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Simple Summary: This study compares the presence of coronary artery calcium on coronary computed tomography angiography in relation to cardiovascular events between Hodgkin lymphoma (HL) survivors treated with thoracic radiotherapy and a matched non-cancer control group. HL survivors have a higher prevalence of coronary artery calcium more than ten years after irradiation. However, HL patients with a coronary artery calcium score of zero still have an increased risk of future cardiovascular events, possibly due to rapid progression of atherosclerosis in the coronary arteries following irradiation. Timely treatment with statins should be considered to prevent rapid acceleration of pre-existing atherosclerosis. Background: Thoracic radiotherapy is one of the corner stones of HL treatment, but it is associated with increased risk of cardiovascular events. As HL is often diagnosed at a young age, long-term follow-up including screening for coronary artery disease (CAD) is recommended. Objectives: This study aims to evaluate the presence of coronary artery calcium score (CACS) in relation to cardiovascular events in HL patients treated with thoracic radiotherapy compared to a non-cancer control group. Methods: Consecutive HL patients who underwent evaluation for asymptomatic CAD with coronary computed tomography angiography > 10 years after thoracic irradiation were included. The study population consisted of 97 HL patients matched to 97 non-cancer patients on gender, age, cardiovascular risk factors, and statin use. Results: Mean age during CT scan in the HL population was 45.5 ± 9.9 and in the non-cancer population 45.5 ± 10.3 years. CACS was elevated (defined as >0) in 49 (50.5%) HL patients and 30 (30.9%) control patients. HL survivors had an odds ratio of 2.28 [95% CI: 1.22–4.28] for having a CACS > 0 compared to the matched population (p = 0.006). Prevalence of CACS > 90th percentile differed significantly: 17.1% in HL survivors vs. 4.6% in the matched population (p = 0.009). Non-obstructive coronary artery stenosis was more prevalent in the HL population than in the control population (45.7% vs. 28.4%, respectively, p = 0.01). During follow-up of 8.5 [5.3; 9.9] years, nine HL patients experienced an event including two patients with a CACS of zero. No events occurred in the control population. Conclusion: In a matched study population, HL survivors have a higher prevalence of a CACS > 0 and an increased risk of cardiovascular events after thoracic irradiation compared to a matched non-cancer control group. [ABSTRACT FROM AUTHOR]

Studies have shown higher survival rates for patients with Hodgkin lymphoma (HL) treated within clinical trials compared to patients treated outside clinical trials. However, endpoints are often limited to overall survival (OS). In this retrospective cohort study, we investigated the effect of trial participation on OS, the incidence of relapse, second cancer, and cardiovascular disease (CVD). The study population consisted of patients with HL, aged between 14 and 51 years at diagnosis, who started their treatment between 1962 and 2002 at three Dutch cancer centres. Patients were either included in the EORTC Lymphoma Group trials (H1–H9) or treated according to standard guidelines at the time. After adjusting for differences in baseline characteristics, trial participation was associated with longer OS (median OS: 29.4 years [95%CI: 27.0–31.6] for treatment inside trials versus 27.4 years [95%CI: 26.0–28.5] for treatment outside trials, p =.046), a lower incidence of relapse (HR = 0.79, 95%CI: 0.63–0.98, p =.036) and a higher incidence of CVD (HR = 1.49, 95%CI: 1.23–1.79, p <.001). The trial effect for CVD was present only for patients treated before 1983. No evidence of differences in the incidence of second cancer was found. Consequently, essential results from clinical trials should be implemented into standard practice without undue delay. [ABSTRACT FROM AUTHOR]

