Abstract
Background:
Mediastinal radiation is associated with increased risk of myocardial infarction (MI) among non-Hodgkin lymphoma (NHL) survivors.
Objective:
To evaluate how pre-existing cardiovascular risk factors (CVRFs) modify the association of mediastinal radiation and MI among a national population of NHL survivors with a range of CVRFs.
Materials and Methods:
Using Danish registries, we identified adults diagnosed with lymphoma 2000-2010. We assessed MI from one year after diagnosis through 2016. We ascertained CVRFs (hypertension, dyslipidemia, and diabetes), vascular disease, and intrinsic heart disease prevalent at lymphoma diagnosis. We used multivariable Cox regression to test the interaction between pre-existing CVRFs and receipt of mediastinal radiation on subsequent MI.
Results:
Among 3151 NHL survivors (median age 63, median follow-up 6.5 years), 96 were diagnosed with MI. Before lymphoma, 32% of survivors had ≥1 CVRF. 8.5% of survivors received mediastinal radiation. In multivariable analysis, we found that mediastinal radiation (HR=1.96; 95% CI=1.09-3.52), and presence of ≥1 CVRF (HR=2.71; 95% CI=1.77-4.15) were associated with an increased risk of MI. Although there was no interaction on the relative scale (p=0.14), we saw a clinically relevant absolute increase in risk for patients with CVRF from 10-year of MI of 10.5% without radiation to 29.5% for those undergoing radiation.
Conclusion:
Patients with CVRFs have an importantly higher risk of subsequent MI if they have mediastinal radiation. Routine evaluation of CVRFs and optimal treatment of pre-existing cardiovascular disease should continue after receiving cancer therapy. In patients with CVRFs, mediastinal radiation should only be given if oncologic benefit clearly outweighs cardiovascular harm.
Keywords: Lymphoma, Cancer Survivorship, Cardiovascular Disease, Myocardial Infarction, Radiation Therapy
Background
Lymphoma survivors experience an increased risk of cardiovascular disease that may manifest long past treatment completion.1–7 Radiotherapy (RT) to the mediastinum, in particular, can damage the heart and surrounding vasculature.8–10 In survivors of lymphoma, mediastinal RT has been associated with an increased risks of atherosclerosis, cardiac ischemia, myocardial infarction (MI), and cardiovascular mortality.9,11–13
Traditional cardiovascular risk factors, including hypertension, dyslipidemia, and diabetes mellitus, independently contribute to the risk of MI among lymphoma survivors.2,14 Among childhood cancer survivors (including those diagnosed with lymphoma), hypertension ascertained in the years after treatment can heighten the cardiovascular risk incurred by radiation.15 Less is known about adults diagnosed with lymphoma who have a history of cardiovascular risk factors and whether cardiovascular risk factors interact with mediastinal RT to increase risk of MI. Our study aimed to understand whether traditional cardiovascular risk factors and mediastinal RT interact to heighten the risk of later MI in a large, national population of NHL survivors with a full range of cardiovascular risk factors.
Material and Methods
Data sources.
Using linked population registries to ascertain demographics, hospital discharges, outpatient prescriptions, and lymphoma diagnoses and treatments, we identified people diagnosed with aggressive non-Hodgkin lymphoma (NHL).16–18_ENREF_1019–21 These lymphomas are generally treated with curative intent; after treatment completion, survivors may be free of symptoms but still have an underlying risk of heart disease that could be mitigated with preventive efforts. We included patients diagnosed at age 15 or older with lymphoma between 2000 and 2010, followed from one year (“landmark” analysis) after diagnosis until December 2016, death, or migration from Denmark. We excluded patients who had a cancer other than lymphoma, who had an MI between diagnosis and the landmark, or who emigrated prior to the landmark. Additionally, patients with missing data on receipt of mediastinal RT were excluded.
Outcome ascertainment.
The primary outcome was MI after the landmark, diagnosed during inpatient or outpatient hospital visit or as cause of death using International Classification of Disease version 10 (ICD-10) codes for MI (I21, I21.0, I21.1, I21.2, I21.3, I21.4, I21.9, I22, I22.0, I22.1, I22.8, and I22.9). We conservatively opted for this acute cardiac outcome, rather than a more inclusive outcome of any cardiac ischemia, because MI is both clinically important and reliably ascertained in the data.
