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Purpose To describe cardiac exposure from breast cancer radiotherapy regimens used during 1970-2009 for the development of dose-response relationships and to consider the associated radiation-risks using existing dose-response relationships. Material and Methods Radiotherapy charts for 771 women in the Netherlands selected for case control studies of heart disease after breast cancer radiotherapy were used to reconstruct 44 regimens on a typical CT-dataset. Doses were estimated for the whole heart (WH), left ventricle (LV) and cardiac valves. Results For breast/chest wall radiotherapy average WH doses decreased during 1970-2009. For internal mammary chain (IMC) radiotherapy WH doses were highest during the 1980s and 1990s when direct anterior fields were used and reduced in the 2000s when oblique fields were introduced. Average doses varied substantially for IMC regimens (WH 2-33 Gy, LV 30 Gy from most regimens. Conclusions Radiation-risks of IHD from breast/chest wall regimens likely reduced during 1970-2009. Direct anterior IMC regimens likely increased the risks of IHD and VHD over this time period but the use of oblique IMC fields from 2003 may have lowered these risks. These data provide a unique opportunity to develop dose-response relationships.

Background: Adjuvant proton beam therapy (PBT) is increasingly available to patients with breast cancer. It achieves better planned dose distributions than standard photon radiotherapy and therefore may reduce the risks. However, clinical evidence is lacking. Methods: A systematic review of clinical outcomes from studies of adjuvant PBT for early breast cancer published 2000-2022 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 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 2-59 months. There were no published randomized trials comparing PBT with photon radiotherapy. Scattering PBT was delivered in seven studies (258 patients) starting 2003-2015 and scanning PBT in 22 studies (1041 patients) starting 2000-2019. Two studies (123 patients) starting 2011 used both PBT types. For one 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% CI 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 radiotherapy.

BackgroundSeveral studies report increases in the incidences of primary central nervous system (CNS) tumors. The reasons for this are unclear.MethodsData on all 188 340 individuals diagnosed with a primary CNS tumor in England (1993–2017) were obtained from the National Cancer Registration and Analysis Service. Data on all computerized tomography (CT) head and magnetic resonance imaging (MRI) brain scans in England (2013–2017) were obtained from the National Health Service Digital. Age-sex-standardized annual incidence rates per 100 000 population (ASR) were calculated by calendar year, tumor behavior, tumor location, and method of diagnosis. Temporal trends were quantified using average annual percent change (AAPC).ResultsThe ASR for all CNS tumors increased from 13.0 in 1993 to 18.6 in 2017 (AAPC: +1.5%, 95% CI: 1.3, 1.7). The ASR for malignant tumors (52% overall) remained stable (AAPC: +0.5%, 95% CI: −0.2, 1.3), while benign tumors (37% overall) increased (AAPC: +2.6%, 95% CI: 1.2, 4.0). Among the 66% of benign tumors that were microscopically confirmed, the ASR increased modestly (AAPC: +1.3%, 95% CI: 0.5, 2.1). However, among the 25% of benign tumors that were radiographically confirmed, the ASR increased substantially (AAPC: 10.2%, 95% CI: 7.9, 12.5), principally driven by large increases in those who are aged 65+ years. The rate of CT head scans in Accident & Emergency (A&E) increased during 2013–2017, with especially large increases in 65–84 and 85+-year-olds (AAPCs: +18.4% and +22.5%).ConclusionsIncreases in CNS tumor incidence in England are largely attributable to the greater detection of benign tumors. This could be the result of the increasing use of neuroimaging, particularly CT head scans in A&E in people who are aged 65+ years.

Background Adjuvant and neoadjuvant breast cancer treatments can reduce breast cancer mortality but may increase mortality from other causes. Information regarding treatment benefits and risks is scattered widely through the literature. To inform clinical practice we collated and reviewed the highest quality evidence. Methods Guidelines were searched to identify adjuvant or neoadjuvant treatment options recommended in early invasive breast cancer. For each option, systematic literature searches identified the highest-ranking evidence. For radiotherapy risks, searches for dose-response relationships and modern organ doses were also undertaken. Results Treatment options recommended in USA and elsewhere included chemotherapy (anthracycline, taxane, platinum, capecitabine), anti-human epidermal growth factor 2 therapy (trastuzumab, pertuzumab, trastuzumab emtansine, neratinib), endocrine therapy (tamoxifen, aromatase inhibitor, ovarian ablation/suppression with varying durations) and bisphosphonates. Radiotherapy options were after breast conserving surgery (whole breast, partial breast, tumour bed boost, regional nodes) and after mastectomy (chest wall, regional nodes). Treatment options were supported by randomised evidence, including >10,000 women for eight treatment comparisons, 1,000-10,000 for fifteen and

Background and Purpose: Breast cancer radiotherapy can increase the risk of subsequent primary oesophageal cancer, with risk increasing according to oesophagus radiation dose. We describe oesophagus exposure from modern breast cancer regimens and discuss the risks of oesophageal cancer for women irradiated recently. Materials and Methods: A systematic review was undertaken of oesophagus doses from breast cancer radiotherapy regimens published during 2010-2020. Mean and maximum oesophagus doses were described for different target regions irradiated and different radiotherapy techniques. Results: In 112 published regimens from 18 countries, oesophagus doses varied with target region. For partial breast irradiation, average mean oesophagus dose was 0.2 Gy (range 0.1-0.4) in four regimens; maximum dose was not reported. For breast or chest wall radiotherapy, average oesophagus doses were mean 1.8 Gy (range 0.1-10.4) in 24 regimens and maximum 6.7 Gy (range 0.4-14.3) in seven regimens. For radiotherapy including a nodal region, average oesophagus doses were higher: mean 11.4 Gy (range 1.1-29.3) in 61 regimens and maximum 34.4 Gy (range 3.4-51.3) in 55 regimens. Average mean oesophagus doses were >10 Gy for intensity modulated nodal radiotherapy, but lower for other node techniques. Conclusions: Mean oesophagus doses from partial breast and breast/chest wall regimens were usually less than 2 Gy, hence radiation-risks will be very small. However, for radiotherapy including lymph nodes, average mean oesophagus dose of 11.4 Gy may nearly double oesophageal cancer risk. Consideration of oesophageal exposure during nodal radiotherapy planning may reduce the risks of radiation-related oesophageal cancer for women irradiated today.