Background: Hodgkin lymphoma (HL) survivors treated with chest radiotherapy have an increased risk of breast cancer (BC). Prior HL treatment and associated cardiovascular disease (CVD) risk may limit BC treatment options. It is unknown how treatment adaptations affect BC and CVD outcomes. Methods: The authors compared 195 BC patients treated with chest/axillary radiotherapy for HL (BC‐HL) with 5988 age‐ and calendar year‐matched patients with first primary BC (BC‐1). Analyses included cumulative incidence functions and Cox regression models, accounting for tumor characteristics and BC treatment. Results: Compared to BC‐1 patients, BC‐HL patients received anthracycline‐containing chemotherapy (23.7% vs. 43.8%, p <.001) and breast‐conserving surgery followed by radiotherapy (7.1% vs. 57.7%, p <.001) less often. BC treatment considerations were reported for 71% of BC‐HL patients. BC‐HL patients had a significantly higher risk of 15‐year overall mortality than BC‐1 patients (61% vs. 23%). Furthermore, risks of BC‐specific mortality and nonfatal BC events were significantly increased among BC‐HL patients, also when accounting for tumor and treatment characteristics (2.2‐ to 4.5‐fold). BC‐HL patients with a screen‐detected BC had a significantly reduced (61%) BC‐specific mortality. One‐third of BC‐HL patients had CVD at BC‐diagnosis, compared to <0.1% of BC‐1 patients. Fifteen‐year CVD‐specific mortality and CVD incidence were significantly higher in BC‐HL patients than in BC‐1 patients (15.2% vs. 0.4% and 40.4% vs. 6.8%, respectively), which was due to HL treatment rather than BC treatment. Conclusions: BC‐HL patients experience a higher burden of CVD and worse BC outcomes than BC‐1 patients. Clinicians should be aware of increased CVD risk when selecting BC treatment for HL survivors. Lay summary: Patients with breast cancer after Hodgkin lymphoma (BC‐HL) may have limited options for BC treatment, due to earlier HL treatment and an associated increased risk of cardiovascular disease (CVD).BC treatment considerations were reported for 71% of BC‐HL patients.We examined whether BC‐HL patients have a higher risk of CVD or BC events (recurrences/metastases) compared to patients with breast cancer that had no earlier tumors (BC‐1).We observed a higher burden of CVD and worse BC outcomes in HL patients compared to BC‐1 patients.Clinicians should be aware of increased CVD risk when selecting BC treatment for HL survivors. Hodgkin lymphoma survivors with radiation‐induced breast cancer experience a higher burden of cardiovascular disease and worse breast cancer outcomes than first primary breast cancer patients. Clinicians should be aware of increased cardiovascular disease risk when selecting breast cancer treatment for Hodgkin lymphoma survivors. [ABSTRACT FROM AUTHOR]

Simple Summary: Radiotherapeutic treatment in classic Hodgkin lymphoma (CHL) survivors contributes to long-term survival but is associated with lifetime increased risk of cardiovascular events. Echocardiographic screening for left ventricular (LV) dysfunction usually assesses left ventricular ejection fraction (LVEF). Global longitudinal strain (GLS) can detect early subclinical LV dysfunction. The aim of this study was to evaluate the association of conventional echocardiographic parameters and GLS in relation to cardiovascular events in CHL survivors treated with thoracic radiotherapy. Impaired GLS was associated with increased risk of cardiovascular events. In addition, conventional echocardiographic parameters, including LVEF and diastolic dysfunction also showed a significant association with cardiovascular events and cardiac death. Assessing LV strain by echocardiography can contribute to early detection of subclinical LV dysfunction and identifying CHL patients at increased risk for cardiovascular events. Background: Treatment with thoracic irradiation for classic Hodgkin lymphoma (CHL) leads to improved survival but also increases the risk of cardiovascular events. Left ventricular (LV) dysfunction is usually assessed by echocardiographic left ventricular ejection fraction (LVEF), whereas global longitudinal strain (GLS) can detect early subclinical LV dysfunction. The purpose of this study was to evaluate if conventional echocardiographic parameters and GLS are associated with cardiovascular events during long-term follow-up. Methods: 161 consecutive CHL patients treated with radiotherapy who underwent echocardiography > 10 years after diagnosis were assessed for eligibility. Multivariable cause-specific Cox regression was performed for a composite outcome of cardiac death and cardiovascular events and the competing outcome of noncardiac death. Results: 129 patients (61.2% female, N = 79) with a mean age of 46.3 ± 11.0 years at index visit were eligible for analysis. GLS was impaired in 51 patients (39.5%) and 10.9% had a LVEF of< 50%. The median E/e' was 9.2 [7.2;12.7]. Adjusted for confounders, GLS > −16% showed a significant association with a near four-fold risk of the composite endpoint (HR = 3.95, 95% CI: 1.83–8.52, p < 0.001). LVEF < 50% (HR = 2.99, p = 0.016) and E/e' (HR = 1.16, p < 0.001) also showed a significant relationship with the outcome. None of the aforementioned parameters were associated with the competing outcome. Conclusions: This study shows that LV dysfunction including impaired GLS in CHL survivors is associated with cardiovascular events and cardiac death. [ABSTRACT FROM AUTHOR]