Pre-existing cardiovascular risk factors among lymphoma survivors.
Each patient was coded as having 0 or ≥1 cardiovascular risk factor – hypertension, dyslipidemia, and diabetes – diagnosed after 1994 but before diagnosis of lymphoma. Hypertension and dyslipidemia were ascertained using both the National Patient Register and, to improve sensitivity, the National Prescription Register. Hypertension was defined by the prescription of an anti-hypertensive, including calcium channel blocker, diuretics, angiotensin inhibitors, beta blockers, or alpha blockers. Dyslipidemia was defined by the receipt of statins. Diabetes was ascertained in the National Patient Register. We coded each patient as having 0, 1, or >1 risk factor at diagnosis of lymphoma.
Covariates.
Receipt of mediastinal RT (yes/no) was determined from the lymphoma registry (LYFO), and RT field was determined algorithmically based on site of treatment when possible. Missing RT data were abstracted from the medical record to the extent possible; because this was a variable of interest, those with missing RT data were excluded from the analysis. We assessed the presence of cardiovascular disease that was diagnosed prior to lymphoma diagnosis and after 1993 using the National Patient Register (see Appendix for ICD-8 and ICD-10 codes). Vascular disease included MI, coronary artery disease, stable and unstable angina, cardiac arrest, stroke, carotid artery disease, and transient ischemic attacks. Intrinsic heart disease included heart failure, pericardial disease, valvular disease, myocardial disease, and cardiomyopathy without clinical heart failure. We included date of birth and sex from the Central Population Register, and date of diagnosis and histology from LYFO.
Analysis:
Our primary analysis was conducted using a landmark analysis approach, with follow-up for MI starting 12 months after diagnosis. We chose this landmark a priori to conservatively reflect a time by which most patients will have completed first-line therapy or, in the setting of primary refractory disease in patients eligible for autologous stem cell transplantation, second-line therapy and subsequent consolidation. Survivors were censored at the date of emigration, new primary cancer diagnosis, lymphoma relapse, or death from any cause. Patients with no event were censored on December 31, 2016. Independent variables in the univariable and multivariable Cox regression analyses were selected a priori to capture a parsimonious set of important predictors of MI: history of any of three cardiovascular risk factors at lymphoma diagnosis, age at diagnosis (years), receipt of RT to the mediastinum, sex, stage, and history of vascular or intrinsic heart disease prior to lymphoma diagnosis. The hypothesized interaction effect of mediastinal RT and presence of cardiovascular risk factors on subsequent MI was tested in a univariable Cox regression modeling the association between MI and a four-level variable (± mediastinal RT and ± ≥1 cardiovascular risk factor), in addition to a multivariable model using a likelihood ratio test. To estimate differences in absolute risk of MI based on presence or absence of mediastinal RT and cardiovascular risk factors, we used the absolute 10-year risk of MI in the reference group (i.e., no cardiovascular risk factors and no mediastinal RT) and transformed the hazard ratio to the absolute scale (see supplementary materials). .
All statistical analyses were conducted using R software version 3.4.3 (R Core Development Team, Vienna, Austria), including the ‘survival’ package.
Results
Prior to the landmark, 1,288 patients died, 2 emigrated, and 15 developed a new cancer. Eighty people with missing radiation data were excluded. Among the remaining analytic cohort of 3,151 NHL survivors, 32% (N=1,002) had at least one cardiovascular risk factor (diabetes, hypertension, or dyslipidemia). (Table 1) The median follow-up time among those who did not develop MI was 6.5 years after the landmark. During follow-up of all survivors, 96 survivors had an MI. A model with a four-level variable indicating both mediastinal RT and cardiovascular risk factors showed a significant association of the presence of both mediastinal RT and ≥1 cardiovascular risk factor with later MI (P<0.001) (Table 2).
Table 1.
