Despite efforts to reduce the incidence of second cancer, the risk was not lower among 5-year survivors of Hodgkin's lymphoma in the Netherlands treated between 1989 and 2000, a period when more ...limited radiation fields and doses were used, than in earlier periods.
Since the late 1960s, when combination chemotherapy and high-energy radiation therapy were introduced for the treatment of Hodgkin’s lymphoma, survival has increased dramatically. Cure has come at a price, however, because the treatment of Hodgkin’s lymphoma has been shown to increase the risk of subsequent malignant neoplasms and other late effects considerably.
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Although very high relative risks have been observed for leukemia (especially among patients who were treated with alkylating agents) and non-Hodgkin’s lymphoma (which was not previously associated with a particular type of therapy), second solid cancers, the occurrence of which is related primarily to radiation therapy, contribute . . .
IMPORTANCE: Hodgkin lymphoma (HL) survivors are at increased risk of cardiovascular diseases. It is unclear, however, how long the increased risk persists and what the risk factors are for various ...cardiovascular diseases. OBJECTIVES: To examine relative and absolute excess risk up to 40 years since HL treatment compared with cardiovascular disease incidence in the general population and to study treatment-related risk factors for different cardiovascular diseases. DESIGN, SETTING, AND PARTICIPANTS: This retrospective cohort study included 2524 Dutch patients diagnosed as having HL at younger than 51 years (median age, 27.3 years) who had been treated from January 1, 1965, through December 31, 1995, and had survived for 5 years since their diagnosis. EXPOSURES: Treatment for HL, including prescribed mediastinal radiotherapy dose and anthracycline dose. MAIN OUTCOMES AND MEASURES: Data were collected from medical records and general practitioners. Cardiovascular events, including coronary heart disease (CHD), valvular heart disease (VHD), and cardiomyopathy and congestive heart failure (HF), were graded according to the Common Terminology Criteria for Adverse Events, version 4.0. RESULTS: After a median follow-up of 20 years, we identified 1713 cardiovascular events in 797 patients. After 35 years or more, patients still had a 4- to 6-fold increased standardized incidence ratio of CHD or HF compared with the general population, corresponding to 857 excess events per 10 000 person-years. Highest relative risks were seen in patients treated before 25 years of age, but substantial absolute excess risks were also observed for patients treated at older ages. Within the cohort, the 40-year cumulative incidence of cardiovascular diseases was 50% (95% CI, 47%-52%). Fifty-one percent of patients with a cardiovascular disease developed multiple events. For patients treated before 25 years of age, cumulative incidences at 60 years or older were 20%, 31%, and 11% for CHD, VHD, and HF as first events, respectively. Mediastinal radiotherapy increased the risks of CHD (hazard ratio HR, 2.7; 95% CI, 2.0-3.7), VHD (HR, 6.6; 95% CI, 4.0-10.8), and HF (HR, 2.7; 95% CI, 1.6-4.8), and anthracycline-containing chemotherapy increased the risks of VHD (HR, 1.5; 95% CI, 1.1-2.1) and HF (HR, 3.0; 95% CI, 1.9-4.7) as first events compared with patients not treated with mediastinal radiotherapy or anthracyclines, respectively. Joint effects of mediastinal radiotherapy, anthracyclines, and smoking appeared to be additive. CONCLUSIONS AND RELEVANCE: Throughout their lives, HL survivors treated at adolescence or adulthood are at high risk for various cardiovascular diseases. Physicians and patients should be aware of this persistently increased risk.
Cardiovascular diseases are increasingly recognized as late effects of Hodgkin lymphoma (HL) treatment. The purpose of this study was to identify the risk factors for coronary heart disease (CHD) and ...to quantify the effects of radiation dose to the heart, chemotherapy, and other cardiovascular risk factors.
