. Validation against expert outlines found significant differences (P<.001) between FCM3 and FCM4. Fuzzy c-means with 3 classes generated segmentation results (mean DSC = 0.70) closest to the experts' outlines. There was good agreement (mean DSC = 0.85) among experts for breast tissue outlining. Segmentation accuracy and expert agreement was significantly higher (P<.005) in the nonsparse group than in the sparse group. CONCLUSIONS: The FCM3 gave the most accurate segmentation of breast tissues on CT data and could therefore be used in adaptive radiation therapy-based on tissue modeling. Breast tissue segmentation methods should be used with caution in patients with sparse fibroglandular tissue distribution..

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PURPOSE: To test a prone position against the international-standard supine position in women undergoing whole-breast-radiotherapy (WBRT) after wide-local-excision (WLE) of early breast cancer (BC) in terms of feasibility, set-up errors, and respiratory motion. METHODS: Following WLE of BC with insertion of tumour-bed clips, patients underwent 4D-CT for WBRT-planning in supine and prone positions (the latter using an in-house-designed platform). Patients were randomised to undergo WBRT fractions 1-7 in one position, switching to the alternate position for fractions 8-15 (40Gy/15-fractions total). Cone-beam CT-images (CBCT) were acquired prior to fractions 1, 4, 7, 8, 11 and 14. CBCT data were matched to planning-CT data using (i) chest-wall and (ii) clips. Systematic and random errors were calculated. Maximal displacement of chest-wall and clips with respiration was measured on 4D-CT. Clinical- to planning-target-volume (CTV-PTV) margins were calculated. Patient-comfort-scores and treatment-times were evaluated. RESULTS: Twenty-five patients were randomized. 192/192 (100%) planned supine fractions and 173/192 (90%) prone fractions were completed. 3D population systematic errors were 1.3-1.9mm (supine) and 3.1-4.3mm (prone) (p=0.02) and random errors 2.6-3.2mm (supine) and 3.8-5.4mm (prone) (p=0.02). Prone positioning reduced chest-wall and clip motion (0.5±0.2mm (prone) versus 2.7±0.5mm (supine) (p<0.001)) with respiration. Calculated CTV-PTV margins were greater for prone (12-16mm) than for supine treatment (10mm). Patient-comfort-scores and treatment times were comparable (p=0.06). CONCLUSIONS: Set-up errors were greater using our prone technique than for our standard supine technique, resulting in the need for larger CTV-PTV margins in the prone position. Further work is required to optimize the prone treatment-platform and technique before it can become a standard treatment option at our institution..

AIM: To assess the role of ipsilateral breast radiotherapy (IBR) in women with occult primary breast cancer presenting with axillary metastases (OPBC). METHODS: Patients with axillary nodal metastases and histological diagnosis of breast cancer without palpable, mammographic or ultrasonographic evidence of a breast primary were identified from a prospectively maintained single institution database. Imaging, surgery, radiotherapy, recurrence and survival data were collected. Patients whose breast cancer primary was detected on MRI (but occult on clinical examination and other imaging) were excluded from the analyses of IBR and outcome, but were included in other exploratory analyses. RESULTS: Fifty-five patients were included between 1975 and 2009. Median follow up was 68 months. Twenty patients had breast magnetic resonance imaging (MRI) in addition to other imaging. A primary breast cancer was detected in 7 of these 20. 48/55 patients had no detectable breast primary. 35/48 patients (73%) were treated with radiotherapy to the conserved breast, and 13/48 (27%) with observation. Patients who had IBR had better 5 year local recurrence free survival (LRFS) (84% versus 34%, p<0.001), and relapse free survival (RFS) (64% versus 34%, p=0.05), but no difference in overall survival (OS) (84% versus 85%, p=0.2). There was no difference in 5 year LRFS (80% versus 90%: p=0.3) between patients who received radiation of 50 Gy in 25 fractions versus ≥60 Gy. CONCLUSION: Patients with OPBC should be managed with IBR and breast conservation, or mastectomy. Our data suggest it is not necessary to irradiate the breast to more than 50 Gy in 25 fractions..