Patient, disease, and treatment characteristics. N=3151
| Characteristic | ||
|---|---|---|
| Age at diagnosis, Median (IQR) | 63 | (54, 72) |
| Sex, N (%) | ||
| Female | 1419 | (45) |
| Male | 1732 | (55) |
| Stage, N (%) | ||
| I | 915 | (30) |
| II | 550 | (18) |
| III | 656 | (21) |
| IV | 967 | (31) |
| Unknown | 63 | (2·0) |
| Diabetes, N (%) | 148 | (4·7) |
| Hypertension, N (%) | 678 | (22) |
| Dyslipidemia, N (%) | 362 | (11) |
| ≥1 cardiovascular risk factor, N (%) | 1002 | (32) |
| Vascular disease, N (%) | 315 | (10) |
| Intrinsic heart disease, N (%) | 148 | (4·7) |
| Received anthracyclines, N (%) | ||
| Yes | 2759 | (88) |
| No | 284 | (9·0) |
| Missing | 108 | (3·4) |
| Mediastinal RT, N (%) | 269 | (8·5) |
IQR = interquartile range
Table 2.
Univariable Cox regression results for associations of mediastinal RT and cardiovascular risk factors with MI.
| Mediastinal RT | # CV risk factors | HR (95% CI) | p-value |
|---|---|---|---|
| No | 0 | 1·00 | |
| No | ≥1 | 2·99 (1·94-4·62) | <0.001 |
| Yes | 0 | 0.95 (0·34-2.66) | 0.9 |
| Yes | ≥1 | 6.70 (3.25-13.82) | <0.001 |
RT= Radiation therapy, CV=Cardiovascular HR=Hazard ratio
The multivariable model including an interaction term between having any cardiovascular risk factor before lymphoma diagnosis and mediastinal RT indicated that the interaction term was not statistically significant (p = 0.14); therefore, the primary multivariable model did not contain this interaction term. In multivariable analysis, receipt of mediastinal RT was significantly associated with increased hazard of MI (HR: 1.96; 95% CI: 1.09-3.52), as was having at least one cardiovascular risk factor before lymphoma diagnosis (HR: 2.71, 95% CI: 1.77-4.15). (Table 3). Older age at diagnosis (HR: 1.05; 95% CI: 1.03-1.06) and having intrinsic heart disease before lymphoma diagnosis (HR: 2.88; 95% CI: 1.50-5.51) were significantly associated with increased hazard of MI, while being female was associated with reduced hazard of MI (HR: 0.58; 95% CI: 0.38-0.89).
Table 3.
Cox regression results for associations with MI.
| Univariable | Multivariable | |||
|---|---|---|---|---|
| HR (95% CI) | p-value | HR (95% CI) | p-value | |
| Age at diagnosis (years) | 1·05 (1·03-1·06) | <0·001 | 1·05 (1·03-1·06) | <0·001 |
| Female versus male sex | 0·67 (0·44-1·01) | 0·058 | 0·58 (0·38-0·89) | 0·013 |
| ≥1 cardiovascular risk factor | 3·33 (2·22-4·99) | <0·001 | 2·71 (1·77-4·15) | <0·001 |
| Vascular disease | 3·41 (2·12-5·51) | <0·001 | 1·30 (0·74-2·26) | 0·4 |
| Intrinsic heart disease | 4·52 (2·51-8·12) | <0·001 | 2·88 (1·50-5·51) | 0·001 |
| Mediastinal RT | 1·54 (0·86-2·76) | 0·15 | 1·96 (1·09-3·52) | 0·025 |
Note: RT=Radiation therapy; HR = hazard ratio; CI = confidence interval
The 10-year risk of MI was 2% among those without mediastinal RT and without cardiovascular risk factors. With this baseline risk, for a person with cardiovascular risk factors, receiving mediastinal RT is associated with a 4.9 percentage-point increase in the risk of an event (i.e. 10-year risk changes from 5.3% to 10.2%), which equates to one additional MI for every 20patients treated with radiation. (Table 4)
Table 4.