Background: We aimed to develop dose–response relationships for heart failure (HF) following radiation and anthracyclines in breast cancer treatment, and to assess HF associations with trastuzumab and endocrine therapies. Methods and Results: A case–control study was performed within a cohort of breast cancer survivors treated during 1980–2009. Cases (n = 102) had HF as first cardiovascular diagnosis and were matched 1:3 on age and date of diagnosis. Individual cardiac radiation doses were estimated, and anthracycline doses and use of trastuzumab and endocrine therapy were abstracted from oncology notes. For HF cases who received radiotherapy, the estimated median mean heart dose (MHD) was 6.8 Gy [interquartile range (IQR) 0.9–13.7]. MHD was not associated with HF risk overall [excess rate ratio (ERR) = 1%/Gy, 95% confidence interval (CI) −2 to 10]. In patients treated with anthracyclines, exposure of ≥20% of the heart to ≥20 Gy was associated with a rate ratio of 5.7 (95% CI 1.7–21.7) compared to Conclusions: In absence of anthracyclines, breast cancer radiotherapy was not associated with increased HF risk. Strongly elevated HF risks were observed after treatment with anthracyclines and also after treatment with trastuzumab. The benefits of these systemic treatments usually exceed the risks of HF, but our results emphasize the need to support ongoing efforts to evaluate preventative strategies.

Highlights • Prescribing was as expected from clinical practice. • 90% received ET prescriptions during the second year after diagnosis. • Prescribing dropped more than five years after diagnosis. • The majority of younger women (under 55) received tamoxifen. • The majority of older women (55+) received AIs., Introduction National cancer registration data were linked to the Primary Care Prescription Database (PCPD) in England. The level of endocrine therapy (ET) prescribed in women after a diagnosis of breast cancer was studied. Materials and methods Cancer registrations for women diagnosed with breast cancer during 1995–2015, who survived to 31st March 2015, were linked to ET prescriptions issued during April–July 2015. Results Among 369 277 survivors of breast cancer diagnosed during 1995–2015, 37% were prescribed ET during April–July 2015. Among women whose breast cancer diagnosis was after 31st July 2010, 81% of those recorded with oestrogen receptor positive (ER+ve) disease were prescribed ET compared with only 6% of those with ER-ve disease. Younger women usually received tamoxifen and older women usually received aromatase inhibitors. Discussion The pattern of ET use observed in these data corresponds to that expected. This provides confidence in the potential of the PCPD for epidemiological research.

BACKGROUND AND PURPOSE:Radiation-related heart disease (RRHD) can occur many decades after thoracic radiotherapy for Hodgkin lymphoma (HL) or childhood cancer (CC). To quantify the likely risk of RRHD for patients treated today, dose-response relationships derived from patients treated in previous decades are used. Publications presenting these dose-response relationships usually include estimates of uncertainties in the risks but ignore the effect of uncertainties in the reconstructed cardiac doses. MATERIALS/METHODS:We assessed the systematic and random uncertainties in the reconstructed doses for published dose-response relationships for RRHD risk in survivors of HL or CC. Using the same reconstruction methods as were used in the original publications, we reconstructed mean heart doses and, wherever possible, mean left-ventricular doses for an independent case-series of test patients. These patients had known, CT-based, cardiac doses which were compared with the reconstructed doses to estimate the magnitude of the uncertainties and their effect on the dose-response relationships. RESULTS:For all five reconstruction methods the relationship between reconstructed and CT-based doses was linear. For all but the simplest reconstruction method, the dose uncertainties were moderate, the effect of the systematic uncertainty on the dose-response relationships was less than 10%, and the effects of random uncertainty were small except at the highest doses. CONCLUSIONS:These results increase confidence in the published dose-response relationships for the risk of RRHD in HL and CC survivors. This may encourage doctors to use these dose-response relationships when estimating individualised risks for patients-an important aspect of personalising radiotherapy treatments today.

Background Improved 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. Methods We assessed cardiovascular disease (CVD) incidence in 14,645 Dutch BC patients aged Results CVD 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 Conclusions Women 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.

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.

Purpose The future of non-operative management of DCIS relies on distinguishing lesions requiring treatment from those needing only active surveillance. More accurate preoperative staging and grading of DCIS would be helpful. We identified determinants of upstaging preoperative breast biopsies showing ductal carcinoma in situ (DCIS) to invasive breast cancer (IBC), or of upgrading them to higher-grade DCIS, following examination of the surgically excised specimen. Methods We studied all women with DCIS at preoperative biopsy in a large specialist cancer centre during 2000–2014. Information from clinical records, mammography, and pathology specimens from both preoperative biopsy and excised specimen were abstracted. Women suspected of having IBC during biopsy were excluded. Results Among 606 preoperative biopsies showing DCIS, 15.0% (95% confidence interval 12.3–18.1) were upstaged to IBC and a further 14.6% (11.3–18.4) upgraded to higher-grade DCIS. The risk of upstaging increased with presence of a palpable lump (21.1% vs 13.0%, pdifference = 0.04), while the risk of upgrading increased with presence of necrosis on biopsy (33.0% vs 9.5%, pdifference