Background: Few studies have examined the impact of treatment-related morbidity on long-term, cause-specific mortality in Hodgkin lymphoma (HL) patients.Methods: This multicenter cohort included 4919 HL patients, treated before age 51 years between 1965 and 2000, with a median follow-up of 20.2 years. Standardized mortality ratios, absolute excess mortality (AEM) per 10 000 person-years, and cause-specific cumulative mortality by stage and primary treatment, accounting for competing risks, were calculated.Results: HL patients experienced a 5.1-fold (AEM = 123 excess deaths per 10 000 person-years) higher risk of death due to causes other than HL. This risk remained increased in 40-year survivors (standardized mortality ratio = 5.2, 95% confidence interval [CI] = 4.2 to 6.5, AEM = 619). At age 54 years, HL survivors experienced similar cumulative mortality (20.0%) from causes other than HL to 71-year-old individuals from the general population. Whereas HL mortality statistically significantly decreased over the calendar period (P < .001), solid tumor mortality did not change in the most recent treatment era. Patients treated in 1989-2000 had lower 25-year cardiovascular disease mortality than patients treated in 1965-1976 (4.3% vs 5.7%; subdistribution hazard ratio = 0.65, 95% CI = 0.46 to 0.93). Infectious disease mortality was not only increased after splenectomy but also after spleen irradiation (hazard ratio = 2.81, 95% CI = 1.55 to 5.07). For stage I-II, primary treatment with chemotherapy (CT) alone was associated with statistically significantly higher HL mortality (P < .001 for CT vs radiotherapy [RT]; P = .04 for CT vs RT+CT) but lower 30-year mortality from causes other than HL (15.8%, 95% CI = 9.7% to 23.3%) compared with RT alone (36.9%, 95% CI = 34.0% to 39.8%, P = .001) and RT and CT combined (29.8%, 95% CI = 26.8% to 32.9%, P = .02).Conclusions: Compared with the general population, HL survivors have a substantially reduced life expectancy. Optimal selection of patients for primary CT is crucial, weighing risks of HL relapse and long-term toxicity. [ABSTRACT FROM AUTHOR]

Background: Solitary fibrous tumor (SFT) is a rare mesenchymal malignancy. Although surgery is potentially curative, the local relapse risk is high after marginal resections. Given the lack of prospective clinical trial data, the objective of the current study was to better define the role of perioperative radiotherapy (RT) in various SFT presentations by location.Methods: This was retrospective study performed across 7 sarcoma centers. Clinical information was retrieved from all adult patients with extrameningeal, primary, localized SFT who were treated between 1990 and 2018 with surgery alone (S) compared with those who also received perioperative RT (S+RT). Differences in treatment characteristics between subgroups were tested using analysis of variance statistics and propensity score matching. Local control and overall survival rates were calculated from the start of treatment until progression or death from any cause.Results: Of all 549 patients, 428 (78%) underwent S, and 121 (22%) underwent S+RT. The median follow-up was 52 months. After correction for mitotic count and surgical margins, S+RT was significantly associated with a lower risk of local progression (hazard ratio, 0.19: P = .029), an observation further confirmed by propensity score matching (P = .012); however, this association did not translate into an overall survival benefit.Conclusions: The results from this retrospective study investigating perioperative RT in patients with primary extrameningeal SFT suggest that combining RT with surgery in the management of this patient population is significantly associated with a reduced risk of local failures, especially in patients who have less favorable resection margins and in those who have tumors with a high mitotic count. [ABSTRACT FROM AUTHOR]

Background: Hodgkin lymphoma (HL) survivors have an increased risk of gastrointestinal (GI) cancer. This study aims to evaluate whether survival of patients who survived HL and developed GI cancer differs from survival of first primary GI cancer patients. Methods: Overall and cause‐specific survival of GI cancer patients in a HL survivor cohort (GI‐HL, N = 104, including esophageal, gastric, small intestinal, and colorectal cancer) was compared with survival of a first primary GI cancer patient cohort (GI‐1, N = 1025, generated by case matching based on tumor site, gender, age, and year of diagnosis). Cox proportional hazards regression was used for survival analyses. Multivariable analyses were adjusted for GI cancer stage, grade of differentiation, surgery, radiotherapy, and chemotherapy. Results: GI‐HL cancers were diagnosed at a median age of 54 years (interquartile range 45‐60). No differences in tumor stage or frequency of surgery were found. GI‐HL patients less often received radiotherapy (8% vs 23% in GI‐1 patients, P < 0.001) and chemotherapy (28% vs 41%, P = 0.01) for their GI tumor. Compared with GI‐1 patients, overall and disease‐specific survival of GI‐HL patients was worse (univariable hazard ratio (HR) 1.30, 95% confidence interval (CI) 1.03‐1.65, P = 0.03; and HR 1.29, 95% CI 1.00‐1.67, P = 0.049, respectively; multivariable HR 1.33, 95% CI 1.05‐1.68, P = 0.02; and HR 1.33, 95% CI 1.03‐1.72, P = 0.03, respectively). Conclusions: Long‐term overall and disease‐specific survival of GI cancer in HL survivors is worse compared with first primary GI cancer patients. Differences in tumor stage, grade of differentiation, or treatment could not explain this worse survival. Hodgkin lymphoma (HL) survivors have an increased risk of gastrointestinal (GI) cancer. This study evaluated whether survival of a cohort of 104 patients who survived HL and developed GI cancer differs from survival of a large population‐based cohort of first primary GI cancer patients. Long‐term overall and disease‐specific survival of GI cancer in HL survivors is worse compared with first primary GI cancer patients and this could not be explained by differences in tumor stage, grade of differentiation, or treatment. [ABSTRACT FROM AUTHOR]

