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The "Assisi Think Tank Meeting" (ATTM) on Breast Cancer, endorsed by the European Society for Radiotherapy & Oncology (ESTRO) and the Italian Association of Radiotherapy and Clinical Oncology (AIRO), and conducted under the auspices of the European Society of Breast Cancer Specialists (EUSOMA), is a bi-annual meeting aiming to identify major clinical challenges in breast cancer radiation therapy (RT) and proposing clinical trials to address them. The topics discussed at the meeting are pre-selected by the steering committee. At the meeting, these topics are discussed in different working groups (WG), after preparation of the meeting by performing a systematic review of existing data and of ongoing trials. Prior to the meeting, each WG designs a survey on the topic to be discussed to reflect current clinical practice and to identify areas requiring further research. Herein, we present the work done by the Assisi WG focusing on lobular carcinoma and the RT perspectives in its treatment, including providing recommendations for locoregional therapy, mainly RT for patients with non-metastatic lobular breast cancer., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 Elsevier B.V. All rights reserved.)

The European Society for Radiotherapy and Oncology (ESTRO) has advocated the establishment of guidelines to optimise precision radiotherapy (RT) in conjunction with contemporary therapeutics for cancer care. Quality assurance in RT (QART) plays a pivotal role in influencing treatment outcomes. Clinical trials incorporating QART protocols have demonstrated improved survival rates with minimal associated toxicity. Nonetheless, in routine clinical practice, there can be variability in the indications for RT, dosage, fractionation, and treatment planning, leading to uncertainty. In pivotal trials reporting outcomes of systemic therapy for breast cancer, there is limited information available regarding RT, and the potential interaction between modern systemic therapy and RT remains largely uncharted. This article is grounded in a consensus recommendation endorsed by ESTRO, formulated by international breast cancer experts. The consensus was reached through a modified Delphi process and was presented at an international meeting convened in Florence, Italy, in June 2023. These recommendations are regarded as both optimal and essential standards, with the latter aiming to define the minimum requirements. A template for a case report form (CRF) has been devised, which can be utilised by all clinical breast cancer trials involving RT. Optimal requirements include adherence to predefined RT planning protocols and centralised QART. Essential requirements aim to reduce variations and deviations from the guidelines in RT, even when RT is not the primary focus of the trial. These recommendations underscore the significance of implementing these practices in both clinical trials and daily clinical routines to generate high-quality data., Competing Interests: Declaration of competing interest IMe declares advisory boards supported by Eli Lilly, Novartis, Pfizer, Pierre Fabre, SeaGen, Daiichi Sankyo, Astra Zeneca. CB declares honoraria supported by declares advisory boards supported by Eli Lilly, Novartis, Pfizer, and Amgen. ML received honoraria and/or participated in advisory board from Roche, Novartis, Lilly, Pfizer, AstraZeneca, Daiichi Sankyo, Gilead, SeaGen, MSD, Exact Sciences, Takeda, Ipsen, Sandoz, Libbs & Knight, a travel grant from Gilead and research support to the Institution from Gilead. EdA disclosed honoraria and/or advisory board from Roche/GNE, Novartis, SeaGen, Zodiac, Libbs, Pierre Fabre, Lilly, AstraZeneca. JC disclosed consulting/advisor for Roche, Celgene, Cellestia, AstraZeneca, SeaGen, Daiichi Sankyo, Erytech, Athenex, Polyphor, Lilly, Merck Sharp & Dohme, GSK, Leuko, Bioasis, Clovis Oncology, Boehringer Ingelheim, Ellipses, Hibercell, BioInvent, Gemoab, Gilead, Menarini, Zymeworks, Reveal Genomics, Expres2ion Biotechnologies. NH disclosed honoraria for lectures and/or consulting from AstraZeneca, Daiichi-Sankyo, Gilead, Lilly, MSD, Novartis, Pierre-Fabre, Pfizer, Roche, Sanofi, Sandoz, SeaGen. HSR disclosed institutional research support by Astellas Pharma Inc., AstraZeneca, Daiichi Sankyo Inc., F. Hoffmann-La Roche AG/Genentech, Inc., Gilead Sciences Inc., GlaxoSmithKline, Lilly, Merck & Co. Inc., Novartis Pharmaceuticals Corporation, OBI Pharma, Pfizer, Pionyr Immunotherapeutics, Sermonix Pharmaceuticals Inc., Taiho Oncology Inc., and Veru Inc. GC reports personal fees for consulting, advisory role and speakers’ bureau from Roche/Genentech, Novartis, Pfizer, Lilly, Foundation Medicine, Samsung and Daiichi Sankyo; honoraria from Ellipses Pharma and fees for travel and accommodations from Roche/Genentech and Pfizer. LV declares participation on advisory board from Daiichi Sankyo and Pfizer. ME declares advisory board supported by Pfizer and Novartis and lecture fees supported by AstraZeneca. GM declares consultancy honoraria from Roche, Novartis, AstraZeneca, Pfizer, Jensen, Lilly, and Sanofi. LDM declares consulting fees from Roche, Novartis, Eli Lilly, MSD, Daiichi Sankyo, SeaGen, Gilead, Eisai, Pierre Fabre, AstraZeneca, Stemline Menarini, Exact Sciences, Agendia, GSK, Pfizer. No other competing interests declared., (Copyright © 2023 The Authors. Published by Elsevier B.V. All rights reserved.)

