Estimated risk of cardiovascular disease and secondary cancers with modern highly conformal radiotherapy for early-stage mediastinal Hodgkin lymphoma

Maraldo, M.V.; Brodin, N. Patrik; Aznar, Marianne C.; Vogelius, I.R.; Rosenschöld, Per Munck af; Petersen, Peter Meidahl; Specht, Lena

doi:10.1093/annonc/mdt156

Cited by 127 publications

(78 citation statements)

References 24 publications

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“…Our PBS plan employed a single anterior field for each patient, while anterior-posterior opposed PBS fields were used in other studies [4,17]. As ML targets usually are anterior and tend to be shallow, posterior PBS fields may unnecessarily increase heart dose.…”

Section: Discussionmentioning

confidence: 99%

“…1.8 Gy(RBE)/fx. The PBS plan employed a single anterior field for each patient, which was in contrast to opposed PBS fields modeled in other studies [4,17]. The treatment planning system (TPS) Eclipse 11.0 (Varian Medical System) was used.…”

Section: Treatment Planningmentioning

confidence: 99%

“…Although PBS has been the most advanced delivery method of proton therapy for two decades, previous reports of proton therapy on lymphoma have been limited to passive scattering, with the exception of several dosimetric study on PBS (e.g. [3,4]) which did not actually treat patients with PBS. Due to its time structure, beam scanning is more susceptible to intra-fractional motion when compared with passive scattering [5].…”

Section: Introductionmentioning

confidence: 99%

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Proton pencil beam scanning for mediastinal lymphoma: treatment planning and robustness assessment

et al. 2016

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Background: Modern radiotherapy (RT) for lymphoma is highly personalized. While advanced imaging is largely employed to define limited treatment volumes, the use of proton pencil beam scanning (PBS) for highly conformal lymphoma RT is still in its infancy. Here, we assess the dosimetric benefits and feasibility of PBS for mediastinal lymphoma (ML). Materials and methods: Ten patients were planned using PBS for involved-site RT. The initial plans were calculated on the average four-dimensional computed tomography (4D-CT). PBS plans were compared with 3D conformal radiotherapy (3D-CRT), intensity-modulated radiotherapy (IMRT), and proton double scattering (DS). In order to evaluate the feasibility of PBS and the plan robustness against interand intra-fractional uncertainties, the 4D dose was calculated on initial and verification CTs. The deviation of planned dose from delivered dose was measured. The same proton beamline was used for all patients, while another beamline with larger spots was employed for patients with large motion perpendicular to the beam. Results: PBS provided the lowest mean lung dose (MLD) and mean heart dose (MHD) for all patients in comparison with 3D-CRT, IMRT, and DS. For eight patients, internal target volume (ITV) D 98% was degraded by <3%; and the MLD and MHD deviated by <10% of prescription over the course of treatment when the PBS field was painted twice in each session. For one patient with target motion perpendicular to the beam (>5 mm), the degradation of ITV D 98% was 9%, which was effectively mitigated by employing large spots. One patient exhibited large dose degradation due to pericardial effusion, which required replanning across all modalities. Conclusions: This study demonstrates that PBS plans significantly reduce MLD and MHD relative to 3D-CRT, IMRT, and DS and identifies requirements for robust free-breathing ML PBS treatments, showing that PBS plan robustness can be maintained with repainting and/or large spots.