Breast cancer radiation therapy cures many women, but where the heart is exposed, it can cause heart disease. We report a systematic review of heart doses from breast cancer radiation therapy that were published during 2003 to 2013.Eligible studies were those reporting whole-heart dose (ie, dose averaged over the whole heart). Analyses considered the arithmetic mean of the whole-heart doses for the CT plans for each regimen in each study. We termed this "mean heart dose."In left-sided breast cancer, mean heart dose averaged over all 398 regimens reported in 149 studies from 28 countries was 5.4 Gy (range,0.1-28.6 Gy). In regimens that did not include the internal mammary chain (IMC), average mean heart dose was 4.2 Gy and varied with the target tissues irradiated. The lowest average mean heart doses were from tangential radiation therapy with either breathing control (1.3 Gy; range, 0.4-2.5 Gy) or treatment in the lateral decubitus position (1.2 Gy; range, 0.8-1.7 Gy), or from proton radiation therapy (0.5 Gy; range, 0.1-0.8 Gy). For intensity modulated radiation therapy mean heart dose was 5.6 Gy (range,0.1-23.0 Gy). Where the IMC was irradiated, average mean heart dose was around 8 Gy and varied little according to which other targets were irradiated. Proton radiation therapy delivered the lowest average mean heart dose (2.6 Gy, range, 1.0-6.0 Gy), and tangential radiation therapy with a separate IMC field the highest (9.2 Gy, range, 1.9-21.0 Gy). In right-sided breast cancer, the average mean heart dose was 3.3 Gy based on 45 regimens in 23 studies.Recent estimates of typical heart doses from left breast cancer radiation therapy vary widely between studies, even for apparently similar regimens. Maneuvers to reduce heart dose in left tangential radiation therapy were successful. Proton radiation therapy delivered the lowest doses. Inclusion of the IMC doubled typical heart dose.

The increasing complexity and cost of conducting randomized trials1 have stimulated interest in using observational data sets to evaluate cancer treatments.

Purpose To quantify the radiation doses received by the heart and coronary arteries from contemporary tangential breast or chest wall radiotherapy. Methods and Materials Fifty consecutive patients with left-sided breast cancer and 5 consecutive patients with right-sided breast cancer treated at a large United Kingdom radiotherapy center during the year 2006 were selected. All patients were irradiated with 6- or 8-MV tangential beams to the breast or chest wall. For each dose plan, dose–volume histograms for the heart and left anterior descending (LAD) coronary artery were calculated. For 5 of the left-sided and all 5 right-sided patients, dose–volume histograms for the right and circumflex coronary arteries were also calculated. Detailed spatial assessment of dose to the LAD coronary artery was performed for 3 left-sided patients. Results For the 50 patients given left-sided irradiation, the average mean (SD) dose was 2.3 (0.7) Gy to the heart and 7.6 (4.5) Gy to the LAD coronary artery, with the distal LAD receiving the highest doses. The right and circumflex coronary arteries received approximately 2 Gy mean dose. Part of the heart received >20 Gy in 22 left-sided patients (44%). For the 5 patients given right-sided irradiation, average mean doses to all cardiac structures were in the range 1.2 to 2 Gy. Conclusions Heart dose from left-tangential radiotherapy has decreased considerably over the past 40 years, but part of the heart still receives >20 Gy for approximately half of left-sided patients. Cardiac dose for right-sided patients was generally from scattered irradiation alone.

Studies of underground miners occupationally exposed to radon have consistently demonstrated an increased risk of lung cancer in both smokers and non-smokers. Radon exposure also occurs elsewhere, especially in houses, and estimates based on the findings for miners suggest that residential radon is responsible for about one in 20 lung cancers in the UK, most being caused in combination with smoking. These calculations depend, however, on several assumptions and more direct evidence on the magnitude of the risk is needed. To obtain such evidence, a case-control study was carried out in south-west England in which 982 subjects with lung cancer and 3185 control subjects were interviewed. In addition, radon concentrations were measured at the addresses at which subjects had lived during the 30-year period ending 5 years before the interview. Lung cancer risk was examined in relation to residential radon concentration after taking into account the length of time that subjects had lived at each address and adjusting for age, sex, smoking status, county of residence and social class. The relative risk of lung cancer increased by 0.08 (95% CI -0.03, 0.20) per 100 Bq m(-3) increase in the observed time-weighted residential radon concentration. When the analysis was restricted to the 484 subjects with lung cancer and the 1637 control subjects with radon measurements available for the entire 30-year period of interest, the corresponding increase was somewhat higher at 0.14 per 100 Bq m(-3) (95% CI 0.01, 0.29), although the difference between this group and the remaining subjects was not statistically significant. When the analysis was repeated taking into account uncertainties in the assessment of radon exposure, the estimated increases in relative risk per 100 Bq m(-3) were larger, at 0.12 (95% CI -0.05, 0.33) when all subjects were included and 0.24 (95% CI -0.01, 0.56) when limited to subjects with radon measurements available for all 30 years. These results are consistent with those from studies of residential radon carried out in other countries in which data on individual subjects have been collected. The combined evidence suggests that the risk of lung cancer associated with residential radon exposure is about the size that has been postulated on the basis of the studies of miners exposed to radon.

We have examined the relationship between diet and lung cancer in a case–control study of 982 cases of lung cancer and 1486 population controls in south-west England in which subjects were interviewed personally about their smoking habits and their consumption of foods and supplements rich in retinol or carotene. Analyses were performed for 15 dietary variables, including intake of pre-formed retinol and carotene. There were significant associations (P< 0.01) with lung cancer risk for 13 of the variables, eight of which remained after adjustment for smoking. When the 15 variables were considered simultaneously, independent significant associations remained for 5: pre-formed retinol (increased risk), and fish liver oil, vitamin pills, carrots and tomato sauce (decreased risk). It is unlikely that all five associations represent biological effects, or that they can all be explained by residual confounding by smoking, or by biases. We conclude that there is at least one as yet unidentified factor that is causally related to lung cancer risk and of considerable importance in terms of attributable risk in this population. © 2001 Cancer Research Campaign http://www.bjcancer.com