Most testicular lymphomas are of diffuse large B-cell (DLBCL) type with an outcome inferior to nodal DLBCL. Within an apparently homogeneous group of testicular DLBCLs, small cell components, plasmacytoid differentiation and lymphoepithelial lesions (LELs), features of extranodal marginal zone lymphoma (eMZL), can be identified. The aim of this study was to define the histological features of testicular DLBCL and correlate this with their clinical behavior and outcome. Thirty-six patients with testicular DLBCL (Ann Arbor stage I/II) were identified through the databases of two Dutch regional cancer registries, diagnosed between 1981 and 1999. Follow-up for patients alive was more than 10 years. Medical records and pathology specimens were reviewed. eMZL features were found in 53% of the cases of localized stage testicular DLBCL. Compared to patients with 'pure' DLBCL, patients with DLBCL with eMZL features presented more often with stage I disease, normal lactate dehydrogenase, smaller tumors and absence of B-symptoms, and they responded more favorably to initial treatment. Their median survival was 48 months versus 12 months for 'pure' DLBCL ( p == 0.87). Features of eMZL were commonly identified in testicular DLBCL and they correlated with a more favorable clinical presentation and better response to initial therapy. However, these differences did not reach statistical significance due to small numbers. [ABSTRACT FROM AUTHOR]

The article presents the response of the authors to a reaction by D. L. Longo to their study on the increased risk of stroke and transient ischemic attack following Hodgkin lymphoma. Longo made a criticism on the use of radiotherapy in the treatment of Hodgkin lymphoma. Longo further mentioned that the effectivity of chemotherapy may be compared to combined modality treatment. The authors argue that Longo overestimated the effectivity of chemotherapy alone in the treatment and underestimated its toxicity.

Background: Hodgkin lymphoma (HL) survivors are at increased risk of 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 of 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. [ABSTRACT FROM AUTHOR]

Background: Survivors of Hodgkin's lymphoma are at increased risk for treatment-related subsequent malignant neoplasms. The effect of less toxic treatments, introduced in the late 1980s, on the long-term risk of a second cancer remains unknown.Methods: We enrolled 3905 persons in the Netherlands who had survived for at least 5 years after the initiation of treatment for Hodgkin's lymphoma. Patients had received treatment between 1965 and 2000, when they were 15 to 50 years of age. We compared the risk of a second cancer among these patients with the risk that was expected on the basis of cancer incidence in the general population. Treatment-specific risks were compared within the cohort.Results: With a median follow-up of 19.1 years, 1055 second cancers were diagnosed in 908 patients, resulting in a standardized incidence ratio (SIR) of 4.6 (95% confidence interval [CI], 4.3 to 4.9) in the study cohort as compared with the general population. The risk was still elevated 35 years or more after treatment (SIR, 3.9; 95% CI, 2.8 to 5.4), and the cumulative incidence of a second cancer in the study cohort at 40 years was 48.5% (95% CI, 45.4 to 51.5). The cumulative incidence of second solid cancers did not differ according to study period (1965-1976, 1977-1988, or 1989-2000) (P=0.71 for heterogeneity). Although the risk of breast cancer was lower among patients who were treated with supradiaphragmatic-field radiotherapy not including the axilla than among those who were exposed to mantle-field irradiation (hazard ratio, 0.37; 95% CI, 0.19 to 0.72), the risk of breast cancer was not lower among patients treated in the 1989-2000 study period than among those treated in the two earlier periods. A cumulative procarbazine dose of 4.3 g or more per square meter of body-surface area (which has been associated with premature menopause) was associated with a significantly lower risk of breast cancer (hazard ratio for the comparison with no chemotherapy, 0.57; 95% CI, 0.39 to 0.84) but a higher risk of gastrointestinal cancer (hazard ratio, 2.70; 95% CI, 1.69 to 4.30).Conclusions: The risk of second solid cancers did not appear to be lower among patients treated in the most recent calendar period studied (1989-2000) than among those treated in earlier periods. The awareness of an increased risk of second cancer remains crucial for survivors of Hodgkin's lymphoma. (Funded by the Dutch Cancer Society.). [ABSTRACT FROM AUTHOR]

We assessed risk, localization, and timing of third malignancies in Hodgkin lymphoma (HL) survivors. In a cohort of 3122 5-year HL survivors diagnosed before the age of 51 years and treated between 1965 and 1995, we examined whether risk factors for second and third malignancies differ and whether the occurrence of a second malignancy affects the risk of subsequent malignancies, using recurrent event analyses. After a median follow-up of 22.6 years, 832 patients developed a second malignancy and 126 patients a third one. The risk of a second malignancy was 4.7-fold increased (95% confidence interval [CI], 4.4-5.1) compared with risk in the general population; the risk for a third malignancy after a second malignancy was 5.4-fold (95% CI, 4.4-6.5) increased. The 10-year cumulative incidence of any third malignancy was 13.3%. Compared with patients still free of a second malignancy, patients with a second malignancy had a higher risk of developing subsequent malignancies. This risk depended on age, with hazard ratios of 2.2,1.6, and 1.1 for patients aged <25,25 to 34, and 35 to 50 years at HL treatment, respectively. In HL survivors who had a second malignancy, treating physicians should be aware of the increased risk of subsequent malignancies. [ABSTRACT FROM AUTHOR]