We conducted a nested case-control study in a cohort of 2,617 5-year HL survivors, treated between 1965 and 1995. Cases were patients diagnosed with CHD as their first cardiovascular event after HL. Detailed treatment information was collected from medical records of 325 cases and 1,204 matched controls. Radiation charts and simulation radiographs were used to estimate in-field heart volume and mean heart dose (MHD). A risk factor questionnaire was sent to patients still alive.
The median interval between HL and CHD was 19.0 years. Risk of CHD increased linearly with increasing MHD (excess relative risk ERR) per Gray, 7.4%; 95% CI, 3.3% to 14.8%). This results in a 2.5-fold increased risk of CHD for patients receiving a MHD of 20 Gy from mediastinal radiotherapy, compared with patients not treated with mediastinal radiotherapy. ERRs seemed to decrease with each tertile of age at treatment (ERR/Gy(<27.5years), 20.0%; ERR/Gy(27.5-36.4years), 8.8%; ERR/Gy(36.5-50.9years), 4.2%; P(interaction) = .149). Having ≥ 1 classic CHD risk factor (diabetes mellitus, hypertension, or hypercholesterolemia) independently increased CHD risk (rate ratio, 1.5; 95% CI, 1.1 to 2.1). A high level of physical activity was associated with decreased CHD risk (rate ratio, 0.5; 95% CI, 0.3 to 0.8).
The linear radiation dose-response relationship identified can be used to predict CHD risk for future HL patients and survivors. Appropriate early management of CHD risk factors and stimulation of physical activity may reduce CHD risk in HL survivors.
Background Information on clinically verified stroke and transient ischemic attack (TIA) following Hodgkin lymphoma is scarce. We quantified the long-term risk of cerebrovascular disease associated ...with the use of radiotherapy and chemotherapy in survivors of Hodgkin lymphoma and explored potential pathogenic mechanisms. Methods We performed a retrospective cohort study among 2201 five-year survivors of Hodgkin lymphoma treated before age 51 between 1965 and 1995. We compared incidence rates of clinically verified stroke and TIA with those in the general population. We used multivariable Cox regression techniques to study treatment-related factors and other risk factors. All statistical tests were two-sided. Results After a median follow-up of 17.5 years, 96 patients developed cerebrovascular disease (55 strokes, 31 TIAs, and 10 with both TIA and stroke; median age = 52 years). Most ischemic events were from large-artery atherosclerosis (36%) or cardioembolisms (24%). The standardized incidence ratio for stroke was 2.2 (95% confidence interval CI = 1.7 to 2.8), and for TIA, it was 3.1 (95% CI = 2.2 to 4.2). The risks remained elevated, compared with those in the general population, after prolonged follow-up. The cumulative incidence of ischemic stroke or TIA 30 years after Hodgkin lymphoma treatment was 7% (95% CI = 5% to 8%). Radiation to the neck and mediastinum was an independent risk factor for ischemic cerebrovascular disease (hazard ratio = 2.5, 95% CI = 1.1 to 5.6 vs without radiotherapy). Treatment with chemotherapy was not associated with an increased risk. Hypertension, diabetes mellitus, and hypercholesterolemia were associated with the occurrence of ischemic cerebrovascular disease, whereas smoking and overweight were not. Conclusions Patients treated for Hodgkin lymphoma experience a substantially increased risk of stroke and TIA, associated with radiation to the neck and mediastinum. Physicians should consider appropriate risk-reducing strategies.
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.
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.
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).
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.
Recently, an increased risk of diabetes mellitus (DM) was observed after abdominal irradiation for childhood cancer. Because many Hodgkin lymphoma (HL) survivors have also been treated with ...infradiaphragmatic radiotherapy, we evaluated the association between HL treatment and DM risk.
Our study cohort comprised 2,264 5-year HL survivors, diagnosed before age 51 years and treated between 1965 and 1995. Treatment and follow-up information was collected from medical records and general practitioners. Radiation dosimetry was performed to estimate radiation dose to the pancreas. Cumulative incidence of DM was estimated, and risk factors for DM were evaluated by using Cox regression.
