Frances K. Duane

Estimating the Risks of Breast Cancer Radiotherapy: Evidence From Modern Radiation Doses to the Lungs and Heart and From Previous Randomized Trials

Purpose Radiotherapy reduces the absolute risk of breast cancer mortality by a few percentage points in suitable women but can cause a second cancer or heart disease decades later. We estimated the absolute long-term risks of modern breast cancer radiotherapy. Methods First, a systematic literature review was performed of lung and heart doses in breast cancer regimens published during 2010 to 2015. Second, individual patient data meta-analyses of 40,781 women randomly assigned to breast cancer radiotherapy versus no radiotherapy in 75 trials yielded rate ratios (RRs) for second primary cancers and cause-specific mortality and excess RRs (ERRs) per Gy for incident lung cancer and cardiac mortality. Smoking status was unavailable. Third, the lung or heart ERRs per Gy in the trials and the 2010 to 2015 doses were combined and applied to current smoker and nonsmoker lung cancer and cardiac mortality rates in population-based data. Results Average doses from 647 regimens published during 2010 to 2015 were 5.7 Gy for whole lung and 4.4 Gy for whole heart. The median year of irradiation was 2010 (interquartile range [IQR], 2008 to 2011). Meta-analyses yielded lung cancer incidence ≥ 10 years after radiotherapy RR of 2.10 (95% CI, 1.48 to 2.98; P < .001) on the basis of 134 cancers, indicating 0.11 (95% CI, 0.05 to 0.20) ERR per Gy whole-lung dose. For cardiac mortality, RR was 1.30 (95% CI, 1.15 to 1.46; P < .001) on the basis of 1,253 cardiac deaths. Detailed analyses indicated 0.04 (95% CI, 0.02 to 0.06) ERR per Gy whole-heart dose. Estimated absolute risks from modern radiotherapy were as follows: lung cancer, approximately 4% for long-term continuing smokers and 0.3% for nonsmokers; and cardiac mortality, approximately 1% for smokers and 0.3% for nonsmokers. Conclusion For long-term smokers, the absolute risks of modern radiotherapy may outweigh the benefits, yet for most nonsmokers (and ex-smokers), the benefits of radiotherapy far outweigh the risks. Hence, smoking can determine the net effect of radiotherapy on mortality, but smoking cessation substantially reduces radiotherapy risk.

A cardiac contouring atlas for radiotherapy.

Background and purpose The heart is a complex anatomical organ and contouring the cardiac substructures is challenging. This study presents a reproducible method for contouring left ventricular and coronary arterial segments on radiotherapy CT-planning scans. Material and methods Segments were defined from cardiology models and agreed by two cardiologists. Reference atlas contours were delineated and written guidelines prepared. Six radiation oncologists tested the atlas. Spatial variation was assessed using the DICE similarity coefficient (DSC) and the directed Hausdorff average distance (d→H,avg). The effect of spatial variation on doses was assessed using six different breast cancer regimens. Results The atlas enabled contouring of 15 cardiac segments. Inter-observer contour overlap (mean DSC) was 0.60–0.73 for five left ventricular segments and 0.10–0.53 for ten coronary arterial segments. Inter-observer contour separation (mean d→H,avg) was 1.5–2.2 mm for left ventricular segments and 1.3–5.1 mm for coronary artery segments. This spatial variation resulted in <1 Gy dose variation for most regimens and segments, but 1.2–21.8 Gy variation for segments close to a field edge. Conclusions This cardiac atlas enables reproducible contouring of segments of the left ventricle and main coronary arteries to facilitate future studies relating cardiac radiation doses to clinical outcomes.

Impact of delineation uncertainties on dose to organs at risk in CT-guided intracavitary brachytherapy

PURPOSE This study quantifies the inter- and intraobserver variations in contouring the organs at risk (OARs) in CT-guided brachytherapy (BT) for the treatment of cervical carcinoma. The dosimetric consequences are reported in accordance with the current Gynecological Groupe Européen de Curiethérapie/European Society for Therapeutic Radiology and Oncology guidelines. METHODS AND MATERIALS A CT planning study of 8 consecutive patients undergoing image-guided BT was conducted. The bladder, rectum, and sigmoid were contoured by five blinded observers on two identical anonymized scans of each patient. This provided 80 data sets for analysis. Dosimetric parameters analyzed were D0.1 cc, D1 cc, and D2 cc. The mean volume of each OAR was calculated. These endpoints were compared between and within the observers. The CT image sets from all patients were evaluated qualitatively. RESULTS The interobserver coefficient of variation for reported D2 cc was 13.2% for the bladder, 9% for the rectum, and 19.9% for the sigmoid colon. Unlike the variation seen in bladder and rectal contours, which differed largely in localization of the organ walls on individual slices, sigmoid colon contours demonstrated large differences in anatomic interpretation. CONCLUSIONS Variation in recorded D2 cc to the bladder and rectum is comparable with the previous published results. Inter- and intraphysician variations in reported D2 cc is high for the sigmoid colon, reflecting varying interpretation of sigmoid colon anatomy. Variation in delineation of the OARs may influence treatment optimization and is a potential source of uncertainty in the image-guided BT planning and delivery process.