Partial breast irradiation (PBI) is currently under investigation in several phase III trials and, following a recent consensus statement, its use off-study may increase despite ongoing uncertainty regarding optimal target volume definition. We review the clinical, pathological and technical evidence for target volume definition in external beam partial breast irradiation (EB-PBI). The optimal method of tumour bed (TB) delineation requires X-ray CT imaging of implanted excision cavity wall markers. The definition of clinical target volume (CTV) as TB plus concentric 15 mm margins is based on the anatomical distribution of multifocal and multicentric disease around the primary tumour in mastectomy specimens, and the clinical locations of local tumour relapse (LR) after breast conservation surgery. If the majority of LR originate from foci of residual invasive and/or intraduct disease in the vicinity of the TB after complete microscopic resection, CTV margin logically takes account of the position of primary tumour within the surgical resection specimen. The uncertain significance of independent primary tumours as sources of preventable LR, and of wound healing responses in stimulating LR, increases the difficulties in defining optimal CTV. These uncertainties may resolve after long-term follow-up of current PBI trials. By contrast, a commonly used 10mm clinical to planning target volume (PTV) margin has a stronger evidence base, although departmental set-up errors need to be confirmed locally. A CTV-PTV margin >10mm may be required in women with larger breasts and/or large seromas, whilst the role of image-guided radiotherapy with or without TB markers in reducing CTV-PTV margins needs to be explored..

BACKGROUND AND PURPOSE: To compare partial-breast clinical target volumes generated using a standard 15 mm margin (CTV(standard)) with those generated using three-dimensional surgical excision margins (CTV(tailored 30)) in women who have undergone wide local excision (WLE) for breast cancer. MATERIAL AND METHODS: Thirty-five women underwent WLE with placement of clips in the anterior, deep and coronal excision cavity walls. Distances from tumour to each of six margins were measured microscopically. Tumour bed was defined on kV-CT images using clips. CTV(standard) was generated by adding a uniform three-dimensional 15 mm margin, and CTV(tailored 30) was generated by adding 30 mm minus the excision margin in three-dimensions. Concordance between CTV(standard) and CTV(tailored 30) was quantified using conformity (CoI), geographical-miss (GMI) and normal-tissue (NTI) indices. An external-beam partial-breast irradiation (PBI) plan was generated to cover 95% of CTV(standard) with the 95% isodose. Percentage-volume coverage of CTV(tailored 30) by the 95% isodose was measured. RESULTS: Median (range) coronal, superficial and deep excision margins were 15.0 (0.5-76.0)mm, 4.0 (0.0-60.0)mm and 4.0 (0.5-35.0)mm, respectively. Median CoI, GMI and NTI were 0.62, 0.16 and 0.20, respectively. Median coverage of CTV(tailored 30) by the PBI-plan was 97.7% (range 84.9-100.0%). CTV(tailored 30) was inadequately covered by the 95% isodose in 4/29 cases. In three cases, the excision margin in the direction of inadequate coverage was

PURPOSE: To compare non-target tissue (including left-anterior-descending coronary-artery (LAD)) dosimetry of prone versus supine whole (WBI) and partial-breast irradiation (PBI). METHODS AND MATERIALS: Sixty-five post-lumpectomy breast cancer patients underwent CT-imaging supine and prone. On each dataset, the whole-breast clinical-target-volume (WB-CTV), partial-breast CTV (tumour-bed + 15 mm), ipsilateral-lung and chest-wall were outlined. Heart and LAD were outlined in left-sided cases (n=30). Tangential-field WBI and PBI plans were generated for each position. Mean LAD, heart, and ipsilateral-lung doses (x(mean)), maximum LAD (LAD(max)) doses, and the volume of chest-wall receiving 50 Gy (V(50Gy)) were compared. RESULTS: Two-hundred and sixty plans were generated. Prone positioning reduced heart and LAD doses in 19/30 WBI cases (median reduction in LAD(mean)=6.2 Gy) and 7/30 PBI cases (median reduction in LAD(max)=29.3 Gy) (no difference in 4/30 cases). However, prone positioning increased cardiac doses in 8/30 WBI (median increase in LAD(mean)=9.5 Gy) and 19/30 PBI cases (median increase in LAD(max)=22.9 Gy) (no difference in 3/30 cases). WB-CTV>1000cm(3) was associated with improved cardiac dosimetry in the prone position for WBI (p=0.04) and PBI (p=0.04). Prone positioning reduced ipsilateral-lung(mean) in 65/65 WBI and 61/65 PBI cases, and chest-wall V(50Gy) in all WBI cases. PBI reduced normal-tissue doses compared to WBI in all cases, regardless of the treatment position. CONCLUSIONS: In the context of tangential-field WBI and PBI, prone positioning is likely to benefit left-breast-affected women of larger breast volume, but to be detrimental in left-breast-affected women of smaller breast volume. Right-breast-affected women are likely to benefit from prone positioning regardless of breast volume..

