David J. Cutter

Risk of Ischemic Heart Disease in Women after Radiotherapy for Breast Cancer

BACKGROUND Radiotherapy for breast cancer often involves some incidental exposure of the heart to ionizing radiation. The effect of this exposure on the subsequent risk of ischemic heart disease is uncertain. METHODS We conducted a population-based case-control study of major coronary events (i.e., myocardial infarction, coronary revascularization, or death from ischemic heart disease) in 2168 women who underwent radiotherapy for breast cancer between 1958 and 2001 in Sweden and Denmark; the study included 963 women with major coronary events and 1205 controls. Individual patient information was obtained from hospital records. For each woman, the mean radiation doses to the whole heart and to the left anterior descending coronary artery were estimated from her radiotherapy chart. RESULTS The overall average of the mean doses to the whole heart was 4.9 Gy (range, 0.03 to 27.72). Rates of major coronary events increased linearly with the mean dose to the heart by 7.4% per gray (95% confidence interval, 2.9 to 14.5; P<0.001), with no apparent threshold. The increase started within the first 5 years after radiotherapy and continued into the third decade after radiotherapy. The proportional increase in the rate of major coronary events per gray was similar in women with and women without cardiac risk factors at the time of radiotherapy. CONCLUSIONS Exposure of the heart to ionizing radiation during radiotherapy for breast cancer increases the subsequent rate of ischemic heart disease. The increase is proportional to the mean dose to the heart, begins within a few years after exposure, and continues for at least 20 years. Women with preexisting cardiac risk factors have greater absolute increases in risk from radiotherapy than other women. (Funded by Cancer Research UK and others.).

Comparisons between different polychemotherapy regimens for early breast cancer: meta-analyses of long-term outcome among 100,000 women in 123 randomised trials.

Summary 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, 2p<0·0001) than with standard 4AC (RR 0·78, SE 0·09, 2p=0·01) or standard CMF (RR 0·76, SE 0·05, 2p<0·0001). In all meta-analyses involving taxane-based or anthracycline-based regimens, proportional risk reductions were little affected by age, nodal status, tumour diameter or differentiation (moderate or poor; few were well differentiated), oestrogen receptor status, or tamoxifen use. Hence, largely independently of age (up to at least 70 years) or the tumour characteristics currently available to us for the patients selected to be in these trials, some taxane-plus-anthracycline-based or higher-cumulative-dosage anthracycline-based regimens (not requiring stem cells) reduced breast cancer mortality by, on average, about one-third. 10-year overall mortality differences paralleled breast cancer mortality differences, despite taxane, anthracycline, and other toxicities. Interpretation 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.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, 2p<0·0001) than with standard 4AC (RR 0·78, SE 0·09, 2p=0·01) or standard CMF (RR 0·76, SE 0·05, 2p<0·0001). In all meta-analyses involving taxane-based or anthracycline-based regimens, proportional risk reductions were little affected by age, nodal status, tumour diameter or differentiation (moderate or poor; few were well differentiated), oestrogen receptor status, or tamoxifen use. Hence, largely independently of age (up to at least 70 years) or the tumour characteristics currently available to us for the patients selected to be in these trials, some taxane-plus-anthracycline-based or higher-cumulative-dosage anthracycline-based regimens (not requiring stem cells) reduced breast cancer mortality by, on average, about one-third. 10-year overall mortality differences paralleled breast cancer mortality differences, despite taxane, anthracycline, and other toxicities. INTERPRETATION 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.