Background and Purpose: In recent years, the treatment landscape for breast cancer has undergone significant advancements, with the introduction of several new anticancer agents. One such agent is trastuzumab emtansine (T-DM1), an antibody drug conjugate that has shown improved outcomes in both early and advanced breast cancer. However, there is currently a lack of comprehensive evidence regarding the safety profile of combining T-DM1 with radiation therapy (RT). In this study, we aim to provide a summary of the available data on the safety of combining RT with T-DM1 in both early and metastatic breast cancer settings., Materials and Methods: This systematic review and meta-analysis project is part of the consensus recommendations by the European Society for Radiotherapy and Oncology (ESTRO) Guidelines Committee on integrating RT with targeted treatments for breast cancer. A thorough literature search was conducted using the PUBMED/MedLine, Embase, and Cochrane databases to identify original studies focusing on the safety profile of combining T-DM1 with RT., Results: After applying eligibility criteria, nine articles were included in the meta-analysis. Pooled data from these studies revealed a high incidence of grade 3 + radionecrosis (17%), while the rates of grade 3 + radiation-related pneumonitis (<1%) and skin toxicity (1%) were found to be very low., Conclusion: Although there is some concern regarding a slight increase in pneumonitis when combining T-DM1 with postoperative RT, the safety profile of this combination was deemed acceptable for locoregional treatment in non-metastatic breast cancer. However, caution is advised when irradiating intracranial sites concurrently with T-DM1. There is a pressing need for international consensus guidelines regarding the safety considerations of combining T-DM1 and RT for breast cancer., Competing Interests: Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2023 The Author(s). Published by Elsevier B.V. All rights reserved.)

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., (Copyright © 2021 Elsevier B.V. All rights reserved.)

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., (Copyright © 2019 Elsevier B.V. All rights reserved.)

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., (Copyright © 2019 The Authors. Published by Elsevier B.V. All rights reserved.)

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., (Copyright © 2019 The Authors. Published by Elsevier B.V. All rights reserved.)