Predicted absolute 10-year risks of MI.
| Mediastinal RT | # CV risk factors | Predicted risk of MI |
|---|---|---|
| No | 0 | 2.0% |
| No | ≥1 | 5.3% |
| Yes | 0 | 3.9% |
| Yes | ≥1 | 10.2% |
RT= Radiation therapy, CV=Cardiovascular HR=Hazard ratio
Note. Using hazard ratios from the regression model (Table 3), the absolute 10-year risk of MI is shown for individuals with and without mediastinal RT and CV risk factors, based on the finding that those with neither mediastinal RT and no CV risk factors have a 10-year risk of MI of 2%
Discussion
In a large, registry-based analysis of lymphoma survivors receiving contemporary treatment, we found increased risk of an MI in patients with cardiovascular risk factors and in those undergoing mediastinal RT. Although we did not find evidence of an interaction on the relative scale, the additive effects on the absolute scale are of clinical relevance. The lack of interaction means that radiation is associated with a doubling of risk of MI, whether or not a patient has a cardiovascular risk factor. Because the baseline risk of MI is higher in patients with at least one cardiovascular risk factor, a doubling of risk is of greater clinical significance in this group.
Radiation-related atherosclerosis may increase over time, and most survivors in our study were followed for under ten years. Studies of mediastinal RT and MI in Hodgkin lymphoma typically demonstrate that elevated MI risk is apparent at approximately five to ten years after diagnosis, with increasing rates over time since treatment.22–25 This suggests that we may have underestimated the relative risk of mediastinal RT, underscoring our conclusion about the effect on patients with CVRFs.
Adults may already have important cardiovascular risk factors when they are diagnosed with lymphoma. Cardiovascular risk was prevalent in our study population; prior to lymphoma diagnosis, 32% had at least one risk factor, 10% had vascular disease, and 4.7% had intrinsic heart disease. Population-based cohorts such as this one are necessary to understand the impact of these important risk factors, as trials may exclude less healthy patients.
Only 77 survivors had at least one cardiovascular risk factor and received mediastinal RT, and power to detect an effect was further limited by the presence of only 9 MI events in this group. Larger cohorts of NHL survivors or cohorts with longer follow-up may reveal that RT administered to patients with prevalent cardiovascular risk factors is more detrimental to the heart. Interactions of cardiovascular risk factors and mediastinal RT have not been found in other studies of survivors treated as adults.
Cardiovascular risk factors are particularly relevant for adults diagnosed with NHL. To prevent MI among survivors, cardiovascular risk factors should be acknowledged in upfront treatment decisions. Similarly, post-treatment monitoring should address prevalent cardiovascular risk. Guidelines from the National Comprehensive Cancer Network for HL survivors recommend annual blood pressure monitoring and aggressive management of cardiovascular risk factors.26 Guidelines from the European Society for Medical Oncology (ESMO) recommend screening and monitoring along the same lines as other patients with a high risk of MI.27
Our study lacked information on lifestyle, including tobacco exposure and physical activity, which we partly address by including three well-defined conditions, partly associated with lifestyle. Ascertaining cardiovascular risk factors using prescription data may undercount diagnosed risk factors; to the extent risk factors are untreated, our estimates of the association with MI risk are likely conservative. Our complete case analysis excluded survivors with missing data on chest radiation, which may have introduced bias; however, there is little reason to expect that survivors with missing data were systematically more or less likely to have cardiovascular risk factors or MI. In addition, the relatively short follow-up time only allows for an investigation into the MI risk in the immediate years after end of treatment. The few MI events in this cohort limited the power to test the interaction between RT and cardiovascular risk factors in multivariable analyses. This study is also limited by the few patients receiving RT, and the lack of dose and 3D volumetric dose estimates to correlate with outcomes. When this cohort of patients underwent radiation therapy (2000-2010), the introduction of advanced imaging (notably PET), 3D planning techniques and individualized RT volumes (IRNT and ISRT) reduced the radiation field sizes. Additionally, standard doses were lowered from 40 Gy or more to 30 Gy. As these techniques continue to improve, cohorts of patients receiving lower doses to the heart will likely experience fewer myocardial infarctions resulting from mediastinal RT.28–31 Currently, however, there are no published studies of population-based cohorts of lymphoma patients who have these data available and that are followed long enough to detect later MI or other cardiovascular events. Despite the absence of detailed information about radiation dose to the heart, our study still found meaningful associations of receipt of mediastinal RT, as well as pre-existing cardiovascular risk factors, and later MI across a population-based cohort of lymphoma survivors.
