SummaryBackgroundPublished findings on breast cancer risk associated with different types of menopausal hormone therapy (MHT) are inconsistent, with limited information on long-term effects. We bring together the epidemiological evidence, published and unpublished, on these associations, and review the relevant randomised evidence.MethodsPrincipal analyses used individual participant data from all eligible prospective studies that had sought information on the type and timing of MHT use; the main analyses are of individuals with complete information on this. Studies were identified by searching many formal and informal sources regularly from Jan 1, 1992, to Jan 1, 2018. Current users were included up to 5 years (mean 1·4 years) after last-reported MHT use. Logistic regression yielded adjusted risk ratios (RRs) comparing particular groups of MHT users versus never users.FindingsDuring prospective follow-up, 108 647 postmenopausal women developed breast cancer at mean age 65 years (SD 7); 55 575 (51%) had used MHT. Among women with complete information, mean MHT duration was 10 years (SD 6) in current users and 7 years (SD 6) in past users, and mean age was 50 years (SD 5) at menopause and 50 years (SD 6) at starting MHT. Every MHT type, except vaginal oestrogens, was associated with excess breast cancer risks, which increased steadily with duration of use and were greater for oestrogen-progestagen than oestrogen-only preparations. Among current users, these excess risks were definite even during years 1–4 (oestrogen-progestagen RR 1·60, 95% CI 1·52–1·69; oestrogen-only RR 1·17, 1·10–1·26), and were twice as great during years 5–14 (oestrogen-progestagen RR 2·08, 2·02–2·15; oestrogen-only RR 1·33, 1·28–1·37). The oestrogen-progestagen risks during years 5–14 were greater with daily than with less frequent progestagen use (RR 2·30, 2·21–2·40 vs 1·93, 1·84–2·01; heterogeneity p<0·0001). For a given preparation, the RRs during years 5–14 of current use were much greater for oestrogen-receptor-positive tumours than for oestrogen-receptor-negative tumours, were similar for women starting MHT at ages 40–44, 45–49, 50–54, and 55–59 years, and were attenuated by starting after age 60 years or by adiposity (with little risk from oestrogen-only MHT in women who were obese). After ceasing MHT, some excess risk persisted for more than 10 years; its magnitude depended on the duration of previous use, with little excess following less than 1 year of MHT use.InterpretationIf these associations are largely causal, then for women of average weight in developed countries, 5 years of MHT, starting at age 50 years, would increase breast cancer incidence at ages 50–69 years by about one in every 50 users of oestrogen plus daily progestagen preparations; one in every 70 users of oestrogen plus intermittent progestagen preparations; and one in every 200 users of oestrogen-only preparations. The corresponding excesses from 10 years of MHT would be about twice as great.FundingCancer Research UK and the Medical Research Council.

Aspects of radiation-induced lung cancer were evaluated in an international study of Hodgkin's disease. The study population consisted of 227 patients with lung cancer and 455 matched controls. Unique features included dose determinations to the specific location in the lung where each cancer developed and quantitative data on both chemotherapy and tobacco use obtained from medical records. The estimated excess relative risk (ERR) per Gy was 0.15 (95% CI: 0.06-0.39), and there was little evidence of departure from linearity even though lung doses for the majority of Hodgkin's disease patients treated with radiotherapy exceeded 30 Gy. The interaction of radiation and chemotherapy that included alkylating agents was almost exactly additive, and a multiplicative relationship could be rejected (P = 0.017). Conversely, the interaction of radiation and smoking was consistent with a multiplicative relationship, but not with an additive relationship (P < 0.001). The ERR/Gy for males was about four times that for females, although the difference was not statistically significant. There was little evidence of modification of the ERR/Gy by time since exposure (after a 5-year minimum latent period), age at exposure, or attained age. Because of the very high radiation doses received by Hodgkin's disease patients and the immunodeficiency inherent to this lymphoma and that associated with chemotherapy, generalizing these findings to other populations receiving considerably lower doses of radiation should be done cautiously.