Background: The use of intensity-modulated radiotherapy (IMRT) in breast cancer reduces clinician-assessed breast tissue toxicity including fibrosis, telangectasia and sub-optimal cosmesis. Patient reported outcome measures (PROMs) are also important as they provide the patient's perspective. This longitudinal study reports on (a) the effect of forward planned field-in-field IMRT (∼simple IMRT) on PROMs compared to standard RT at 5 years after RT, (b) factors affecting PROMs at 5years after RT and (c) the trend of PROMs over 5 years of follow up., Methods: PROMs were assessed at baseline (pre-RT), 6, 24 and 60 months after completion of RT using global health (EORTC QLQ C30) and 4 breast symptom questions (BR23). Also, 4 breast RT-specific questions were included at 6, 24 and 60 months: change in skin appearance, firmness to touch, reduction in breast size and overall change in breast appearance since RT. The benefits of simple IMRT over standard RT at 5 years after RT were assessed using standard t-test for global health and logistic regression analysis for breast symptom questions and breast RT-specific questions. Clinical factors affecting PROMs at 5 years were investigated using a multivariate analysis. A repeated mixed model was applied to explore the trend over time for each of PROMs., Results: (89%) 727/815, 84%, 81% and 61% patients completed questionnaires at baseline, 6, 24 and 60 months respectively. Patients reported worse toxicity for all four BR23 breast symptoms at 6 months, which then improved over time (p<0.0001). They also reported improvement in skin appearance and breast hardness over time (p<0.0001), with no significant change for breast shrinkage (p=0.47) and overall breast appearance (p=0.13). At 5years, PROMs assessments did not demonstrate a benefit for simple IMRT over standard radiotherapy. Large breast volume, young age, baseline surgical cosmesis and post-operative infection were the most important variables to affect PROMs., Conclusions: This study was unable to demonstrate the benefits of IMRT on PROMs at 5years. PROMs are influenced by non-radiotherapy factors and surgical factors should be optimised to improve patients' outcome. Only a small proportion of patients report moderate-severe breast changes post radiotherapy, with most PROMs improving over time. The difference in clinician assessment and PROMs outcome requires further investigation., (Crown Copyright © 2014. Published by Elsevier Ireland Ltd. All rights reserved.)

Background and Purpose: This study was designed to identify common single nucleotide polymorphisms (SNPs) associated with toxicity 2years after radiotherapy., Materials and Methods: A genome wide association study was performed in 1850 patients from the RAPPER study: 1217 received adjuvant breast radiotherapy and 633 had radical prostate radiotherapy. Genotype associations with both overall and individual endpoints of toxicity were tested via univariable and multivariable regression. Replication of potentially associated SNPs was carried out in three independent patient cohorts who had radiotherapy for prostate (516 RADIOGEN and 862 Gene-PARE) or breast (355 LeND) cancer., Results: Quantile-quantile plots show more associations at the P<5×10(-7) level than expected by chance (164 vs. 9 for the prostate cases and 29 vs. 4 for breast cases), providing evidence that common genetic variants are associated with risk of toxicity. Strongest associations were for individual endpoints rather than an overall measure of toxicity in all patients. However, in general, significant associations were not validated at a nominal 0.05 level in the replication cohorts., Conclusions: This largest GWAS to date provides evidence of true association between common genetic variants and toxicity. Associations with toxicity appeared to be tumour site-specific. Future GWAS require higher statistical power, in particular in the validation stage, to test clinically relevant effect sizes of SNP associations with individual endpoints, but the required sample sizes are achievable., (Copyright © 2014. Published by Elsevier Ireland Ltd.)

Background and Purpose: Post mastectomy radiotherapy (PMRT) reduces loco-regional recurrence (LRR) and has been associated with survival benefit. It is recommended for patients with T3/T4 tumours and/or ⩾ 4 positive lymph nodes (LN). The role of PMRT in 1-3 positive LN and LN negative patients is contentious. The C-PMRT index has been designed for selecting PMRT patients, using independent prognostic factors for LRR. This study reports a 10 year experience using this index., Materials and Methods: The C-PMRT index was constructed using the following prognostic factors (a) number of positive LN/lymphovascular invasion, (b) tumour size (c) margin status and (d) tumour grade. Patients were categorised as high (H) risk, intermediate (I) risk and low (L) risk. PMRT was recommended for H and I risk patients. The LRR, distant metastasis and overall survival (OS) rates were measured from the day of mastectomy., Results: From 1999 to 2009, 898 invasive breast cancers in 883 patients were treated by mastectomy (H: 323, I: 231 and L: 344). At a median follow up of 5.2 years, 4.7% (42/898) developed LRR. The 5-year actuarial LRR rates were 6%, 2% and 2% for the H, I and L risk groups, respectively. 1.6% (14/898) developed isolated LRR (H risk n = 4, I risk group n = 0 and L risk n = 10). The 5-year actuarial overall survival rates were 67%, 77% and 90% for H, I and L risk groups, respectively., Conclusion: Based on published literature, one would have expected a higher LRR rate in the I risk group without adjuvant RT. We hypothesise that the I risk group LRR rates have been reduced to that of the L risk group by the addition of RT. Apart from LN status and tumour size, other prognostic factors should also be considered in selecting patients for PMRT. This pragmatic tool requires further validation., (Crown Copyright © 2014. Published by Elsevier Ireland Ltd. All rights reserved.)