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Section: Discussionmentioning

confidence: 99%

Section: Treatment Planningmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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Proton pencil beam scanning for mediastinal lymphoma: treatment planning and robustness assessment

et al. 2016

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“…For breast cancer, it has been shown that smaller radiation volumes than mantle field are associated with substantially lower risk, 9,26,28 which is important in view of the smaller field sizes currently used in HL treatment. 9,37 Furthermore, alkylating chemotherapy and pelvic radiotherapy appear to reduce the risk of radiotherapy-associated breast cancer, due to the high frequency of premature menopause after chemotherapy. 9,26,28,32,33 A long vs short duration of intact ovarian function after radiation was a strong predictor of subsequent breast cancer risk.…”

Section: Introductionmentioning

confidence: 99%

“…The risk of radiotherapy-related CVD after HL is expected to decrease significantly over time, because fewer patients receive combined modality treatment and radiotherapy policies have changed. 37,59 If radiotherapy is applied, the target volumes are smaller, 3-dimensional conformal radiotherapy planning is used, and the applied dose is lower. 37 Additional advanced techniques such as deepinspiration breath-hold and intensity modulated RT with butterfly techniques further significantly reduce doses to the heart and cardiac substructures.…”

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confidence: 99%

Long-term risk of second malignancy and cardiovascular disease after Hodgkin lymphoma treatment

Leeuwen

2016

Hematology

104

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Long-term survivors of Hodgkin lymphoma (HL) experience several late adverse effects of treatment, with second malignant neoplasms (SMNs) and cardiovascular diseases (CVDs) being the leading causes of death in these patients. Other late effects have also been identified, such as pulmonary dysfunction, endocrinopathies (thyroid dysfunction, infertility), neck muscle atrophy, and persistent fatigue. HL survivors have two-to fourfold increased risks to develop SMNs and CVD compared with the general population. With respect to SMNs, radiotherapy is associated with 1.5-to 15-fold increased risk of solid malignancies. The relative risk (RR) of solid tumors increases steadily with increasing follow-up time from 5 to 15 years since radiotherapy, and remains elevated for at least 40 years. The RR of solid SMNs increases strongly with younger age at first treatment. Risks of lung, breast, and gastrointestinal (GI) cancers increase with higher radiation dose. Alkylating agent chemotherapy, especially procarbazine, does not only increase risk of leukemia but also of solid malignancies, in particular, cancers of the lung and GI tract. In contrast, gonadotoxic chemotherapy decreases the risk of radiation-associated breast cancer, through induction of premature menopause. Smoking appears to multiply the radiation-and chemotherapy-associated risks of lung cancer. Both radiotherapy and chemotherapy for HL may cause cardiovascular toxicity. Radiotherapy increases the risk of coronary heart disease, valvular heart disease, congestive heart failure (HF), and pericarditis, whereas anthracycline-containing chemotherapy increases the risks of HF and valvular heart disease. Cardiovascular toxicity following radiotherapy is usually observed from 5 to at least 35 years after therapy, whereas anthracycline-related toxicity is already observed during treatment, up to at least 25 years. The joint effects of anthracyclines, radiotherapy, and conventional cardiovascular risk factors (eg, hypertension, smoking, and physical inactivity) appear to be additive rather than multiplicative. HL survivors need lifelong risk-based screening for selected SMNs and CVDs. Furthermore, preventive strategies should include lifestyle and drug-based interventions to minimize exposure to conventional risk factors for cancer and CVD. Learning Objectives• Know treatment-related risk factors for the development of second malignancy and CVDs after HL • Be aware of the content of use surveillance guidelines for HL survivors, aimed at reduction of morbidity and mortality from second malignancy and CVDs

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Cardiovascular Disease After Hodgkin Lymphoma Treatment

et al. 2015

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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.

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Estimated risk of cardiovascular disease and secondary cancers with modern highly conformal radiotherapy for early-stage mediastinal Hodgkin lymphoma

Abstract: In early-stage, mediastinal HL modern radiotherapy provides superior results compared with MF. However, there is no single best radiotherapy technique for HL-the decision should be made at the individual patient level.

Cited by 127 publications

References 24 publications

Proton pencil beam scanning for mediastinal lymphoma: treatment planning and robustness assessment

Proton pencil beam scanning for mediastinal lymphoma: treatment planning and robustness assessment

Long-term risk of second malignancy and cardiovascular disease after Hodgkin lymphoma treatment

Cardiovascular Disease After Hodgkin Lymphoma Treatment

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