Our population-based registry study investigated cardiovascular risk among a large cohort of NHL survivors, taking into account the risk of MI among a population with wide variation in age, receipt of mediastinal RT, and presence of pre-existing cardiovascular risk factors. As treatments improve for lymphoma, survivors are living longer, and reducing cardiovascular risk is critical. There are currently no guidelines for radiation-induced cardiac toxicity in lymphoma survivors. Given that pre-existing cardiovascular risk factors add further to the risk of MI, we suggest that routine evaluation and optimal treatment of pre-existing cardiovascular disease should be performed before, during, and after receiving radiation therapy. More specifically, for patients with CVRFs who are candidates for mediastinal RT, we recommend careful evaluation of the dose, field, and fractionation to offset the risk of MI. If the increase in cardiovascular risk appears to outweigh the decrease in oncologic risk, mediastinal RT may not be justified.
Supplementary Material
Sources of funding:
Leukemia & Lymphoma Society, National Institutes of Health, The Danish Cancer Society, and Danish Council for Independent Research.
Funding:
This work was supported by the Leukemia & Lymphoma Society as a Clinical Research Scholar Award (T.S.), National Institutes of Health grant under Grant R03 CA186223; The Danish Cancer Society; The Danish Council for Independent Research; and the National Institutes of Health under Cancer Center Support Grant P30 CA008748 (Memorial Sloan Kettering).
Disclosures:
Dr. Salz reports no conflicts of interest.
Dr. Zabor reports no conflicts of interest.
Dr. De Nully Brown reports personal fees from Novartis, personal fees from Incyte, and personal fees from Takeda, outside the submitted work.
Dr. Oksbjerg Dalton reports no conflicts of interest.
Dr. Raghunathan reports no conflicts of interest.
Dr. Matasar reports no conflicts of interest.
Dr. Steingart reports no conflicts of interest.
Dr. Hjalgrim reports no conflicts of interest.
Dr. Specht reports personal fees and non-financial support from Takeda, personal fees from MSD, non-financial support from Merck, personal fees from Kyowa Kirin, and grants from Varian, outside the submitted work.
Dr. Oeffinger reports no conflicts of interest.
Dr. Johansen reports no conflicts of interest.
Dr. Vickers has stock options in Opko and receives royalties from the sale of a prostate cancer test, the 4Kscore, marketed by Opko. These have no direct impact on the current paper.
Appendix. ICD-8 and ICD-10 codes for pre-existing cardiovascular diseases and risk factors
| Variable | Diagnosis | Codes |
|---|---|---|
| Vascular disease | Myocardial infarction (ICD-8) | 410, 410.09, 410.99, 411, 411.09, 411.99 |
| Myocardial infarction (ICD-10) | I21, I21.0, I21.1, I21.2, I21.3, I21.4, I21.9, I22, I22.0, I22.1, I22.8, I22.9 | |
| Coronary artery disease (ICD-8) | 412, 412.09, 412.99, 414, 414.09, 414.99 | |
| Coronary artery disease (ICD-10) | I25, I25.1, I25.2, I25.3, I25.4, I25.6, I25.8 | |
| Angina (ICD-8) | 413, 413.09, 413.99 | |
| Angina (ICD-10) | I20, I20.0, I20.1, I20.8, I20.9, I24, I24.0, I24.8, I24.9 | |
| Cardiac arrest (ICD-10) | I46, I46.0, I46.1, I46.9 | |
| Stroke (ICD-8) | 430, 430.08, 430.09, 431, 431.08, 431.09, 433, 433.09, 433.99, 434, 434.09, 434.99, 436.01, 436.9 | |