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Funding Acknowledgements Type of funding sources: None. Background Long-term survivors of Hodgkin (HL) and non-Hodgkin (NHL) lymphomas experience late adverse effects of mediastinal radiotherapy and/or anthracycline containing chemotherapy, which lead to premature cardiovascular morbidity and mortality. It is unknown whether early stages of myocardial dysfunction and heart failure in these survivors can be detected by cardiovascular magnetic resonance imaging (CMR). Purpose To identify early sensitive markers for the detection of subclinical late cardiotoxicity using CMR in asymptomatic survivors of HL and (primary mediastinal large B-cell lymphoma) NHL. Methods For this prospective observational study, we included 80 HL or selected NHL survivors, who have been free of disease for ≥5 years and were treated with mediastinal radiotherapy (RT) with/without chemotherapy. Patients with known cardiac disease were excluded. Included patients were compared to 40 age- and sex matched healthy controls. CMR included 1) cine imaging for assessment of left ventricular (LV) and right ventricular (RV) dimensions, systolic function and strain; 2) 2-dimensional late gadolinium enhancement (LGE) imaging; 3) T2 mapping and 4) pre- and post-contrast T1 mapping (MOLLI) for assessment of native T1 values and extracellular volume (ECV). Results Of the 80 patients, 78 (98%) had a history of HL and 2 (2%) of NHL with a mean age of 47 ± 11 years (46% male). All patients were treated with mediastinal RT which was combined with anthracycline containing chemotherapy in 68 (85%) patients. The median interval between diagnosis and CMR was 20 [14 – 26] years. Differences in CMR characteristics between patients and healthy controls are shown in the table. LV end-systolic volume was statistically significantly higher, but LV ejection fraction and mass were significantly lower in patients compared to healthy controls. RV volumes were significantly lower in patients, but RV ejection fraction was preserved. Strain parameters of the LV, i.e. global longitudinal strain, global circumferential strain and global radial strain, were slightly but significantly reduced in patients. No significant differences were found in myocardial T2 times and ECV; however, native myocardial T1 time was significantly higher in patients compared to healthy controls. LGE was detected in 25% of the patients and in the majority of patients with LGE this was classified as hinge point fibrosis. Conclusion Asymptomatic survivors of HL and NHL are not exempt of late cardiotoxicity, which can be detected by subtle changes in LV myocardial function, strain and native T1 value with CMR. Furthermore, late gadolinium enhancement was present in 25% of the patients. Further longitudinal studies are needed to assess the implication of these changes in relation to clinical outcome.

Cardiovascular complications after therapy for Hodgkin lymphoma have been related to radiotherapy on the mediastinum, but have only incidentally been studied in NHL. As cardiovascular disease occurs commonly in the normal population, it is important to realize that risk factors as age, hypertension and life-style (diet and smoking) may be more outspoken in patients with NHL, who are generally older than patients with Hodgkin lymphoma. Moreover, although most patients with aggressive NHL will initially receive only chemotherapy, many will be treated with more than one therapy modality, incorporating stem cell transplantation or radiotherapy, because of early failure or relapses. Therefore, risk estimation of cardiovascular disease in NHL patients requires comparison to population-based rates. Here, we evaluated whether patients with aggressive NHL treated in 4 EORTC trials between 1980–1999 have an increased excess cardiovascular risk, compared to Dutch population rates. Relative risks (RR) and absolute excessive risks (AER per 1000 person-years) of cardiovascular disease were determined in 476 (Dutch and Belgian) patients and compared to incidence rates from the Continuous Morbidity Registry Nijmegen. Analyses were restricted to those patients treated with at least 6 cycles of doxorubicin-based chemotherapy and with a minimal follow-up time of 0.5 years. Only serious late events requiring daily medication and/or clinical interventions were recorded. Cumulative incidences of cardiovascular disease were estimated in the competing risk model by Gray with death by any cause as competing event. The overall cumulative incidence of cardiovascular disease was 12% at 5 and 22% at 10 years. At a median follow-up of 8.4 years, 66 cases of chronic heart failure (RR 5.4, 95% CI 4.1–6.9, AER 20.8), 17 myocardial infarctions (RR 1.2; 0.8–1.8, AER 0.8), 12 strokes (RR 1.8; 1.1–2.4, AER 1.5) and 9 other large vessel occlusions were registered. The large vascular events including strokes occurred in 16/21 patients after radiotherapy given in the same area. Pre-existent hypertension, NHL at young age (&lt;55 years) and (any) salvage treatment increased risk of cardiovascular disease. Excess risk for myocardial infarction or stroke after radiotherapy on respectively the mediastinum or neck depended on cumulative radiation dose and was only seen after more than 40 Gy. Excess risk for chronic heart failure was registerd in both non-irradiated (RR 4.4) and irradiated patients, with an extremely high RR of 32 (13.7–57.0) if &gt;40 Gy had been given. In conclusion, NHL patients treated with doxorubicin-based chemotherapy, especially those who are young, have hypertension, or received salvage treatment or radiotherapy above 40 Gy, are at high risk of cardiovascular disease and need lifelong monitoring in this regard.