After a median follow-up of 21.5 years, 157 patients developed DM. Overall cumulative incidence of DM after 30 years was 8.3% (95% CI, 6.9% to 9.8%). After para-aortic radiation with ≥ 36 Gy, the 30-year cumulative incidence of DM was 14.2% (95% CI, 10.7% to 18.3%). Irradiation with ≥ 36 Gy to the para-aortic lymph nodes and spleen was associated with a 2.30-fold increased risk of DM (95% CI, 1.54- to 3.44-fold) whereas para-aortic radiation alone with ≥ 36 Gy was associated with a 1.82-fold increased risk (95% CI, 1.02- to 3.25-fold). Lower doses (10 to 35 Gy) did not significantly increase risk of DM. The risk of DM significantly increased with higher mean radiation doses to the pancreatic tail (P < .001).
Radiation to the para-aortic lymph nodes increases the risk of developing DM in 5-year HL survivors. Screening for DM should be considered in follow-up guidelines for HL survivors, and treating physicians should be alert to this increased risk.
Abstract
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.
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.
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.
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.
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 (
= 0.006). Prevalence of CACS > 90th percentile differed significantly: 17.1% in HL survivors vs. 4.6% in the matched population (
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,
= 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.
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.
Currently, preoperative radiotherapy for all soft-tissue sarcomas is identical at a 50-Gy dose level, which can be associated with morbidity, particularly wound complications. The observed clinical ...radiosensitivity of the myxoid liposarcoma subtype might offer the possibility to reduce morbidity.
To assess whether a dose reduction of preoperative radiotherapy for myxoid liposarcoma would result in comparable oncological outcome with less morbidity.
The Dose Reduction of Preoperative Radiotherapy in Myxoid Liposarcomas (DOREMY) trial is a prospective, single-group, phase 2 nonrandomized controlled trial being conducted in 9 tertiary sarcoma centers in Europe and the US. Participants include adults with nonmetastatic, biopsy-proven and translocation-confirmed myxoid liposarcoma of the extremity or trunk who were enrolled between November 24, 2010, and August 1, 2019. Data analyses, using both per-protocol and intention-to-treat approaches, were conducted from November 24, 2010, to January 31, 2020.
The experimental preoperative radiotherapy regimen consisted of 36 Gy in once-daily 2-Gy fractions, with subsequent definitive surgical resection after an interval of 4 or more weeks.
As a short-term evaluable surrogate for local control, the primary end point was centrally reviewed pathologic treatment response. The experimental regimen was regarded as a success when 70% or more of the resection specimens showed extensive treatment response, defined as 50% or greater of the tumor volume containing treatment effects. Morbidity outcomes consisted of wound complications and late toxic effects.
Among the 79 eligible patients, 44 (56%) were men and the median (interquartile range) age was 45 (39-56) years. Two patients did not undergo surgical resection because of intercurrent metastatic disease. Extensive pathological treatment response was observed in 70 of 77 patients (91%; posterior mean, 90.4%; 95% highest probability density interval, 83.8%-96.4%). The local control rate was 100%. The rate of wound complication requiring intervention was 17%, and the rate of grade 2 or higher toxic effects was 14%.
The findings of the DOREMY nonrandomized clinical trial suggest that deintensification of preoperative radiotherapy dose is effective and oncologically safe and is associated with less morbidity than historical controls, although differences in radiotherapy techniques and follow-up should be considered. A 36-Gy dose delivered in once-daily 2-Gy fractions is proposed as a dose-fractionation approach for myxoid liposarcoma, given that phase 3 trials are logistically impossible to execute in rare cancers.
ClinicalTrials.gov Identifier: NCT02106312.
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.
This retrospective study of perioperative radiotherapy in patients with primary extrameningeal solitary fibrous tumors suggests that combining radiotherapy with surgery in the management of this population significantly reduces the risk of local failures, especially in patients who have less favorable resection margins or tumors with a high mitotic count.
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