Radiation-Related Heart Disease: Current Knowledge and Future Prospects

INTRODUCTIONIt has been recognized since the 1960s that the heart may bedamaged by substantial doses of radiation [>30 Gray (Gy)],such as used to occur during mantle radiotherapy for Hodg-kin lymphoma. During the last few years, however, evidencethat radiation-related heart disease (RRHD) can occur fol-lowing doses below 20 Gy has emerged from several inde-pendent sources. Those sources include studies of breastcancer patients who received mean cardiac doses of 3 to 17Gy when given radiotherapy following surgery and studiesof survivors of the atomic bombings of Japan who receiveddoses of up to 4 Gy.At doses above 30 Gy, an increased risk of RRHD can be-comes apparent within a year or two of exposure, and the riskincreases with higher radiotherapy dose, younger age at irra-diation, and the presence of conventional risk factors. Atlower doses, the typical latency period is much longer andis often more than a decade. The nature and magnitude ofthe risk following lower doses is not well characterized,and it is not yet clear whether there is a threshold dose belowwhich there is no risk.The evidence regarding RRHD comes from several differ-ent disciplines. The present review brings together informa-tion from pathology, radiobiology, cardiology, radiationoncology, and epidemiology; it summarizes current knowl-edge, identifies gaps in that knowledge, and outlines somepotential strategies for filling them.CURRENT KNOWLEDGEPathologyThe pathological expressions of RRHD documented fol-lowing therapeutic irradiation can be broadly reduced tofour conditions: pericarditis, pericardial fibrosis, diffusemyocardial fibrosis, and coronary artery disease (CAD)(1, 2). Radiation may also cause valvular disease, althoughtheevidence for this isnotasstrong.None of these conditionsis specific to radiation.Radiation-related pericarditis is characterized by an exu-date of a variable amount of protein-rich fluid within thepericardial sac (pericardial effusion). Rapid accumulationof this fluid can, in rare cases, cause potentially fatal cardiactamponade. Almost invariably, fibrin accumulates on the

Risk for Valvular Heart Disease After Treatment for Hodgkin Lymphoma

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 (P trend < .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.

Dose and Fractionation in Radiation Therapy of Curative Intent for Non-Small Cell Lung Cancer: Meta-Analysis of Randomized Trials

Purpose The 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 Materials Eligible 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. Results 3795 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<.001), average age at randomization (P<.001), and year trial started (P for trend=.004), but not for proportion of patients with squamous cell carcinoma (P=.2). Conclusions In trials with concurrent chemotherapy, higher radiation therapy doses resulted in poorer survival, possibly caused, at least in part, by high levels of toxicity. Where radiation therapy was given without chemotherapy, progressively higher radiation therapy doses resulted in progressively longer survival, and no upper dose level was found above which there was no further benefit. These findings support the consideration of further radiation therapy dose escalation trials, making use of modern treatment methods to reduce toxicity.

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.

Cardiac Mortality Among 200 000 Five-Year Survivors of Cancer Diagnosed at 15 to 39 Years of Age: The Teenage and Young Adult Cancer Survivor Study

Background: Survivors of teenage and young adult cancer are acknowledged as understudied. Little is known about their long-term adverse health risks, particularly of cardiac disease that is increased in other cancer populations where cardiotoxic treatments have been used. Methods: The Teenage and Young Adult Cancer Survivor Study cohort comprises 200 945 5-year survivors of cancer diagnosed at 15 to 39 years of age in England and Wales from 1971 to 2006, and followed to 2014. Standardized mortality ratios, absolute excess risks, and cumulative risks were calculated. Results: Two thousand sixteen survivors died of cardiac disease. For all cancers combined, the standardized mortality ratios for all cardiac diseases combined was greatest for individuals diagnosed at 15 to 19 years of age (4.2; 95% confidence interval, 3.4–5.2) decreasing to 1.2 (95% confidence interval, 1.1–1.3) for individuals aged 35 to 39 years (2P for trend <0.0001). Similar patterns were observed for both standardized mortality ratios and absolute excess risks for ischemic heart disease, valvular heart disease, and cardiomyopathy. Survivors of Hodgkin lymphoma, acute myeloid leukaemia, genitourinary cancers other than bladder cancer, non-Hodgkin lymphoma, lung cancer, leukaemia other than acute myeloid, central nervous system tumour, cervical cancer, and breast cancer experienced 3.8, 2.7, 2.0, 1.7, 1.7, 1.6, 1.4, 1.3 and 1.2 times the number of cardiac deaths expected from the general population, respectively. Among survivors of Hodgkin lymphoma aged over 60 years, almost 30% of the total excess number of deaths observed were due to heart disease. Conclusions: This study of over 200 000 cancer survivors shows that age at cancer diagnosis was critical in determining subsequent cardiac mortality risk. For the first time, risk estimates of cardiac death after each cancer diagnosed between the ages of 15 and 39 years have been derived from a large population-based cohort with prolonged follow-up. The evidence here provides an initial basis for developing evidence-based follow-up guidelines.