Late side-effects of breast cancer radiotherapy: Second cancer incidence and non-breast-cancer mortality among 40,000 women in 75 trials

Introduction Breast cancer radiotherapy cures many women, but, as with other therapies, can cause late side-effects. Methods We undertook meta-analyses of individual patient data from the trials of breast cancer radiotherapy, relating various characteristics of the regimens tested to cause-specific mortality rate ratios (RRs) and second cancer incidence RRs. Doses to cardiac structures were calculated for trials with some heart disease death(s), lung doses were calculated for megavoltage trials with some lung cancer(s) in the second decade after radiotherapy, and oesophagus doses were calculated for megavoltage trials with some oesophageal cancer(s). Trial radiotherapy regimens were reconstructed for a woman with typical anatomy using virtual simulation and 3-dimensional CT planning (and, for a few regimens, manual planning). Results Information was available on 40,781 women in 75 evenly randomised comparisons of radiotherapy versus not. Median follow-up was 9.7 years and 20,345 died, 6064 without recurrence. Smoking information for included women was unavailable. Mean normal tissue radiation doses for irradiated women were: heart 6.3 Gy (range Allocation to radiotherapy increased non-breast-cancer mortality (RR=1.15, 95% CI 1.09–1.22, 2p Second cancer incidence was increased (RR=1.23, 1.12–1.36, 2p Conclusions Since these trials, normal tissue doses from breast cancer radiotherapy have at least halved so the excess relative risks will be at least halved. Background disease rates have also changed, so the absolute risks will be different for women today. Modelling the effects of such changes suggests that for women who have smoked throughout adult life and will continue smoking, even modern radiotherapy may cause an absolute lung cancer risk of a few per cent, making this the main late side-effect in smokers. However, for non-smokers (and ex-smokers) with healthy hearts who would, under current guidelines, be offered radiotherapy, the expected reduction in breast cancer mortality greatly outweighs any increase in other mortality. Citation Format: Taylor C, Correa C, Anderson S, Duane F, Ewertz M, Jagsi R, Pierce L, Swain S, Whelan T, Wang Z, Wang Y, Peto R, McGale P. Late side-effects of breast cancer radiotherapy: Second cancer incidence and non-breast-cancer mortality among 40,000 women in 75 trials. [abstract]. In: Proceedings of the Thirty-Eighth Annual CTRC-AACR San Antonio Breast Cancer Symposium: 2015 Dec 8-12; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2016;76(4 Suppl):Abstract nr S5-08.

Exposure of the lungs in breast cancer radiotherapy: A systematic review of lung doses published 2010-2015.

Background and purpose We report a systematic review of lung radiation doses from breast cancer radiotherapy. Methods and materials Studies describing breast cancer radiotherapy regimens published during 2010–2015 and reporting lung dose were included. Doses were compared between different countries, anatomical regions irradiated, techniques and use of breathing adaptation. Results 471 regimens from 32 countries were identified. The average mean ipsilateral lung dose (MLDipsi) was 9.0 Gy. MLDipsi for supine radiotherapy with no breathing adaption was 8.4 Gy for whole breast/chest wall (WB/CW) radiotherapy, 11.2 Gy when the axilla/supraclavicular fossa was irradiated, and 14.0 Gy with the addition of internal mammary chain irradiation; breathing adaptation reduced MLDipsi by 1 Gy, 2 Gy and 3 Gy respectively (p < 0.005). For WB/CW radiotherapy, MLDipsi was lowest for tangents in prone (1.2 Gy) or lateral decubitus (0.8 Gy) positions. The highest MLDipsi was for IMRT in supine position (9.4 Gy). The average mean contralateral lung dose (MLDcont) for WB/CW radiotherapy was higher for IMRT (3.0 Gy) than for tangents (0.8 Gy). Conclusions Lung doses from breast cancer radiotherapy varied substantially worldwide, even between studies describing similar regimens. Lymph node inclusion and IMRT use increased exposure, while breathing adaptation and prone/lateral decubitus positioning reduced it.