Purpose: Previous efforts to predict absolute risk of treatment-related cardiovascular diseases (CVDs) have mostly focused on childhood cancer survivors. We aimed to develop prediction models for risk of coronary heart disease (CHD) and heart failure (HF) for survivors of adolescent/adult Hodgkin lymphoma (HL)., Methods: For model development, we used a multicenter cohort including 1,433 5-year HL survivors treated between 1965 and 2000 and age 18-50 years at HL diagnosis, with complete data on administered chemotherapy regimens, radiotherapy volumes and doses, and cardiovascular follow-up. Using cause-specific hazard models, covariate-adjusted cumulative incidences for CHD and HF were estimated in the presence of competing risks of death because of other causes than CHD and HF. Age at HL diagnosis, sex, smoking status, radiotherapy, and anthracycline treatment were included as predictors. External validation for the CHD model was performed using a Canadian cohort of 708 HL survivors treated between 1988 and 2004 and age 18-50 years at HL diagnosis., Results: After a median follow-up of 24 years, 341 survivors had developed CHD and 102 had HF. We were able to predict CHD and HF risk at 20 and 30 years after treatment with moderate to good overall calibration and moderate discrimination (areas under the curve: 0.68-0.74), which was confirmed by external validation for the CHD model (areas under the curve: 0.73-0.74). On the basis of our model including prescribed mediastinal radiation dose, 30-year risks ranged from 4% to 78% for CHD and 3% to 46% for HF, depending on risk factors., Conclusion: We developed and validated prediction models for CHD and HF with good overall calibration and moderate discrimination. These models can be used to identify HL survivors who might benefit from targeted screening for CVD and early treatment for CVD risk factors.

Background: Due to its specific physical characteristics, proton irradiation is especially suited for irradiation of chordomas and chondrosarcoma in the axial skeleton. Robust plan optimization renders the proton beam therapy more predictable upon individual setup errors. Reported experience with the planning and delivery of robustly optimized plans in chordoma and chondrosarcoma of the mobile spine and sacrum, is limited. In this study, we report on the clinical use of robustly optimized, intensity modulated proton beam therapy in these patients., Methods: We retrospectively reviewed patient, treatment and acute toxicity data of all patients with chordoma and chondrosarcoma of the mobile spine and sacrum, treated between 1 April 2019 and 1 April 2020 at our institute. Anatomy changes during treatment were evaluated by weekly cone-beam CTs (CBCT), supplemented by scheduled control-CTs or ad-hoc control-CTs. Acute toxicity was scored weekly during treatment and at 3 months after therapy according to CTCAE 4.0., Results: 17 chordoma and 3 chondrosarcoma patients were included. Coverage of the high dose clinical target volume was 99.8% (range 56.1-100%) in the nominal and 80.9% (range 14.3-99.6%) in the voxel-wise minimum dose distribution. Treatment plan adaptation was needed in 5 out of 22 (22.7%) plans. Reasons for plan adaptation were either reduced tumor coverage or increased dose to the OAR., Conclusions: Robustly optimized intensity modulated proton beam therapy for chordoma and chondrosarcoma of the mobile spine is feasible. Plan adaptations due to anatomical changes were required in approximately 23 percent of treatment courses., Competing Interests: Conflict of interest statement None of the authors on this manuscript have any conflict of interest to declare., (Copyright © 2021 The Authors. Published by Elsevier B.V. All rights reserved.)

Background: Thoracic irradiation is one of the cornerstones of Hodgkin lymphoma (HL) treatment, which contributes to high rates of long-term survivorship, but begets a life-long increased risk of heart disease including heart failure. At the cardio-oncology (CO) clinic, persistent sinus tachycardia or elevated resting heart rate (RHR) is frequently observed in these patients. The aim of this study was to evaluate the relation between RHR and left ventricular (LV) dysfunction., Methods: In 75 HL survivors visiting our CO-clinic echocardiographic evaluation of LV systolic and diastolic function including global longitudinal strain (GLS) was performed to assess subclinical LV dysfunction., Results: Median age of HL diagnosis was 24 [25th-75th percentile: [19], [29]] years with a 17 [12], [25] year interval to CO-clinic visit and 31 patients (41%) were male. Average RHR was 78 ± 14 bpm and 40% of patients (N = 30) had an elevated RHR defined as ≥ 80 bpm. While there was no difference in LV ejection fraction (55.6 ± 4.3 vs . 54.8 ± 6.6; p  = 0.543), patients with elevated RHR had abnormal GLS (-15.9% vs . -18.3%, p  = 0.045) and higher prevalence of diastolic dysfunction (73.3% vs . 46.7%; p  = 0.022). GLS, E/e' ratio and presence of diastolic dysfunction were independently associated with RHR when correcting for age, sex and mantle field irradiation. A significant improvement was observed of the RHR-association model with solely extracardiac confounders when LV-function parameters were added to the model (F-statistic = 6.36, p  = 0.003)., Conclusions: This study indicates RHR as a possible marker for subclinical LV-dysfunction in HL survivors., (© 2021 The Authors.)