BACKGROUND: Moderate differences in efficacy between adjuvant chemotherapy regimens for breast cancer are plausible, and could affect treatment choices. We sought any such differences. METHODS: We undertook individual-patient-data meta-analyses of the randomised trials comparing: any taxane-plus-anthracycline-based regimen versus the same, or more, non-taxane chemotherapy (n=44,000); one anthracycline-based regimen versus another (n=7000) or versus cyclophosphamide, methotrexate, and fluorouracil (CMF; n=18,000); and polychemotherapy versus no chemotherapy (n=32,000). The scheduled dosages of these three drugs and of the anthracyclines doxorubicin (A) and epirubicin (E) were used to define standard CMF, standard 4AC, and CAF and CEF. Log-rank breast cancer mortality rate ratios (RRs) are reported. FINDINGS: In trials adding four separate cycles of a taxane to a fixed anthracycline-based control regimen, extending treatment duration, breast cancer mortality was reduced (RR 0·86, SE 0·04, two-sided significance [2p]=0·0005). In trials with four such extra cycles of a taxane counterbalanced in controls by extra cycles of other cytotoxic drugs, roughly doubling non-taxane dosage, there was no significant difference (RR 0·94, SE 0·06, 2p=0·33). Trials with CMF-treated controls showed that standard 4AC and standard CMF were equivalent (RR 0·98, SE 0·05, 2p=0·67), but that anthracycline-based regimens with substantially higher cumulative dosage than standard 4AC (eg, CAF or CEF) were superior to standard CMF (RR 0·78, SE 0·06, 2p=0·0004). Trials versus no chemotherapy also suggested greater mortality reductions with CAF (RR 0·64, SE 0·09, 2pINTERPRETATION: 10-year gains from a one-third breast cancer mortality reduction depend on absolute risks without chemotherapy (which, for oestrogen-receptor-positive disease, are the risks remaining with appropriate endocrine therapy). Low absolute risk implies low absolute benefit, but information was lacking about tumour gene expression markers or quantitative immunohistochemistry that might help to predict risk, chemosensitivity, or both. FUNDING: Cancer Research UK; British Heart Foundation; UK Medical Research Council.

The dose-response relationship for radiation-induced leukemia was examined in a pooled analysis of three exposed populations: Japanese atomic bomb survivors, women treated for cervical cancer, and patients irradiated for ankylosing spondylitis. A total of 383 leukemias were observed among 283,139 study subjects. Considering all leukemias apart from chronic lymphocytic leukemia, the optimal relative risk model had a dose response with a purely quadratic term representing induction and an exponential term consistent with cell sterilization at high doses; the addition of a linear induction term did not improve the fit of the model. The relative risk decreased with increasing time since exposure and increasing attained age, and there were significant (P < 0.00001) differences in the parameters of the model between datasets. These differences were related in part to the significant differences (P = 0.003) between the models fitted to the three main radiogenic leukemia subtypes (acute myeloid leukemia, acute lymphocytic leukemia, chronic myeloid leukemia). When the three datasets were considered together but the analysis was repeated separately for the three leukemia subtypes, for each subtype the optimal model included quadratic and exponential terms in dose. For acute myeloid leukemia and chronic myeloid leukemia, there were reductions of relative risk with increasing time after exposure, whereas for acute lymphocytic leukemia the relative risk decreased with increasing attained age. For each leukemia subtype considered separately, there was no indication of a difference between the studies in the relative risk and its distribution as a function of dose, age and time (P > 0.10 for all three subtypes). The nonsignificant indications of differences between the three datasets when leukemia subtypes were considered separately may be explained by random variation, although a contribution from differences in exposure dose-rate regimens, inhomogeneous dose distribution within the bone marrow, inadequate adjustment for cell sterilization effects, or errors in dosimetry could have played a role.

The Chernobyl accident, which occurred April 26, 1986, resulted in a large release of radionuclides, which were deposited over a very wide area, particularly in Europe. Although an increased risk of thyroid cancer in exposed children has been clearly demonstrated in the most contaminated regions, the impact of the accident on the risk of other cancers as well as elsewhere in Europe is less clear. The objective of the present study was to evaluate the human cancer burden in Europe as a whole from radioactive fallout from the accident. Average country- and region-specific whole-body and thyroid doses from Chernobyl were estimated using new dosimetric models and radiological data. Numbers of cancer cases and deaths possibly attributable to radiation from Chernobyl were estimated, applying state-of-the-art risk models derived from studies of other irradiated populations. Simultaneously, trends in cancer incidence and mortality were examined over time and by dose level. The risk projections suggest that by now Chernobyl may have caused about 1,000 cases of thyroid cancer and 4,000 cases of other cancers in Europe, representing about 0.01% of all incident cancers since the accident. Models predict that by 2065 about 16,000 (95% UI 3,400-72,000) cases of thyroid cancer and 25,000 (95% UI 11,000-59,000) cases of other cancers may be expected due to radiation from the accident, whereas several hundred million cancer cases are expected from other causes. Although these estimates are subject to considerable uncertainty, they provide an indication of the order of magnitude of the possible impact of the Chernobyl accident. It is unlikely that the cancer burden from the largest radiological accident to date could be detected by monitoring national cancer statistics. Indeed, results of analyses of time trends in cancer incidence and mortality in Europe do not, at present, indicate any increase in cancer rates -- other than of thyroid cancer in the most contaminated regions -- that can be clearly attributed to radiation from the Chernobyl accident.

Recent analyses of mortality among atomic bomb survivors have suggested a linear dose-response relationship between ionizing radiation and diseases of the circulatory system for exposures in the range 0-4 Sv. If confirmed, this has substantial implications. We have therefore reviewed the published literature to see if other epidemiological data support this finding. Other studies allowing a comparison of the rates of circulatory disease in individuals drawn from the same population but exposed to ionizing radiation at different levels within the range 0-5 Gy or 0-5 Sv were identified through systematic literature searches. Twenty-six studies were identified. In some, disease rates among those exposed at different levels may have differed for reasons unrelated to radiation exposure, while many had low power to detect effects of the relevant magnitude. Among the remainder, one study found appreciable evidence that exposure to low-dose radiation was associated with circulatory diseases, but five others, all with appreciable power, did not. We conclude that the other epidemiological data do not at present provide clear evidence of a risk of circulatory diseases at doses of ionizing radiation in the range 0-4 Sv, as suggested by the atomic bomb survivors. Further evidence is needed to characterize the possible risk.