| Stroke (ICD-10) | G46, G46.0, G46.1, G46.2, G46.3, G46.4, G46.5, G46.6, G46.7, G46.8, I60.0, I60.1, I60.2, I60.3, I60.4, I60.5, I60.6, I60.7, I60.8, I60.9, I61, I61.0, I61.1, I61.2, I61.3, I61.4, I61.5, I61.6, I61.8, I61.9, I63, I63.0, I63.1, I63.2, I63.3, I63.4, I63.5, I63.6, I63.8, I63.9, I64 | |
| Carotid artery disease (ICD-8) | 432, 432.01, 432.02, 432.08, 432.09, 432.9, 432.91, 432.92, 432.98, 432.99 | |
| Carotid artery disease (ICD-10) | I65, I65.0, I65.1, I65.2, I65.8, I65.9, I66, I66.0, I66.1, I66.2, I66.3, I66.8, I66.9 | |
| Transient ischemic attack (ICD-8) | 435, 435.09, 435.99 | |
| Transient ischemic attack (ICD-10) | G45, G45.0, G45.1, G45.2, G45.3, G45.4, G45.8, G45.9 | |
| Intrinsic heart disease | Heart failure (ICD-8) | 427.09, 427.1, 427.11, 427.19, 428, 428.99, 782.49 |
| Heart failure (ICD-10) | I11.0, I13.0, I13.2, I50, I50.0, I50.1, I50.9 | |
| Pericardial disease (ICD-8) | 393, 393.01, 393.08, 393.09, 420, 420.08, 420.09, 423, 423.01, 423.02, 423.08, 423.09 | |
| Pericardial disease (ICD-10) | I30, I30.0, I30.8, I30.9, I31, I31.0, I31.1, I31.2, I31.3, I31.8, I31.9, I32 | |
| Valvular disease (ICD-8) | 394, 394.9, 394.91, 394.92, 394.98, 394.99, 395, 395.9, 395.91, 395.92, 395.98, 395.99, 396, 396.9, 396.91, 396.92, 396.93, 396.94, 396.98, 396.99, 397, 424, 424.01, 424.02, 424.08, 424.09, 424.1, 424.11, 424.12, 424.18, 424.19, 424.9, 424.91, 424.92, 424.99 | |
| Valvular disease (ICD-10) | I34, I34.0, I34.1, I34.2, I34.8, I34.9, I35, I35.0, I35.1, I35.2, I35.8, I35.9, I36, I36.0, I36.1, I36.2, I36.8, I36.9, I37, I37.0, I37.1, I37.2, I37.8, I37.9 | |
| Myocardial disease (ICD-8) | 422, 422.99 | |
| Myocardial disease (ICD-10) | I40, I40.1, I40.8, I40.9, I41, I41.8, I51.4 | |
| Cardiomyopathy (ICD-8) | 425, 425.99, 426, 426.08, 426.09, 427, 429, 429.08, 429.09, 426.00 | |
| Cardiomyopathy (ICD-10) | I25.5, I42, I42.0, I42.1, I42.2, I42.3, I42.4, I42.5, I42.7, I42.8, I42.9, I43, I43.8, I51.7 |
Contributor Information
Dr. Talya Salz, Department of Epidemiology and Biostatistics, Memorial Sloan Kettering Cancer Center, 485 Lexington Ave., 2nd Floor New York, NY 10017, USA.
Emily C. Zabor, Department of Quantitative Health Sciences & Taussig Cancer Institute, Cleveland Clinic 9500 Euclid Avenue, CA60, Cleveland, OH 44195, USA.
Peter De Nully Brown, Rigshospitalet, Department of Hematology, 9 Blegdamsvej 2100 Copenhagen, Denmark.
Susanne Oksbjerg Dalton, Survivorship, Danish Cancer Society Research Center, 49 Strandboulevarden; 2100 Copenhagen, Denmark.
Nirupa J. Raghunathan, Department of General Internal Medicine, Memorial Sloan Kettering Cancer Center, 1275 York Avenue, New York, NY 10065, USA.
Matthew J. Matasar, Memorial Sloan Kettering Cancer Center, 1275 York Avenue, New York, NY 10065, USA.
Richard Steingart, Cardiology Service, Department of Medicine, Memorial Sloan Kettering Cancer Center, 1275 York Avenue, New York, NY 10065, USA.
Henrik Hjalgrim, Statens Serum Institut, 5 Artillerivej, DK-2300 Copenhagen S.
Lena Specht, Dept. of Oncology, Section 3994, Rigshospitalet, University of Copenhagen, 9 Blegdamsvej, 2100 Copenhagen, Denmark.
Andrew J. Vickers, Department of Epidemiology and Biostatistics, Memorial Sloan Kettering Cancer Center, 485 Lexington Ave., 2nd Floor New York, NY 10017, USA.
Kevin C. Oeffinger, 2424 Erwin Dr, Suite 601, Duke Cancer Institute, Durham, NC 27705, USA.
Christoffer Johansen, CASTLE - Cancer Late Effect Research, Oncology Clinic, 9601, Center for Surgery and Cancer, Rigshospitalet, Blegdamsvej 58, 2100 Copenhagen, Denmark.