Background: Few studies have examined the impact of treatment-related morbidity on long-term, cause-specific mortality in Hodgkin lymphoma (HL) patients., Methods: This multicenter cohort included 4919 HL patients, treated before age 51 years between 1965 and 2000, with a median follow-up of 20.2 years. Standardized mortality ratios, absolute excess mortality (AEM) per 10 000 person-years, and cause-specific cumulative mortality by stage and primary treatment, accounting for competing risks, were calculated., Results: HL patients experienced a 5.1-fold (AEM = 123 excess deaths per 10 000 person-years) higher risk of death due to causes other than HL. This risk remained increased in 40-year survivors (standardized mortality ratio = 5.2, 95% confidence interval [CI] = 4.2 to 6.5, AEM = 619). At age 54 years, HL survivors experienced similar cumulative mortality (20.0%) from causes other than HL to 71-year-old individuals from the general population. Whereas HL mortality statistically significantly decreased over the calendar period (P < .001), solid tumor mortality did not change in the most recent treatment era. Patients treated in 1989-2000 had lower 25-year cardiovascular disease mortality than patients treated in 1965-1976 (4.3% vs 5.7%; subdistribution hazard ratio = 0.65, 95% CI = 0.46 to 0.93). Infectious disease mortality was not only increased after splenectomy but also after spleen irradiation (hazard ratio = 2.81, 95% CI = 1.55 to 5.07). For stage I-II, primary treatment with chemotherapy (CT) alone was associated with statistically significantly higher HL mortality (P < .001 for CT vs radiotherapy [RT]; P = .04 for CT vs RT+CT) but lower 30-year mortality from causes other than HL (15.8%, 95% CI = 9.7% to 23.3%) compared with RT alone (36.9%, 95% CI = 34.0% to 39.8%, P = .001) and RT and CT combined (29.8%, 95% CI = 26.8% to 32.9%, P = .02)., Conclusions: Compared with the general population, HL survivors have a substantially reduced life expectancy. Optimal selection of patients for primary CT is crucial, weighing risks of HL relapse and long-term toxicity., (© The Author(s) 2020. Published by Oxford University Press.)

Knowledge of imaging findings related to therapy administered to patients with sarcoma is pivotal in selecting appropriate care for these patients. Imaging studies are performed as surveillance in asymptomatic patients or because symptoms, including anxiety, develop. In addition to detection of recurrent disease and assessment of response to therapy, diagnosis of conditions related to therapy that may or may not need treatment has a marked positive impact on quality of life. The purpose of this review is to assist radiologists, nuclear physicians, and others clinicians involved in the diagnosis and treatment of these patients in recognizing imaging findings related to therapy and not to activity of the previously treated sarcoma. Imaging findings are time dependent and often specific in relation to therapy given., Competing Interests: Disclosure The authors report no conflicts of interest in this work., (Thieme. All rights reserved.)

Female Hodgkin lymphoma (HL) patients treated with chest radiotherapy (RT) have a very high risk of breast cancer. The contribution of genetic factors to this risk is unclear. We therefore examined 211 155 germline single-nucleotide polymorphisms (SNPs) for gene-radiation interaction on breast cancer risk in a case-only analysis including 327 breast cancer patients after chest RT for HL and 4671 first primary breast cancer patients. Nine SNPs showed statistically significant interaction with RT on breast cancer risk (false discovery rate, <20%), of which 1 SNP in the PVT1 oncogene attained the Bonferroni threshold for statistical significance. A polygenic risk score (PRS) composed of these SNPs (RT-interaction-PRS) and a previously published breast cancer PRS (BC-PRS) derived in the general population were evaluated in a case-control analysis comprising the 327 chest-irradiated HL patients with breast cancer and 491 chest-irradiated HL patients without breast cancer. Patients in the highest tertile of the RT-interaction-PRS had a 1.6-fold higher breast cancer risk than those in the lowest tertile. Remarkably, we observed a fourfold increased RT-induced breast cancer risk in the highest compared with the lowest decile of the BC-PRS. On a continuous scale, breast cancer risk increased 1.4-fold per standard deviation of the BC-PRS, similar to the effect size found in the general population. This study demonstrates that genetic factors influence breast cancer risk after chest RT for HL. Given the high absolute breast cancer risk in radiation-exposed women, these results can have important implications for the management of current HL survivors and future patients., (© 2019 by The American Society of Hematology.)