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PURPOSE: To compare tumor bed (TB) volumes delineated using magnetic resonance imaging plus computed tomography and clips (MRCT) with those delineated using CT and clips (CT/clips) alone in postlumpectomy breast cancer patients positioned prone and to determine the value of MRCT for planning partial breast irradiation (PBI). METHODS AND MATERIALS: Thirty women with breast cancer each had 6 to 12 titanium clips secured in the excision cavity walls at lumpectomy. Patients underwent CT imaging in the prone position, followed by MRI (T(1)-weighted [standard and fat-suppressed] and T(2)-weighted sequences) in the prone position. TB volumes were delineated separately on CT and on fused MRCT datasets. Clinical target volumes (CTV) (where CTV = TB + 15 mm) and planning target volumes (PTV) (where PTV = CTV + 10 mm) were generated. Conformity indices between CT- and MRCT-defined target volumes were calculated (ratio of the volume of agreement to total delineated volume). Discordance was expressed as a geographical miss index (GMI) (where the GMI = the fraction of total delineated volume not defined by CT) and a normal tissue index (the fraction of total delineated volume designated as normal tissue on MRCT). PBI dose distributions were generated to cover CT-defined CTV (CTV(CT)) with >or=95% of the reference dose. The percentage of MRCT-defined CTV (CTV(MRCT)) receiving >or=95% of the reference dose was measured. RESULTS: Mean conformity indices were 0.54 (TB), 0.84 (CTV), and 0.89 (PTV). For TB volumes, the GMI was 0.37, and the NTI was 0.09. Median percentage volume coverage of CTV(CT) was 97.1% (range, 95.3%-100.0%) and of CTV(MRCT) was 96.5% (range, 89.0%-100.0%). CONCLUSIONS: Addition of MR to CT/clip data generated TB volumes that were discordant with those based on CT/clips alone. However, clinically satisfactory coverage of CTV(MRCT) by CTV(CT)-based tangential PBI fields provides support for CT/clip-based TB delineation remaining the method of choice for PBI/breast boost radiotherapy planned using tangential fields..

Practical guidelines for the use of FDG PET in the management of lymphoma are given, based on the evidence presented in the previous article. A statement and recommendations are given where appropriate. The recommendations are summarized at the end of the paper..

[18F]Fluorodeoxyglucose positron emission tomography (18F-FDG PET) is playing an increasing role in the management of both Hodgkin and non-Hodgkin lymphoma, offering potential advantages in the accuracy of disease assessment at a number of points in the management pathway. This review evaluates the current level of confidence in the use of PET technology in (1) initial staging, (2) the assessment of early response to chemotherapy, (3) the assessment of residual masses at completion of initial treatment, (4) follow-up, and (5) radiotherapy planning..

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Quantitative measures of radiation-induced breast stiffness are required to support clinical studies of novel breast radiotherapy regimens and exploration of personalised therapy, however, variation between shear-wave elastography (SWE) machines may limit the usefulness of shear-wave speed (cs) for this purpose. Mean cs measured in four healthy volunteers’ breasts and a phantom using 2D-SWE machines Acuson S2000 (Siemens Medical Solutions) and Aixplorer (Supersonic Imagine) were compared. Shear-wave speed was measured in the skin region, subcutaneous adipose tissue and parenchyma. cs estimates were on average 2.3% greater when using the Aixplorer compared to S2000 in vitro. In vivo, cs estimates were on average 43.7%, 36.3% and 49.9% significantly greater (p << 0.01) when using the Aixplorer compared to S2000, for skin region, subcutaneous adipose tissue and parenchyma, respectively. In conclusion, despite relatively small differences between machines observed in vitro, large differences in absolute measures of shear wave speed measured were observed in vivo, which may prevent pooling of cross-machine data in clinical studies of the breast..