Introduction: The dose-volume effect of radiation therapy on breast tissue is poorly understood. We estimate NTCP parameters for breast fibrosis after external beam radiotherapy., Materials and Methods: We pooled individual patient data of 5856 patients from 2 trials including whole breast irradiation followed with or without a boost. A two-compartment dose volume histogram model was used with boost volume as the first compartment and the remaining breast volume as second compartment. Results from START-pilot trial (n=1410) were used to test the predicted models., Results: 26.8% patients in the Cambridge trial (5 years) and 20.7% patients in the EORTC trial (10 years) developed moderate-severe breast fibrosis. The best fit NTCP parameters were BEUD3(50)=136.4 Gy, γ50=0.9 and n=0.011 for the Niemierko model and BEUD3(50)=132 Gy, m=0.35 and n=0.012 for the Lyman Kutcher Burman model. The observed rates of fibrosis in the START-pilot trial agreed well with the predicted rates., Conclusions: This large multi-centre pooled study suggests that the effect of volume parameter is small and the maximum RT dose is the most important parameter to influence breast fibrosis. A small value of volume parameter 'n' does not fit with the hypothesis that breast tissue is a parallel organ. However, this may reflect limitations in our current scoring system of fibrosis., (Copyright © 2013 Elsevier Ireland Ltd. All rights reserved.)

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., (Copyright © 2013 Elsevier Ireland Ltd. All rights reserved.)

Background and Purpose: Reported associations between risk of radiation-induced normal tissue injury and single nucleotide polymorphisms (SNPs) in TGFB1, encoding the pro-fibrotic cytokine transforming growth factor-beta 1 (TGF-β1), remain controversial. To overcome publication bias, the international Radiogenomics Consortium collected and analysed individual patient level data from both published and unpublished studies., Materials and Methods: TGFB1 SNP rs1800469 c.-1347T>C (previously known as C-509T) genotype, treatment-related data, and clinically-assessed fibrosis (measured at least 2years after therapy) were available in 2782 participants from 11 cohorts. All received adjuvant breast radiotherapy. Associations between late fibrosis or overall toxicity, reported by STAT (Standardised Total Average Toxicity) score, and rs1800469 genotype were assessed., Results: No statistically significant associations between either fibrosis or overall toxicity and rs1800469 genotype were observed with univariate or multivariate regression analysis. The multivariate odds ratio (OR), obtained from meta-analysis, for an increase in late fibrosis grade with each additional rare allele of rs1800469 was 0.98 (95% Confidence Interval (CI) 0.85-1.11). This CI is sufficiently narrow to rule out any clinically relevant effect on toxicity risk in carriers vs. non-carriers with a high probability., Conclusion: This meta-analysis has not confirmed previous reports of association between fibrosis or overall toxicity and rs1800469 genotype in breast cancer patients. It has demonstrated successful collaboration within the Radiogenomics Consortium., (Copyright © 2012 Elsevier Ireland Ltd. All rights reserved.)