Background and Purpose: The impact of treatment accuracy on NTCP-based patient selection for proton therapy is currently unknown. This study investigates this impact for oropharyngeal cancer patients., Materials and Methods: Data of 78 patients was used to automatically generate treatment plans for a simultaneously integrated boost prescribing 70 Gy RBE /54.25 Gy RBE in 35 fractions. IMRT treatment plans were generated with three different margins; intensity modulated proton therapy (IMPT) plans for five different setup and range robustness settings. Four NTCP models were evaluated. Patients were selected for proton therapy if NTCP reduction was ≥10% or ≥5% for grade II or III complications, respectively., Results: The degree of robustness had little impact on patient selection for tube feeding dependence, while the margin had. For other complications the impact of the robustness setting was noticeably higher. For high-precision IMRT (3 mm margin) and high-precision IMPT (3 mm setup/3% range error), most patients were selected for proton therapy based on problems swallowing solid food (51.3%) followed by tube feeding dependence (37.2%), decreased parotid flow (29.5%), and patient-rated xerostomia (7.7%)., Conclusions: Treatment accuracy has a significant impact on the number of patients selected for proton therapy. Therefore, it cannot be ignored in estimating the number of patients for proton therapy., (Copyright © 2017 The Authors. Published by Elsevier B.V. All rights reserved.)

Background: Young women treated with chest radiation therapy (RT) for Hodgkin lymphoma (HL) experience a strongly increased risk of breast cancer (BC). It is unknown whether endogenous and exogenous gonadal hormones affect RT-associated BC risk., Methods: We conducted a nested case-control study among female 5-year HL survivors treated before age 41. Hormone exposure and HL treatment data were collected through medical records and questionnaires for 174 BC case patients and 466 control patients. Radiation dose to breast tumor location was estimated based on RT charts, simulation films, and mammography reports., Results: We observed a linear radiation dose-response curve with an adjusted excess odds ratio (EOR) of 6.1%/Gy (95% confidence interval [CI]: 2.1%-15.4%). Women with menopause <30 years (caused by high-dose procarbazine or pelvic RT) had a lower BC risk (OR, 0.13; 95% CI, 0.03-0.51) than did women with menopause ≥50 years. BC risk increased by 6.4% per additional year of post-RT intact ovarian function (P<.001). Among women with early menopause (<45 years), hormone replacement therapy (HRT) use for ≥2 years did not increase BC risk (OR, 0.86; 95% CI, 0.32-2.32), whereas this risk was nonsignificantly increased among women without early menopause (OR, 3.69; 95% CI, 0.97-14.0; P for interaction: .06). Stratification by duration of post-RT intact ovarian function or HRT use did not statistically significantly modify the radiation dose-response curve., Conclusions: BC risk in female HL survivors increases linearly with radiation dose. HRT does not appear to increase BC risk for HL survivors with therapy-induced early menopause. There are no indications that endogenous and exogenous gonadal hormones affect the radiation dose-response relationship., (Copyright © 2017 Elsevier Inc. All rights reserved.)

Introduction: Sexual function is an important aspect of quality of life, and may be impaired after (pelvic) radiation., Aim: The aim of this study was to identify practice, responsibility attitudes, knowledge, and barriers of Dutch radiation oncologists regarding sexual counseling., Methods: A cross-sectional survey was performed using a 28-item questionnaire sent to all members of the Dutch Society for Radiotherapy and Oncology., Main Outcome Measures: Self-reported practice, knowledge, barriers, need for training and responsibility attitudes in regard to demographic characteristics., Results: Of the surveyed sample, 54.6% of the radiation oncologists completed the instrument (n = 119). Frequency of discussing sexual function was fluctuating, depending on the type of tumor. The majority of the responding radiation oncologists (75%) agreed that discussing sexual function is their responsibility, about one-third (33.6%) pointed at the involved specialist (surgeon, urologist, gynecologist, or oncologist), a fifth also considered the general practitioner responsible (21%). Additional training about discussing sexuality was required according to 44.4%, the majority agreed that sexual counseling should be a regular component of radiation oncology residency (n = 110, 94%). Barriers most mentioned included patient is too ill (36.2%), no angle or reason for asking (32.4%), advanced age of the patient (27%) and culture/religion (26.1%). For prostate cancer patients, phosphodiesterase 5 inhibitor information was supplied regularly (49.2%) and often (40.7%)., Conclusions: Radiation oncologists generally perform sexual counseling in case of pelvic radiation therapy, but not consistently in case of gastrointestinal, breast, and other cancers. The majority of radiation oncologists considered counseling on sexual functioning as a part of their job, some also pointed at the referring specialist or general practitioner. The findings suggest that awareness about sexual dysfunction is present among radiation oncologists, but responsibility for active counseling is uncertain. Results emphasize the need for providing educational and practical training, as well as a list for specialized referral., (© 2015 International Society for Sexual Medicine.)

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 25-42 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., (Copyright © 2015 Elsevier Inc. All rights reserved.)