Data are presented on the risks of cancers other than lung cancer in a cohort of iron miners from northern Sweden occupationally exposed to elevated levels of the radioactive gas radon. Compared with rates for the four northernmost counties of Sweden, mortality was increased for all cancers other than lung cancer (ratio of observed to expected deaths 1.21, 95% confidence interval 1.03-1.41), stomach cancer (ratio of observed to expected deaths 1.45, 95% confidence interval 1.04-1.98), and rectal cancer (ratio of observed to expected deaths 1.94, 95% confidence interval 1.03-3.31). Despite these overall increases, mortality was not significantly associated with cumulative exposure to radon, either for all cancers other than lung cancer or for any site of cancer other than lung cancer individually. However, the data from this cohort on its own have limited power; and for several sites of cancer the data in this study would be consistent with a radon-related increase. Further study of cancers other than lung cancer in populations exposed to radon is required.

BACKGROUND AND PURPOSE: We evaluated the accuracy of three methods of estimating radiation dose to the heart from two-dimensional tangential radiotherapy for breast cancer, as used in Denmark during 1982-2002.MATERIAL AND METHODS: Three tangential radiotherapy regimens were reconstructed using CT-based planning scans for 40 patients with left-sided and 10 with right-sided breast cancer. Setup errors and organ motion were simulated using estimated uncertainties. For left-sided patients, mean heart dose was related to maximum heart distance in the medial field.RESULTS: For left-sided breast cancer, mean heart dose estimated from individual CT-scans varied from 8Gy, and maximum dose from 5 to 50Gy for all three regimens, so that estimates based only on regimen had substantial uncertainty. When maximum heart distance was taken into account, the uncertainty was reduced and was comparable to the uncertainty of estimates based on individual CT-scans. For right-sided breast cancer patients, mean heart dose based on individual CT-scans was always CONCLUSIONS: The use of stored individual simulator films provides a method for estimating heart doses in left-tangential radiotherapy for breast cancer that is almost as accurate as estimates based on individual CT-scans.

The hazards of exposure to some types of ionising radiation were recognized shortly after the discovery of the X-ray in 1895: by 1902 the first radiation-associated cancer was reported in a skin sore and, within a few years, a large number of such skin cancers had been observed. The first report of leukaemia in radiation workers appeared in 1911. Since then there have been many reviews of the health effects of ionising radiation, most notably in the reports of the United Nations Scientific Committee on the Effects of Atomic Radiation (UNSCEAR) (see, for example, UNSCEAR, 2006). The International Agency for Research on Cancer's Monographs on the Carcinogenic Risk to Humans also reviewed the effects of ionising radiation, both in the form of exposure to external γ or X-rays (IARC, 2000) and as α and β particles from internalised radionuclides (IARC, 2001), and all these types of radiation were classified as carcinogenic to humans.

For some time, there has been compelling evidence both from randomised-controlled trials and from observational studies, that some of the breast-cancer radiotherapy regimens used in the past have led to increased risk of mortality from heart disease. There is also some evidence that the more recent regimens used in the USA are associated with lower risks than previous ones, but it is not clear whether current regimens are free from cardiac risk, especially in the light of recent evidence from the survivors of the bombings of Hiroshima and Nagasaki, in whom a clear relationship was observed between the risk of mortality from heart disease and radiation dose for doses in the range 0-4 Gy. Mortality from radiation-induced heart disease usually occurs at least a decade after irradiation. Symptomatic heart disease might have a much shorter induction period, but little information about it is available at present. Subclinical vascular abnormalities have been observed within months of irradiation, via myocardial perfusion imaging studies, but little is known about the relationship between these and later overt heart disease. At present, few data relate heart dose and other specific characteristics of breast radiotherapy to cardiac outcome. Further information on these topics is needed to enable estimation of the cardiac risk, that is likely to arise from radiotherapy regimens in current use and from those being considered for future use. Such knowledge would facilitate radiotherapy treatment planning and enable a reduction in cardiac risk while maintaining the known benefit in terms of breast cancer mortality.

Background: Ductal carcinoma in situ (DCIS), accounts for one fifth of all screen-detected neoplastic breast lesions. Contemporary research in DCIS focuses on separating lesions that need active treatment from those that can be safely left under surveillance. This, in turn, relies on accurate determination of invasive status and DCIS grade at time of initial biopsy. Most previous studies have examined factors associated with upstaging the diagnosis from DCIS to invasive breast cancer (IBC) following surgery, and few have evaluated factors associated with upgrading the diagnosis to a higher grade of DCIS. This is because upgrading has not traditionally influenced clinical management in the way that upstaging has done. However, recent interest in non-operative treatment for low-risk DCIS has meant that accurate determination of grade at time of initial biopsy has become more important. We aimed to compare risk factors for upgrading and upstaging of biopsies in DCIS. Method: We undertook a cohort study of all women diagnosed with DCIS at a large specialist cancer centre between 2000–2014. Information from the clinical records was abstracted, including the pre-operative mammography (MMG) and pathology information from the initial biopsy. We also abstracted pathology information regarding the excised specimen in order to identify women whose diagnosis was subsequently upgraded or upstaged. We looked for factors that were predictive for upgrading or upstaging. Result: A total of 641 women were diagnosed with DCIS at initial biopsy. Of these, 72 (11%) were upgraded: 26 (4%) from grade 1 to grade 2, 2 (0.3%) from grade 1 to grade 3 and 44 (7%) from grade 2 to grade 3. A further 115 (18%) were upstaged to IBC: 20 of these (3%) had grade 1 DCIS on initial biopsy, 47 (7%) had grade 2, 43 (7%) grade 3, and for 5 (1%) biopsy grade was not available. Necrosis on biopsy increased the risk of upgrading (with necrosis: 14% upgraded, without: 10% upgraded, p for difference 0.02) and also of upstaging (with necrosis: 23% upstaged, without: 15% upstaged, p for difference Conclusion: Our findings suggest that consideration of MMG lesion size and necrosis on biopsy may be helpful in selecting low-risk women for non-operative management of DCIS, as may use of the 9G vacuum-assisted method of biopsy. Citation Format: Mannu GS, Groen E, Wang Z, Schaapveld M, Lips E, Chung M, Joore I, Leeuwen Fv, Teerstra J, Winter-Warnars GAO, Darby SC, Wesseling J. Risk factors for upgrading and upstaging of pre-operative biopsies in ductal carcinoma in situ [abstract]. In: Proceedings of the 2017 San Antonio Breast Cancer Symposium; 2017 Dec 5-9; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2018;78(4 Suppl):Abstract nr P2-03-10.