Population-Based Long-Term Cardiac-Specific Mortality Among 34,489 Five-Year Survivors of Childhood Cancer in Great Britain.

Background: Increased risks of cardiac morbidity and mortality among childhood cancer survivors have been described previously. However, little is known about the very long-term risks of cardiac mortality and whether the risk has decreased among those more recently diagnosed. We investigated the risk of long-term cardiac mortality among survivors within the recently extended British Childhood Cancer Survivor Study. Methods: The British Childhood Cancer Survivor Study is a population-based cohort of 34 489 five-year survivors of childhood cancer diagnosed from 1940 to 2006 and followed up until February 28, 2014, and is the largest cohort to date to assess late cardiac mortality. Standardized mortality ratios and absolute excess risks were used to quantify cardiac mortality excess risk. Multivariable Poisson regression models were used to evaluate the simultaneous effect of risk factors. Likelihood ratio tests were used to test for heterogeneity and trends. Results: Overall, 181 cardiac deaths were observed, which was 3.4 times that expected. Survivors were 2.5 times and 5.9 times more at risk of ischemic heart disease and cardiomyopathy/heart failure death, respectively, than expected. Among those >60 years of age, subsequent primary neoplasms, cardiac disease, and other circulatory conditions accounted for 31%, 22%, and 15% of all excess deaths, respectively, providing clear focus for preventive interventions. The risk of both overall cardiac and cardiomyopathy/heart failure mortality was greatest among those diagnosed from 1980 to 1989. Specifically, for cardiomyopathy/heart failure deaths, survivors diagnosed from 1980 to 1989 had 28.9 times the excess number of deaths observed for survivors diagnosed either before 1970 or from 1990 on. Conclusions: Excess cardiac mortality among 5-year survivors of childhood cancer remains increased beyond 50 years of age and has clear messages in terms of prevention strategies. However, the fact that the risk was greatest in those diagnosed from 1980 to 1989 suggests that initiatives to reduce cardiotoxicity among those treated more recently may be having a measurable impact.

Risk of heart failure in survivors of Hodgkin lymphoma: effects of cardiac exposure to radiation and anthracyclines.

Hodgkin lymphoma (HL) survivors treated with radiotherapy and/or chemotherapy are known to have increased risks of heart failure (HF), but a radiation dose-response relationship has not previously been derived. A case-control study, nested in a cohort of 2617 five-year survivors of HL diagnosed before age 51 years during 1965 to 1995, was conducted. Cases (n = 91) had moderate or severe HF as their first cardiovascular diagnosis. Controls (n = 278) were matched to cases on age, sex, and HL diagnosis date. Treatment and follow-up information were abstracted from medical records. Mean heart doses and mean left ventricular doses (MLVD) were estimated by reconstruction of individual treatments on representative computed tomography datasets. Average MLVD was 16.7 Gy for cases and 13.8 Gy for controls (Pdifference = .003). HF rate increased with MLVD: relative to 0 Gy, HF rates following MVLD of 1-15, 16-20, 21-25, and ≥26 Gy were 1.27, 1.65, 3.84, and 4.39, respectively (Ptrend < .001). Anthracycline-containing chemotherapy increased HF rate by a factor of 2.83 (95% CI: 1.43-5.59), and there was no significant interaction with MLVD (Pinteraction = .09). Twenty-five-year cumulative risks of HF following MLVDs of 0-15 Gy, 16-20 Gy, and ≥21 Gy were 4.4%, 6.2%, and 13.3%, respectively, in patients treated without anthracycline-containing chemotherapy, and 11.2%, 15.9%, and 32.9%, respectively, in patients treated with anthracyclines. We have derived quantitative estimates of HF risk in patients treated for HL following radiotherapy with or without anthracycline-containing chemotherapy. Our results enable estimation of HF risk for patients before treatment, during radiotherapy planning, and during follow-up.