Purpose: This study investigates (i) the effect of verification protocols on treatment accuracy and PTV margins for partial breast and boost breast radiotherapy with short fractionation schema (15 fractions), (ii) the effect of deformation of the excision cavity (EC) on PTV margin size, (iii) the imaging dose required to achieve specific PTV margins., Methods and Materials: Verification images using implanted EC markers were studied in 36 patients. Target motion was estimated for a 15 fraction partial breast regimen using imaging protocols based on on-line and off-line motion correction strategies (No Action Level (NAL) and the extended NAL (eNAL) protocols). Target motion was used to estimate a PTV margin for each protocol. To evaluate treatment errors due to deformation of the excision cavity, individual marker positions were obtained from 11 patients. The mean clip displacement and daily variation in clip position during radiotherapy were determined and the contribution of these errors to PTV margin calculated. Published imaging dose data were used to estimate total dose for each protocol. Finally the number of images required to obtain a specific PTV margin was evaluated and hence, the relationship between PTV margins and imaging dose was investigated., Results: The PTV margin required to account for excision cavity motion, varied between 10.2 and 2.4mm depending on the correction strategy used. Average clip movement was 0.8mm and average variation in clip position during treatment was 0.4mm. The contribution to PTV margin from deformation was estimated to be small, less than 0.2mm for both off-line and on-line correction protocols., Conclusion: A boost or partial breast PTV margin of ∼10 mm, is possible with zero imaging dose and workload, however, patients receiving boost radiotherapy may benefit from a margin reduction of ∼4 mm with imaging doses from 0.4cGy to 25cGy using an eNAL protocol. PTV margin contributions from deformation errors are likely to be small in comparison to other sources of error, i.e., set up or delineation., (Copyright © 2012 Elsevier Ireland Ltd. All rights reserved.)

Background and Purpose: We describe a feasibility study testing the use of gold seeds for the identification of post-operative tumour bed after breast conservation surgery (BCS)., Materials and Methods: Fifty-three patients undergoing BCS for invasive cancer were recruited. Successful use was defined as all six seeds correctly positioned around the tumour bed during BCS, unique identification of all implanted seeds on CT planning scan and ≥ 3 seeds uniquely identified at verification to give couch displacement co-ordinates in 10/15 fractions. Planning target volume (PTV) margin size for four correction strategies were calculated from these data. Variability in tumour bed contouring was investigated with five radiation oncologists outlining five CT datasets., Results: Success in inserting gold seeds, identifying them at CT planning and using them for on-treatment verification was recorded in 45/51 (88%), 37/38 (97%) and 42/43 (98%) of patients, respectively. The clinicians unfamiliar with CT breast planning consistently contoured larger volumes than those already trained. Margin size ranged from 10.1 to 1.4mm depending on correction strategy., Conclusion: It is feasible to implant tumour bed gold seeds during BCS. Whilst taking longer to insert than surgical clips, they have the advantage of visibility for outlining and verification regardless of the ionising radiation beam quality. Appropriate correction strategies enable margins of the order of 5mm as required by the IMPORT trials however, tackling clinician variability in contouring is important., (Copyright © 2011 Elsevier Ireland Ltd. All rights reserved.)

Background and Purpose: Several small studies have reported associations between TGFB1 single nucleotide polymorphisms (SNPs), considered to increase secretion of TGF-β1, and greater than 3-fold increases in incidence of fibrosis - an indicator of late toxicity after radiotherapy in breast cancer patients., Materials and Methods: Two SNPs in TGFB1, C-509T (rs1800469) and L10P (rs1800470), were genotyped in 778 breast cancer patients who had received radiotherapy to the breast. Late radiotherapy toxicity was assessed two years after radiotherapy using a validated photographic technique, clinical assessment and patient questionnaires., Results: On photographic assessment, 210 (27%) patients showed some degree of breast shrinkage, whilst 45 (6%) patients showed marked breast shrinkage. There was no significant association of genotype at either of the TGFB1 SNPs with any measure of late radiation toxicity., Conclusion: This adequately powered trial failed to confirm previously reported increases in fibrosis with TGFB1 genotype - any increase greater than 1.36 can be excluded with 95% confidence. Similar frequent failures to replicate associations with candidate genes have been resolved using genome-wide association scans: this methodology detects common, low risk alleles but requires even larger patient numbers for adequate statistical power., (Copyright © 2010 Elsevier Ireland Ltd. All rights reserved.)

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., ((c) 2009 Elsevier Ireland Ltd. All rights reserved.)