Background: Radiotherapy (RT) forms a vital component of treatment for breast cancer, contributing to the increasing number of survivors worldwide. It is known from historical cohorts that breast RT increased the risk of developing heart disease 10 years or more following treatment. It is less certain whether the lower cardiac radiation doses received during modern RT still increase cardiac risk. Cardiovascular Magnetic Resonance (CMR) imaging has the potential to provide early surrogate markers of radiation-induced heart disease that may help predict which women will be at increased risk in the future. Methods: This is a prospective longitudinal imaging study to evaluate CMR findings in a cohort of women receiving adjuvant RT for early breast cancer at the Oxford Cancer Centre. The patients undergo CMR imaging (with gadolinium enhancement and adenosine stress), Doppler echocardiography, blood testing (including BNP and troponin), ECG and clinical examination prior to RT, within 72 hours of completing RT, and at 3 months, 6 months and 5 years following RT. The results of these investigations will be related to cardiac radiation exposure estimated using 3D-dosimetric data obtained by analysis of CT-based RT planning. Recruitment and Provisional Results: As of May 2011, 30 women have been recruited. The women had a mean age of 57.1 years (range = 42.0 to 63.9). All women had left-sided cancer and none received adjuvant cytotoxic chemotherapy. The mean whole heart dose was 1.47 Gray (range = 0.65 to 4.20), the mean left ventricle dose was 2.03 (range = 0.88 to 6.99) and the mean left coronary artery dose was 7.55 Gray (range = 1.50 to 24.59). Preliminary analysis of the first 10 participants showed that all had a normal left ventricular ejection fraction at baseline (mean 76%, range 60–82%) and immediately following RT (mean reduction 3%, p=0.18). None had myocardial oedema as detected by T2-STIR imaging or fibrosis and scarring as demonstrated by late gadolinium enhancement (LGE). Conclusion and Future Plans: Preliminary results suggest that the relatively low heart doses received by the women undergoing modern CT-planned left breast RT at the Oxford Cancer Centre do not result in any cardiovascular abnormality detectable by CMR imaging. Further and updated results will be available for the San Antonio Breast Cancer Symposium. Recruitment will continue until at least 20 women have completed baseline scans and follow-up scans up to 6 months. At this stage a full analysis will be performed including a wider range of CMR endpoints including: - Overall LV systolic function (EF and volumes) - Regional wall motion analysis - T2-weighted imaging (oedema) - T1 and T2 mapping (quantitative T1 and T2 relaxation times) - Tagged myocardial strain analysis - Stress perfusion defects (endothelial/microcapillary damage) - Late gadolinium (LGE) imaging (fibrosis/scarring) Depending on the results of this analysis, recruitment may be expanded to include women with either lower cardiac risk (e.g. with right-sided breast cancer) or higher cardiac risk (e.g. receiving anthracycline chemotherapy). Citation Information: Cancer Res 2011;71(24 Suppl):Abstract nr P3-13-06.

The number of long-term cancer survivors in the general population of the UK is substantial and increasing rapidly. Many cancer survivors have been treated with radiotherapy but the likely number of radiotherapy-related second cancers has not previously been estimated. We used estimates of the numbers of cancer survivors in the UK at the beginning of 2007, in conjunction with estimates of the relative risk of a second primary cancer associated with previous radiotherapy from the United States Surveillance Epidemiology and End Results (SEER) programme, to estimate the numbers of incident cancers in the UK in 2007 that were associated with radiotherapy for a previous cancer and that may have been caused by it. We estimated that 1,346 cases of cancer, or about 0.45% of the 298,000 new cancers registered in the UK in 2007, were associated with radiotherapy for a previous cancer. The largest numbers of radiotherapy-related second cancers were lung cancer (23.7% of the total), oesophageal cancer (13.3%), and female breast cancer (10.6%); 54% of radiotherapy-related second cancers were in individuals aged 75 or over. The highest percentages of second cancers related to radiotherapy were among survivors of Hodgkin's disease and cancers of the oral cavity and pharynx and cervix uteri; over 15% of second cancers among these survivors were associated with radiotherapy for the first cancer. These calculations, which involve a number of assumptions and approximations, provide a reasonable, if conservative, estimate of the fraction of incident cancers in the UK that are attributable to past radiation therapy.

Purpose To assess the value of maximum heart distance (MHD) in predicting the dose and biologically effective dose (BED) to the heart and the left anterior descending (LAD) coronary artery for left-tangential breast or chest wall irradiation. Methods and Materials A total of 50 consecutive breast cancer patients given adjuvant left-tangential irradiation at a large U.K. radiotherapy center during 2006 were selected. For each patient, the following were derived using three-dimensional computed tomography (CT) planning: (1) mean dose and BED to the heart, (2) mean dose and BED to the LAD coronary artery, (3) MHD, (4) position of the CT slice showing the maximum area of the irradiated heart relative to the mid-plane slice, and (5) sternal and contralateral breast thickness (measures of body fat). Results A strong linear correlation was found between the MHD and the mean heart dose. For every 1-cm increase in MHD, the mean heart dose increased by 2.9% on average (95% confidence interval 2.5–3.3). A strong linear-quadratic relationship was seen between the MHD and the mean heart BED. The mean LAD coronary artery dose and BED were also correlated with the MHD but the associations were weaker. These relationships were not affected by body fat. The mid-plane CT slice did not give a reliable assessment of cardiac irradiation. Conclusion The MHD is a reliable predictor of the mean heart dose and BED and gives an approximate estimate of the mean LAD coronary artery dose and BED. Doses predicted by the MHD could help assess the risk of radiation-induced cardiac toxicity where individual CT-based cardiac dosimetry is not possible.

This Workshop was organised by the Organisation of European Cancer Institutes (OECI) to provide a forum for discussing the late side-effects resulting from different cancer treatments. One of the main Workshop objectives was to generate recommendations on how to improve knowledge and, consequently, long-term care for cancer survivors.