Can Observational Data Replace Randomized Trials

TO THE EDITOR: The increasing complexity and cost of conducting randomized trials have stimulated interest in using observational data sets to evaluate cancer treatments. Determining the causal effect of treatments from observational data is, however, challenging because more aggressive treatments are selectively prescribed for patients with adverse disease characteristics or favorable comorbidity profiles. Associations may, therefore, arise between treatments and outcomes that are the result of confounding and are not causal. Relatively little is known about the extent of such confounding or the degree to which it can be removed through stratification by prognostic variables. Breast cancer is one of the commonest conditions for which radiotherapy is prescribed. We have therefore used it to examine this issue. We analyzed data on women registered between 1990 and 2008 in the SEER public-use data set. Women were excluded if they were younger than 20 or older than 80 years when diagnosed, had previous cancer, unknown cancer laterality, bilateral cancer, or unknown radiotherapy status. Each woman entered the study on the date of her breast cancer diagnosis and left on the earliest of the following events: death, loss to follow-up, turning age 85 years, or January 1, 2009. Two analyses were conducted. In the first, deaths and person-years were stratified by five basic variables; the second stratification also included all available prognostic variables. Mortality ratios were estimated by maximum likelihood using Poisson regression. Calculations were performed using STATAversion 12 (STATA, College Station, TX). Information was also collated from the Early Breast Cancer Trialists’ Collaborative Group (EBCTCG) meta-analyses of randomized trials of radiotherapy versus not. Analyses were stratified by trial, individual follow-up year, age at randomization, and nodal status. After breast-conserving surgery, with only basic variables in the stratification, radiotherapy was associated with reduced mortality for all the causes examined (Appendix Table A1, online only). Stratifying for all available prognostic variables changed the estimates, but all remained significantly below one. Notably, the rate ratio for mortality from all causes except breast cancer (0.69) was lower than that for breast cancer (0.74). After mastectomy in node-positive disease, with only basic variables in the stratification, radiotherapy was associated with increased breast cancer mortality and all-cause mortality, and decreased mortality from all causes except breast cancer. Stratifying for prognostic variables changed the death rate ratios for breast cancer from 1.35 to 0.89 and all causes of death from 1.21 to 0.85, but the rate ratio for mortality from all causes except breast cancer (0.74) was still lower than that for breast cancer (0.89). Estimates of the effects of radiotherapy in the EBCTCG meta-analyses of randomized trials were then compared with the corresponding death rate ratios in the SEER data stratified by all available variables (basic and prognostic; Fig 1). After breastconserving surgery, the breast cancer death rate ratio in the EBCTCG data was 0.83 for all women and did not differ significantly between pN0 (node-negative disease) and pN1 (node-positive disease; P5 .76), whereas in the SEER data the corresponding death rate ratio for all women was lower (0.74 v 0.83; P 5 .04), and differed significantly between pN0 and pN1 (0.84 v 0.73; P 5 .008). After mastectomy, the breast cancer death rate ratio in the EBCTCG data was 0.85, similar to that after breast-conserving surgery, and it did not differ significantly according to the number of positive nodes (P for heterogeneity 5 .53). In contrast, in the SEER data, there was substantial heterogeneity in the breast cancer death rate ratios according to the number of positive nodes (P for heterogeneity , .001). In women with one to three positive nodes, postmastectomy radiotherapy was associated with significantly increased breast cancer mortality in the SEER data (1.10; 95%CI, 1.02 to 1.18) and significantly decreased breast cancer mortality in the EBCTCG data (0.80; 95% CI, 0.67 to 0.95). For mortality from all causes except breast cancer, there were also major qualitative differences between the EBCTCG and SEER data. In the EBCTCGdata, radiotherapywas associatedwith significantly higher rates of mortality from all causes except breast cancer, including from heart disease and from lung cancer. In the SEER data, radiotherapy was associated with significantly lower rates of mortality from all causes except breast cancer, including from heart disease. SEER is one of the largest, most detailed data sets. If we had used these SEER analyses to draw conclusions about the causal effects of radiotherapy, we would have concluded that radiotherapy after breastconserving surgery is more effective in node-positive than in nodenegative disease, and that radiotherapy after mastectomy in women with one to three positive nodes causes death from breast cancer. We would have also concluded that radiotherapy prevents mortality from all causes except breast cancer, including from heart disease and from accidents and violence (Appendix Table A1). These results contradict those of the randomized trials. We conclude, as have others, that nonrandomized comparisons are liable to provide misleading estimates of treatment effects. Therefore, they need careful justification every time they are used.