Background and Purpose: This large trial was designed to investigate whether correction of dose inhomogeneities using intensity-modulated radiotherapy (IMRT) reduces late toxicity and improves quality of life in patients with early breast cancer. This paper reports baseline characteristics of trial participants and dosimetry results., Materials and Methods: Standard tangential plans of 1145 trials were analysed. Patients with inhomogeneous plans, defined by ICRU recommendations, were randomised to forward-planned IMRT or standard radiotherapy., Results: Twenty-nine percentage of patients had adequate dosimetry with standard 2D radiotherapy. In the randomised patients, the decreases in mean volumes receiving greater than 107% (Vol>107) and less than 95% (Vol<95) of the prescribed dose in the IMRT compared with the control group were 34.0 cm(3) (95% CI 26.4-41.6; P<0.0001) and 48.1 cm(3) (95% CI 34.4-61.9; P<0.0001), respectively. In this study, 90% of patients who had a breast separation greater > or = 21 cm had Vol>107>2 cm(3) on standard radiotherapy plans., Conclusion: This large trial, in which patients with all breast sizes were eligible, confirmed that breast dosimetry can be significantly improved with a simple method of forward-planned IMRT and has little impact on radiotherapy resources. It is shown that patients with larger breasts are more likely to have dose inhomogeneities and breast separation gives some indication of this likelihood. Photographic assessment of patients at 2 years after radiotherapy, as the next part of this randomised controlled trial, will show whether these results for IMRT translate into improved cosmetic outcome in patients with early breast cancer. This would provide impetus for the widespread adoption of 3D planning and IMRT.

Background and Purpose: Complex radiation techniques, such as conformal radiotherapy for partial breast irradiation, require accurate localisation of the tumour bed. This study investigated high definition 3D ultrasound for breast tumour bed localisation. Study aims were: firstly, to determine how easily a tumour cavity could be visualised with 3D ultrasound; secondly, to determine the accuracy of computed tomography (CT) and 3D ultrasound co-registration; thirdly, to compare 3D ultrasound with other methods of localisation., Materials and Methods: 3D ultrasound examinations were carried out in 40 women attending for breast radiotherapy. 3D position data were co-registered with the radiotherapy planning CT. 2D ultrasound and CT, surgical clips and CT, and CT alone were also used to localise the tumour bed in 32/40, 14/40 and 5/40 patients, respectively. Tumour bed volume and centre of gravity measurements for all methods of localisation were compared., Results: Mean surgery to imaging interval was 44 days (range 23-86 days). The post-operative cavity was seen in all cases using the 3D ultrasound, and was graded as highly visible, visible and subtle in 21/40 (53%), 12/40 (30%) and 7/40 (17%) cases, respectively. There was a statistically significant improvement in the ability of 3D ultrasound to localise the tumour bed compared with 2D ultrasound. CT-ultrasound registration was achieved in all cases. Two-dimensional and 3D ultrasound showed smaller tumour bed volumes than clips., Conclusions: Three-dimensional ultrasound localisation of the tumour bed appears superior to 2D ultrasound. It can also be co-registered with a planning CT, thus allowing additional information on the size and location of the tumour bed to be integrated into complex radiotherapy planning.

Background and Purpose: To assess inter-clinician variability amongst specialist paediatric radiation oncologists in delineating clinical target volumes for treating medulloblastoma as a quality assurance exercise prior to the introduction of the SIOP PNET 4 trial protocol of conformal radiotherapy to the posterior fossa and tumour bed., Patients and Methods: Participants from 17 UK centres attended an educational meeting and then completed a clinical planning exercise to outline: (1) the whole posterior fossa and (2) the tumour bed. Quantitative analysis of the volumes, lengths, spatial positioning and axial planes for each individual was carried out and variation between individuals analysed., Results: Outlining of the posterior fossa was reasonably consistent, although most variation was seen in defining the superior border of the tentorium. A major difference was the decision whether or not to include the post-surgical meningocoele in the clinical target volume (CTV). The CTV for the tumour bed was under treated by all participants due to lack of inclusion of pre-operative tumour extent., Conclusions: This exercise demonstrated several ambiguities in the draft protocol and highlighted particular areas of inter-clinician variation. Consequently the protocol was revised and improved to take account of these findings. We recommend that planning exercises, in conjunction with education and training, should be implemented before the start of any new radiotherapy trial. In the future, the use of image transfer will allow prospective peer review of target volumes before treatment commences. These measures are essential to ensure that alterations in clinical practice are achieved in a uniform way.