Axillary conservation in women with 1-2 sentinel node-positive breast cancer: Further research is needed

The practice of completion axillary dissection after a positive sentinel node biopsy in women with early breast cancer has been declining. The morbidity associated with axillary dissection can be disabling and impair quality of life. Axillary conservation spares patients the common complications of lymphoedema, pain, neuropathy, and restricted shoulder movement. This change in practice followed the publication of the American College of Surgeons Oncology Group (ACOSOG) Z-11 randomised trial. In this study, 891 patients with 1–2 positive sentinel lymph nodes (SLNs) who underwent breast-conserving surgery for a primary tumour ≤5 cm and were clinically node-negative at diagnosis were randomised to axillary dissection or not. Adjuvant whole breast irradiation was mandatory but information on radiation doses and treatment volumes was not available. The majority of patients received adjuvant systemic therapy. In the axillary dissection group, 27% of patients had additional involved lymph nodes. At a median follow-up of nine years, there was no difference in axillary recurrence rates (≤1.1%) between the two groups. No difference in local recurrence rates, disease free survival (DFS) or overall survival was observed. Two other recent studies indicated that axillary dissection did not improve outcomes. The International Breast Cancer Study Group 23-01 trial of 934 patients investigated the role of axillary dissection or not in patients with a primary tumour ≤5 cm who had axillary micrometastases in 1-2 SLNs. In the axillary dissection group 13% had additional involved lymph nodes but there was no difference in local recurrence (2%), regional recurrence (≤1%), disease free survival or overall survival at a median follow-up of five years. In the European Organisation for Research and Treatment of Cancer (EORTC) AMAROS trial, 1425 patients with positive SLNs were randomised to axillary dissection or axillary irradiation. In the axillary dissection group, 33% had additional involved lymph nodes. With a median follow-up of five years, there was no difference in axillary recurrence rates (≤1%), DFS or overall survival between the two groups. The 5-year rate of lymphoedema was 11% in the axillary radiation arm compared to 23% in the axillary dissection arm.

Cardiac Structure Injury After Radiotherapy for Breast Cancer: Cross-Sectional Study With Individual Patient Data

Purpose Incidental cardiac irradiation can cause cardiac injury, but little is known about the effect of radiation on specific cardiac segments. Methods For 456 women who received breast cancer radiotherapy between 1958 and 2001 and then later experienced a major coronary event, information was obtained on the radiotherapy regimen they received and on the location of their cardiac injury. For 414 women, all with documented location of left ventricular (LV) injury, doses to five LV segments were estimated. For 133 women, all with documented location of coronary artery disease with ≥ 70% stenosis, doses to six coronary artery segments were estimated. For each segment, numbers of women with left-sided and right-sided breast cancer were compared. Results Of women with LV injury, 243 had left-sided breast cancer and 171 had right-sided breast cancer (ratio of left v right, 1.42; 95% CI, 1.17 to 1.73), reflecting the higher typical LV radiation doses in left-sided cancer (average dose left-sided, 8.3 Gy; average dose right-sided, 0.6 Gy; left minus right dose difference, 7.7 Gy). For individual LV segments, the ratios of women with left- versus right-sided radiotherapy were as follows: inferior, 0.94 (95% CI, 0.70 to 1.25); lateral, 1.42 (95% CI, 1.04 to 1.95); septal, 2.09 (95% CI, 1.37 to 3.19); anterior, 1.85 (95% CI, 1.39 to 2.46); and apex, 4.64 (95% CI, 2.42 to 8.90); corresponding left-minus-right dose differences for these segments were 2.7, 4.9, 7.2, 10.4, and 21.6 Gy, respectively ( Ptrend < .001). For women with coronary artery disease, the ratios of women with left- versus right-radiotherapy for individual coronary artery segments were as follows: right coronary artery proximal, 0.48 (95% CI, 0.26 to 0.91); right coronary artery mid or distal, 1.69 (95% CI, 0.85 to 3.36); circumflex proximal, 1.46 (95% CI, 0.72 to 2.96); circumflex distal, 1.11 (95% CI, 0.45 to 2.73); left anterior descending proximal, 1.89 (95% CI, 1.07 to 3.34); and left anterior descending mid or distal, 2.33 (95% CI, 1.19 to 4.59); corresponding left-minus-right dose differences for these segements were -5.0, -2.5, 1.6, 3.5, 9.5, and 38.8 Gy ( Ptrend = .002). Conclusion For individual LV and coronary artery segments, higher radiation doses were strongly associated with more frequent injury, suggesting that all segments are sensitive to radiation and that doses to all segments should be minimized.