Data Availability Statement
Access to data in this manuscript are not possible due to GDPR regulations.
References
- 1.Andre M, Mounier N, Leleu X, et al. Second cancers and late toxicities after treatment of aggressive non-Hodgkin lymphoma with the ACVBP regimen: a GELA cohort study on 2837 patients. Blood 103:1222–8, 2004 [DOI] [PubMed] [Google Scholar]
- 2.Moser EC, Noordijk EM, van Leeuwen FE, et al. Long-term risk of cardiovascular disease after treatment for aggressive non-Hodgkin lymphoma. Blood 107:2912–9, 2006 [DOI] [PubMed] [Google Scholar]
- 3.Salz T, Zabor EC, de Nully Brown P, et al. Preexisting Cardiovascular Risk and Subsequent Heart Failure Among Non-Hodgkin Lymphoma Survivors. J Clin Oncol 35:3837–3843, 2017 [DOI] [PMC free article] [PubMed] [Google Scholar]
- 4.Kamel MG, El-Qushayri AE, Thach TQ, et al. Cardiovascular mortality trends in non-Hodgkin’s lymphoma: a population-based cohort study. Expert Rev Anticancer Ther 18:91–100, 2018 [DOI] [PubMed] [Google Scholar]
- 5.Abuamsha H, Kadri AN, Hernandez AV: Cardiovascular mortality among patients with non-Hodgkin lymphoma: Differences according to lymphoma subtype. Hematol Oncol 37:261–269, 2019 [DOI] [PubMed] [Google Scholar]
- 6.Zhao J, Su L, Zhong J: Risk Factors for Cancer-specific Mortality and Cardiovascular Mortality in Patients With Diffuse Large B-cell Lymphoma. Clin Lymphoma Myeloma Leuk 20:e858–e863, 2020 [DOI] [PubMed] [Google Scholar]
- 7.Thanarajasingam G, Minasian LM, Baron F, et al. Beyond maximum grade: modernising the assessment and reporting of adverse events in haematological malignancies. Lancet Haematol 5:e563–e598, 2018 [DOI] [PMC free article] [PubMed] [Google Scholar]
- 8.Jaworski C, Mariani JA, Wheeler G, et al. Cardiac complications of thoracic irradiation. J Am Coll Cardiol 61:2319–28, 2013 [DOI] [PubMed] [Google Scholar]
- 9.Gaya AM, Ashford RF: Cardiac complications of radiation therapy. Clin Oncol (R Coll Radiol) 17:153–9, 2005 [DOI] [PubMed] [Google Scholar]
- 10.Darby SC, Ewertz M, McGale P, et al. Risk of ischemic heart disease in women after radiotherapy for breast cancer. N Engl J Med 368:987–98, 2013 [DOI] [PubMed] [Google Scholar]
- 11.Boyne DJ, Mickle AT, Brenner DR, et al. Long-term risk of cardiovascular mortality in lymphoma survivors: A systematic review and meta-analysis. Cancer Med 7:4801–4813, 2018 [DOI] [PMC free article] [PubMed] [Google Scholar]
- 12.Vallerio P, Maloberti A, Palazzini M, et al. Thoracic radiotherapy as a risk factor for heart ischemia in subjects treated with chest irradiation and chemotherapy and without classic cardiovascular RISK factors. Radiother Oncol 152:146–150, 2020 [DOI] [PubMed] [Google Scholar]
- 13.Heidenreich PA, Hancock SL, Lee BK, et al. Asymptomatic cardiac disease following mediastinal irradiation. J Am Coll Cardiol 42:743–9, 2003 [DOI] [PubMed] [Google Scholar]
- 14.Armenian SH, Xu L, Ky B, et al. Cardiovascular Disease Among Survivors of Adult-Onset Cancer: A Community-Based Retrospective Cohort Study. J Clin Oncol, 2016 [DOI] [PMC free article] [PubMed] [Google Scholar]
- 15.Armstrong GT, Oeffinger KC, Chen Y, et al. Modifiable Risk Factors and Major Cardiac Events Among Adult Survivors of Childhood Cancer. Journal of Clinical Oncology 31:3673–80, 2013 [DOI] [PMC free article] [PubMed] [Google Scholar]