Purpose To compare the effect of breast cancer radiotherapy as estimated from observational data with findings from randomized trials. Materials and Methods Rate ratios were obtained for selected end points among 13,932 women randomly assigned to receive radiotherapy or not in trials contributing to recent meta-analyses by the Early Breast Cancer Trialists’ Collaborative Group. Estimates of the same quantities were derived for 393,840 women registered with breast cancer in the US SEER registries between 1973 and 2008. Results In the randomized trials, radiotherapy after breast-conserving surgery reduced mortality from both breast cancer (rate ratio, 0.82; 95% CI, 0.75 to 0.90) and all causes (rate ratio, 0.92; 95% CI, 0.86 to 0.99). Reductions of similar magnitude were seen in the trials of radiotherapy after mastectomy in node-positive disease (rate ratios, breast cancer 0.84; 95% CI, 0.76 to 0.94; all causes, 0.89; 95% CI, 0.81 to 0.97). In the observational data, radiotherapy after breast-conserving surgery was associated with much larger mortality reductions (rate ratios, breast cancer, 0.64; 95% CI, 0.62 to 0.66; all causes, 0.63; 95% CI, 0.62 to 0.65), whereas radiotherapy after mastectomy in node-positive disease was associated with substantial increases in mortality (rate ratios, breast cancer, 1.34; 95% CI, 1.31 to 1.37; all causes, 1.23; 95% CI, 1.22 to 1.25). Detailed adjustment of the observational data for potential confounders did not reduce the divergence from the randomized data. Conclusion This study of mortality after radiotherapy for breast cancer found strikingly divergent results between the Early Breast Cancer Trialists’ Collaborative Group meta-analyses of randomized data and the SEER observational data, even when efforts had been made to remove confounding and selection biases. Nonrandomized comparisons are liable to provide misleading estimates of treatment effects. Therefore, they need careful justification every time they are used.

PurposeThe optimum dose and fractionation in radiation therapy of curative intent for non-small cell lung cancer remains uncertain. We undertook a published data meta-analysis of randomized trials to examine whether radiation therapy regimens with higher time-corrected biologically equivalent doses resulted in longer survival, either when given alone or when given with chemotherapy.Methods and MaterialsEligible studies were randomized comparisons of 2 or more radiation therapy regimens, with other treatments identical. Median survival ratios were calculated for each comparison and pooled.Results3795 patients in 25 randomized comparisons of radiation therapy dose were studied. The median survival ratio, higher versus lower corrected dose, was 1.13 (95% confidence interval [CI] 1.04-1.22) when radiation therapy was given alone and 0.83 (95% CI 0.71-0.97) when it was given with concurrent chemotherapy (P for difference=.001). In comparisons of radiation therapy given alone, the survival benefit increased with increasing dose difference between randomized treatment arms (P for trend=.004). The benefit increased with increasing dose in the lower-dose arm (P for trend=.01) without reaching a level beyond which no further survival benefit was achieved. The survival benefit did not differ significantly between randomized comparisons where the higher-dose arm was hyperfractionated and those where it was not. There was heterogeneity in the median survival ratio by geographic region (P

Purpose Cardiovascular diseases are increasingly recognized as late effects of Hodgkin lymphoma (HL) treatment. The purpose of this study was to identify the risk factors for coronary heart disease (CHD) and to quantify the effects of radiation dose to the heart, chemotherapy, and other cardiovascular risk factors. Patients and Methods We conducted a nested case-control study in a cohort of 2,617 5-year HL survivors, treated between 1965 and 1995. Cases were patients diagnosed with CHD as their first cardiovascular event after HL. Detailed treatment information was collected from medical records of 325 cases and 1,204 matched controls. Radiation charts and simulation radiographs were used to estimate in-field heart volume and mean heart dose (MHD). A risk factor questionnaire was sent to patients still alive. Results The median interval between HL and CHD was 19.0 years. Risk of CHD increased linearly with increasing MHD (excess relative risk [ERR]) per Gray, 7.4%; 95% CI, 3.3% to 14.8%). This results in a 2.5-fold increased risk of CHD for patients receiving a MHD of 20 Gy from mediastinal radiotherapy, compared with patients not treated with mediastinal radiotherapy. ERRs seemed to decrease with each tertile of age at treatment (ERR/Gy, 20.0%; ERR/Gy27.5-36.4years, 8.8%; ERR/Gy36.5-50.9years, 4.2%; Pinteraction = .149). Having ≥ 1 classic CHD risk factor (diabetes mellitus, hypertension, or hypercholesterolemia) independently increased CHD risk (rate ratio, 1.5; 95% CI, 1.1 to 2.1). A high level of physical activity was associated with decreased CHD risk (rate ratio, 0.5; 95% CI, 0.3 to 0.8). Conclusion The linear radiation dose-response relationship identified can be used to predict CHD risk for future HL patients and survivors. Appropriate early management of CHD risk factors and stimulation of physical activity may reduce CHD risk in HL survivors.

Background: Hodgkin lymphoma (HL) survivors are at increased risk for developing valvular heart disease (VHD). We evaluated the determinants of the risk and the radiation dose-response. Methods: A case-control study was nested in a cohort of 1852 five-year HL survivors diagnosed at ages 15 to 41 years and treated between 1965 and 1995. Case patients had VHD of at least moderate severity as their first cardiovascular diagnosis following HL treatment. Control patients were matched to case patients for age, gender, and HL diagnosis date. Treatment and follow-up data were abstracted from medical records. Radiation doses to heart valves were estimated by reconstruction of individual treatments on representative computed tomography datasets. All statistical tests were two-sided. Results: Eighty-nine case patients with VHD were identified (66 severe or life-threatening) and 200 control patients. Aortic (n = 63) and mitral valves (n = 42) were most frequently affected. Risks increased more than linearly with radiation dose. For doses to the affected valve(s) of less than or equal to 30, 31–35, 36–40, and more than 40 Gy, VHD rates increased by factors of 1.4, 3.1, 5.4, and 11.8, respectively (Ptrend < .001). Approximate 30-year cumulative risks were 3.0%, 6.4%, 9.3%, and 12.4% for the same dose categories. VHD rate increased with splenectomy by a factor of 2.3 (P = .02). Conclusions: Radiation dose to the heart valves can increase the risk for clinically significant VHD, especially at doses above 30 Gy. However, for patients with mediastinal involvement treated today with 20 or 30 Gy, the 30-year risk will be increased by only about 1.4%. These findings may be useful for patients and doctors both before treatment and during follow-up.