Cardiovascular disease incidence after internal mammary chain irradiation and anthracycline-based chemotherapy for breast cancer

BackgroundImproved breast cancer (BC) survival and evidence showing beneficial effects of internal mammary chain (IMC) irradiation underscore the importance of studying late cardiovascular effects of BC treatment.MethodsWe assessed cardiovascular disease (CVD) incidence in 14,645 Dutch BC patients aged <62 years, treated during 1970–2009. Analyses included proportional hazards models and general population comparisons.ResultsCVD rate-ratio for left-versus-right breast irradiation without IMC was 1.11 (95% CI 0.93–1.32). Compared to right-sided breast irradiation only, IMC irradiation (interquartile range mean heart doses 9–17 Gy) was associated with increases in CVD rate overall, ischaemic heart disease (IHD), heart failure (HF) and valvular heart disease (hazard ratios (HRs): 1.6–2.4). IHD risk remained increased until at least 20 years after treatment. Anthracycline-based chemotherapy was associated with an increased HF rate (HR = 4.18, 95% CI 3.07–5.69), emerging <5 years and remaining increased at least 10–15 years after treatment. IMC irradiation combined with anthracycline-based chemotherapy was associated with substantially increased HF rate (HR = 9.23 95% CI 6.01–14.18), compared to neither IMC irradiation nor anthracycline-based chemotherapy.ConclusionsWomen treated with anthracycline-based chemotherapy and IMC irradiation (in an older era) with considerable mean heart dose exposure have substantially increased incidence of several CVDs. Screening may be appropriate for some BC patient groups.

PO-0691: Radiation doses to cardiac structures in women treated for breast cancer in Sweden and Denmark between 1958 and 2001

Purpose/Objective: Whilst moderate hypofractionation radiation therapy (HFRT) is routinely used in many European centres data supporting its use in Indians is unavailable. Indian patients were likely to present with more advanced disease and there are questions on biological dissimalirity between Caucasians and Indians. This analyses reports the demographic data, toxicity profile and control outcomes of the breast cancer patients. Materials and Methods: From May 2011 to January 2014, 496 patients with breast cancer underwent HFRT with 3DCRT (4005cGy in 15 fractions) to whole breast or chest wall and/or supraclavicular fossa following curative surgery. The demographic data with respect to age, sex, neoadjuvant chemotherapy, type of surgery(modified radical mastectomy (MRM) vs Breast conservation surgery (BCS), histopathology (grade, tumour size, nodal status, ER/PR/Her2Neu status, margins and LVI), Nottingham Prognostic Index score (NPI) and Cambridge score were analyzed. Locoregional (LRR) and distant failures were analyzed using Kaplan Meier curves, univariate and multivariate analyses was done using the Cox regression model to identify predictors of failure. Results: The mean age at presentation was 52 years (23 – 88 years) and 206 patients (41.6 % ) had breast conservation surgery. Patients who are younger than 40 years had higher rates of breast conservation surgery (p=0.01) irrespective of the tumour size. The histopathological variables and prognostic indexes were not significantly different across various age groups. The hypofractionated radiation therapy was well tolerated with 1.2 % and 7.1% having grade 3 and 2 acute skin toxicity. At 6 months 13.5% had Gr 1 and 1.6% Gr 2 lymphoedema, 5% reported distortion with no reported long term pneumonitis or cardiac complications. The median follow up period was 18.5 months. 90.2 % of the patients were on regular follow up. The crude LRR and distant failure rate was 3.42% (17 patients) and 7.66% (38 patients). In patients who failed loco-regionally had higher NPI score, greater than 70 % had node positive, tumour size > 2 cm, Gr 3 tumours. In univariate Cox regression analysis, patients with positive nodal status (p=0.007), grade 3(p=0.003), MRM (p=0.034) and triple negative status (p=0.027) had significant higher distant failure rates while nodal status (p=0.005) alone stood significant risk factor for LRR. In multivariate analysis, node positivity was remained significant for locoregional recurrence but none of the factors were significant for distant metastases. The actuarial locoregional failure and distant metastases at 2 years were 3.4 % and 11.2% respectively Conclusions: HFRT was well tolerated and loco-regional and distant failure rates were comparable to the published data establishing its safety and effectiveness in Indian population. Node positivity, grade 3 and triple negative tumours are more aggressive and tend to have higher locoregional and distant failure. PO-0691 Radiation doses to cardiac structures in women treated for breast cancer in Sweden and Denmark between 1958 and 2001 F.K. Duane, P. McGale, S.C. Darby, D. Cutter, C. Correa, B. Gigante, M. Jensen, E.L. Lorenzen, D. Brønnum, S. Warren, S. Hackett, K. Rahimi, P. Hall, M. Ewertz, C.W. Taylor University of Oxford, Clinical Trial Service Unit, Oxford, United Kingdom University of Southern Florida, Cancer Center and Research Institute, Tampa, USA Karolinska Insitutet, Unit of Cardiovascular Epidemiology, IMM Rigshospitalet, Danish Breast Cancer Cooperative Group, Copenhagen, Denmark University of Southern Denmark, Institute of Clinical Research, Odense, Denmark Aalborg Hospital, Oncology Department, Aalborg, Denmark University of Oxford, Gray Institute for Radiation Oncology & Biology, Oxford, United Kingdom University of Oxford, The George Centre for Healthcare Innovation, Oxford, United Kingdom Karolinska Institutet, Department of Medical Epidemiology and Biostatistics, Stockholm, Sweden