- 16.Pedersen CB: The Danish Civil Registration System. Scand J Public Health 39:22–5, 2011 [DOI] [PubMed] [Google Scholar]
- 17.Helweg-Larsen K: The Danish Register of Causes of Death. Scand J Public Health 39:26–9, 2011 [DOI] [PubMed] [Google Scholar]
- 18.Arboe B, El-Galaly TC, Clausen MR, et al. The Danish National Lymphoma Registry: Coverage and Data Quality. PLoS One 11:e0157999, 2016 [DOI] [PMC free article] [PubMed] [Google Scholar]
- 19.Lynge E, Sandegaard JL, Rebolj M: The Danish National Patient Register. Scand J Public Health 39:30–3, 2011 [DOI] [PubMed] [Google Scholar]
- 20.Dalton SO, Steding-Jessen M, Gislum M, et al. Social inequality and incidence of and survival from cancer in a population-based study in Denmark, 1994-2003: Background, aims, material and methods. Eur J Cancer 44:1938–49, 2008 [DOI] [PubMed] [Google Scholar]
- 21.Kildemoes HW, Sorensen HT, Hallas J: The Danish National Prescription Registry. Scand J Public Health 39:38–41, 2011 [DOI] [PubMed] [Google Scholar]
- 22.Ng AK: Review of the cardiac long-term effects of therapy for Hodgkin lymphoma. Br J Haematol 154:23–31, 2011 [DOI] [PubMed] [Google Scholar]
- 23.Reinders JG, Heijmen BJ, Olofsen-van Acht MJ, et al. Ischemic heart disease after mantlefield irradiation for Hodgkin’s disease in long-term follow-up. Radiother Oncol 51:35–42, 1999 [DOI] [PubMed] [Google Scholar]
- 24.Hancock SL, Tucker MA, Hoppe RT: Factors affecting late mortality from heart disease after treatment of Hodgkin’s disease. Jama 270:1949–55, 1993 [PubMed] [Google Scholar]
- 25.Adams MJ, Lipsitz SR, Colan SD, et al. Cardiovascular status in long-term survivors of Hodgkin’s disease treated with chest radiotherapy. Journal of Clinical Oncology 22:3139–3148, 2004 [DOI] [PubMed] [Google Scholar]
- 26.Hoppe RT, Advani RH, Ai WZ, et al. Hodgkin Lymphoma Version 1.2017, NCCN Clinical Practice Guidelines in Oncology. J Natl Compr Canc Netw 15:608–638, 2017 [DOI] [PubMed] [Google Scholar]
- 27.Curigliano G, Cardinale D, Suter T, et al. Cardiovascular toxicity induced by chemotherapy, targeted agents and radiotherapy: ESMO Clinical Practice Guidelines. Ann Oncol 23 Suppl 7:vii155–66, 2012 [DOI] [PubMed] [Google Scholar]
- 28.Hoppe BS, Bates JE, Mendenhall NP, et al. The Meaningless Meaning of Mean Heart Dose in Mediastinal Lymphoma in the Modern Radiation Therapy Era. Pract Radiat Oncol 10:e147–e154, 2020 [DOI] [PubMed] [Google Scholar]
- 29.Levis M, Filippi AR, Fiandra C, et al. Inclusion of heart substructures in the optimization process of volumetric modulated arc therapy techniques may reduce the risk of heart disease in Hodgkin’s lymphoma patients. Radiother Oncol 138:52–58, 2019 [DOI] [PubMed] [Google Scholar]
- 30.Lundgaard AY, Hjalgrim LL, Dejanovic D, et al. Relapse localization in Danish pediatric patients with Hodgkin lymphoma. Acta Oncol 60:658–666, 2021 [DOI] [PubMed] [Google Scholar]
- 31.Gillespie EF, Rodin D: Should We Contour Cardiac Substructures in Routine Practice? How Autosegmentation Helped Us Get There (or Not). International Journal of Radiation Oncology*Biology*Physics 112:633–635, 2022 [DOI] [PubMed] [Google Scholar]
Associated Data
This section collects any data citations, data availability statements, or supplementary materials included in this article.
Supplementary Materials
Data Availability Statement
Access to data in this manuscript are not possible due to GDPR regulations.