Expert consensus-based recommendations regarding key issues in the use of primary (or neoadjuvant) systemic treatment (PST) in patients with early breast cancer are a valuable resource for practising oncologists. PST remains a valuable therapeutic approach for the assessment of biological antitumor activity and clinical efficacy of new treatments in clinical trials. Neoadjuvant trials provide endpoints, such as pathological complete response (pCR) to treatment, that potentially translate into meaningful improvements in overall survival and disease-free survival. Neoadjuvant trials need fewer patients and are less expensive than adjuvant trial, and the endpoint of pCR is achieved in months, rather than years. For these reasons, the neoadjuvant setting is ideal for testing emerging targeted therapies in early breast cancer. Although pCR is an early clinical endpoint, its role as a surrogate for long-term outcomes is the key issue. New and better predictors of treatment efficacy are needed to improve treatment and outcomes. After PST, accurate management of post-treatment residual disease is mandatory. The surgery of the sentinel lymph-node could be an acceptable option to spare the axillary dissection in case of clinical negativity (N0) of the axilla at the diagnosis and/or after PST. No data exists yet to support the modulation of the extent of locoregional radiation therapy on the basis of the response attained after PST although trials are underway.

Purpose: To describe a new method to estimate the mean heart dose for Hodgkin lymphoma patients treated several decades ago, using delineation of the heart on radiation therapy simulation X-rays. Mean heart dose is an important predictor for late cardiovascular complications after Hodgkin lymphoma (HL) treatment. For patients treated before the era of computed tomography (CT)-based radiotherapy planning, retrospective estimation of radiation dose to the heart can be labor intensive. Methods and Materials: Patients for whom cardiac radiation doses had previously been estimated by reconstruction of individual treatments on representative CT data sets were selected at random from a case-control study of 5-year Hodgkin lymphoma survivors (n=289). For 42 patients, cardiac contours were outlined on each patient's simulation X-ray by 4 different raters, and the mean heart dose was estimated as the percentage of the cardiac contour within the radiation field multiplied by the prescribed mediastinal dose and divided by a correction factor obtained by comparison with individual CT-based dosimetry. Results: According to the simulation X-ray method, the medians of the mean heart doses obtained from the cardiac contours outlined by the 4 raters were 30 Gy, 30 Gy, 31 Gy, and 31 Gy, respectively, following prescribed mediastinal doses of 2542 Gy. The absolute-agreement intraclass correlation coefficient was 0.93 (95% confidence interval 0.85-0.97), indicating excellent agreement. Mean heart dose was 30.4 Gy with the simulation X-ray method, versus 30.2 Gy with the representative CT-based dosimetry, and the between-method absolute-agreement intraclass correlation coefficient was 0.87 (95% confidence interval 0.80-0.95), indicating good agreement between the two methods. Conclusion: Estimating mean heart dose from radiation therapy simulation X-rays is reproducible and fast, takes individual anatomy into account, and yields results comparable to the labor-intensive representative CT-based method. This simpler method may produce a meaningful measure of mean heart dose for use in studies of late cardiac complications. (C) 2015 Elsevier Inc. All rights reserved.

Summary Background Radiotherapy for early breast cancer can decrease breast cancer mortality but increase other mortality, mainly from heart disease and lung cancer. The mean cardiac dose from irradiation of a left-sided breast cancer can be two or three times that for a right-sided breast cancer. The mean ipsilateral (ie, on the same side as the breast cancer) lung dose can also be two or three times the mean contralateral lung dose. Particularly during the 1970s, when typical heart and lung exposures were greater than now, the laterality of an irradiated breast cancer could measurably affect cardiac mortality and mortality from cancer of the right or the left lung decades later. This study aimed to assess the hazards in the general US population from routine cancer-registry and death-certificate data. Methods We analysed data for 308 861 US women with early breast cancer of known laterality (left-sided or right-sided) who were registered in the US Surveillance Epidemiology and End Results (SEER) cancer registries during 1973–2001 and followed prospectively for cause-specific mortality until Jan 1, 2002. Findings 115 165 (37%) received radiotherapy. Among those who did not, tumour laterality was of little relevance to subsequent mortality. For women diagnosed during 1973–82 and irradiated, the cardiac mortality ratio (left versus right tumour laterality) was 1·20 (95% CI 1·04–1·38) less than 10 years afterwards, 1·42 (1·11–1·82) 10–14 years afterwards, and 1·58 (1·29–1·95) after 15 years or more (trend: 2p=0·03). For women diagnosed during 1983–92 and irradiated, the cardiac mortality ratio was 1·04 (0·91–1·18) less than 10 years afterwards and 1·27 (0·99–1·63) 10 or more years afterwards. For women diagnosed during 1993–2001 and irradiated the cardiac mortality ratio was 0·96 (0·82–1·12), with none yet followed for 10 years. Among women irradiated for breast cancer who subsequently developed an ipsilateral or contralateral lung cancer, the lung cancer mortality ratio (ipsilateral versus contralateral) for women diagnosed during 1973–82 and irradiated was 1·17 (0·62–2·19), 2·00 (1·00–4·00), and 2·71 (1·65–4·48), respectively, less than 10 years, 10–14 years, and 15 or more years afterwards (trend: 2p=0·04). For women irradiated after 1982 there is, as yet, little information on lung cancer risks more than 10 years afterwards. Interpretation US breast cancer radiotherapy regimens of the 1970s and early 1980s appreciably increased mortality from heart disease and lung cancer 10–20 years afterwards with, as yet, little direct evidence on the hazards after more than 20 years. Since the early 1980s, improvements in radiotherapy planning should have reduced such risks, but the long-term hazards in the general populations of various countries still need to be monitored directly.