Background: Hodgkin lymphoma (HL) survivors are at increased risk of 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 of 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., (© The Author 2015. Published by Oxford University Press.)

Purpose: Survivors of Hodgkin's lymphoma (HL) are at risk of secondary tumors. We investigated the risk of secondary skin cancers after radiotherapy compared to treatment without radiation and to an age-matched population., Material and Methods: We conducted a retrospective cohort study of 889 HL patients treated between 1965 and 2005. Data on secondary skin cancers and treatment fields were retrieved. Incidence rates were compared to observed rates in the Dutch population., Results: 318 skin cancers were diagnosed in 86 patients, showing significantly higher risks of skin cancers, the majority being BCC. The standardized incidence ratio (SIR) of BCC in HL survivors was significantly increased (SIR 5.2, 95% CI 4.0-6.6), especially in those aged <35 years at diagnosis (SIR 8.0, 95% CI 5.8-10.7). SIR increased with longer follow-up to 15.9 (95% CI 9.1-25.9) after 35 years, with 626 excess cases per 10,000 patients per year. Most (57%) skin cancers developed within the radiation fields, with significantly increased risk in patients treated with radiotherapy compared to chemotherapy alone (p=0·047, HR 2·75, 95% CI 1·01-7.45)., Conclusion: Radiotherapy for HL is associated with a strongly increased long-term risk of secondary skin cancers, both compared to the general population and to treatment with chemotherapy alone., (Copyright © 2013 Elsevier Ireland Ltd. All rights reserved.)

Study Design: A cross-sectional study., Objective: The purpose of this report is to define the role of postoperative radiotherapy in the prevention of local recurrence (LR)., Summary of Background Data: Sacrococcygeal chordoma is a slow growing, malignant tumor with a clinical poor outcome due to a high LR rate. Several studies emphasize that margin-free tumor resection is the most important predictor of LR. However, even after extralesional resection a high LR up to 80% remains., Methods: A retrospective series of 15 patients who underwent surgical treatment for sacrococcygeal chordoma in one center between 1981 and 2003 was reviewed. Overall survival and continuous disease-free survival rates were compared between patients with intralesional resection with standard radiotherapy and patients with extralesional resection and no standard radiotherapy., Results: The median age at surgery was 53 years. The mean follow-up was 7 years or until death. Mean duration of preoperative complaints was 3 years. In 10 patients, an en bloc resection was (histologic resection margins were free) performed and in 5 patients, an intralesional resection was achieved. All but one patients with intralesional resection received radiotherapy (>50 Gy) and patients with extralesional resection only received radiotherapy in case of LR (6 of 10 patients). After extralesional resection (no initial radiotherapy), all 10 patients had LR of the tumor with a mean time to recurrence of 2 years. Six of these ten patients received radiotherapy after LR and had mean survival duration of 7 years. Only one (of five patients) in the group with intralesional resection and postoperative radiotherapy had LR after 11 years. The time to recurrence was significantly longer and we found a trend toward a longer overall survival in the group that received immediate radiotherapy after surgery., Conclusion: The results support the strategy to add radiotherapy as standard adjuvant therapy to sacrococcygeal chordoma tumor resection.

Purpose: In early-stage Hodgkin's lymphoma (HL), subtotal nodal irradiation (STNI) and combined chemotherapy/radiotherapy produce high disease control rates but also considerable late toxicity. The aim of this study was to reduce this toxicity using a combination of low-intensity chemotherapy and involved-field radiotherapy (IF-RT) without jeopardizing disease control., Patients and Methods: Patients with stage I or II HL were stratified into two groups, favorable and unfavorable, based on the following four prognostic factors: age, symptoms, number of involved areas, and mediastinal-thoracic ratio. The experimental therapy consisted of six cycles of epirubicin, bleomycin, vinblastine, and prednisone (EBVP) followed by IF-RT. It was randomly compared, in favorable patients, to STNI and, in unfavorable patients, to six cycles of mechlorethamine, vincristine, procarbazine, prednisone, doxorubicin, bleomycin, and vinblastine (MOPP/ABV hybrid) and IF-RT., Results: Median follow-up time of the 722 patients included was 9 years. In 333 favorable patients, the 10-year event-free survival rates (EFS) were 88% in the EBVP arm and 78% in the STNI arm (P = .0113), with similar 10-year overall survival (OS) rates (92% v 92%, respectively; P = .79). In 389 unfavorable patients, the 10-year EFS rate was 88% in the MOPP/ABV arm compared with 68% in the EBVP arm (P < .001), leading to 10-year OS rates of 87% and 79%, respectively (P = .0175)., Conclusion: A treatment strategy for early-stage HL based on prognostic factors leads to high OS rates in both favorable and unfavorable patients. In favorable patients, the combination of EBVP and IF-RT can replace STNI as standard treatment. In unfavorable patients, EBVP is significantly less efficient than MOPP/ABV.