Optimized Volumetric Modulated Arc Therapy Versus 3D-CRT for Early Stage Mediastinal Hodgkin Lymphoma Without Axillary Involvement: A Comparison of Second Cancers and Heart Disease Risk

doi:10.1016/j.ijrobp.2015.02.030

International Journal of Radiation OncologyBiologyPhysics

Volume 92, Issue 1, 1 May 2015, Pages 161-168

https://doi.org/10.1016/j.ijrobp.2015.02.030 Get rights and content

Purpose

The purpose of this study was to evaluate the risks of second cancers and cardiovascular diseases associated with an optimized volumetric modulated arc therapy (VMAT) planning solution in a selected cohort of stage I/II Hodgkin lymphoma (HL) patients treated with either involved-node or involved-site radiation therapy in comparison with 3-dimensional conformal radiation therapy (3D-CRT).

Methods and Materials

Thirty-eight patients (13 males and 25 females) were included. Disease extent was mediastinum alone (n=8, 21.1%); mediastinum plus unilateral neck (n=19, 50%); mediastinum plus bilateral neck (n=11, 29.9%). Prescription dose was 30 Gy in 2-Gy fractions. Only 5 patients had mediastinal bulky disease at diagnosis (13.1%). Anteroposterior 3D-CRT was compared with a multiarc optimized VMAT solution. Lung, breast, and thyroid cancer risks were estimated by calculating a lifetime attributable risk (LAR), with a LAR ratio (LAR_VMAT-to-LAR_3D-CRT) as a comparative measure. Cardiac toxicity risks were estimated by calculating absolute excess risk (AER).

Results

The LAR ratio favored 3D-CRT for lung cancer induction risk in mediastinal alone (P=.004) and mediastinal plus unilateral neck (P=.02) presentations. LAR ratio for breast cancer was lower for VMAT in mediastinal plus bilateral neck presentations (P=.02), without differences for other sites. For thyroid cancer, no significant differences were observed, regardless of anatomical presentation. A significantly lower AER of cardiac (P=.038) and valvular diseases (P<.0001) was observed for VMAT regardless of disease extent.

Conclusions

In a cohort of patients with favorable characteristics in terms of disease extent at diagnosis (large prevalence of nonbulky presentations without axillary involvement), optimized VMAT reduced heart disease risk with comparable risks of thyroid and breast cancer, with an increase in lung cancer induction probability. The results are however strongly influenced by the different anatomical presentations, supporting an individualized approach.

Introduction

The combination of brief chemotherapy followed by radiation therapy (RT) represents the therapeutic golden standard for early stage Hodgkin lymphoma (HL) (1); nonetheless, the role of radiation is still debated with some concerns for late toxicity (second malignancies, cardiac disease). Current radiation therapy protocols may combine limited radiation volumes with advanced planning and delivery techniques, such as intensity modulated RT (IMRT). This innovative approach should be associated with less radiation-related morbidity through an improved sparing of normal tissues. Current strategies for volume reduction consist of either involved node RT (INRT), defined by European Organization for Research and Treatment of Cancer (EORTC) lymphoma group (2) for the EORTC-Lymphoma Study Association and Fondazione Italiana Linfomi H10 trial and by the German Hodgkin Study Group (3) for the HD17 trial, or in involved-site RT (ISRT), recently defined by the International Lymphoma Radiation Oncology Group (4). Both INRT and ISRT concepts include only the nodal sites of macroscopic disease at diagnosis, and the prechemotherapy involvement determines the clinical target volumes. The difference is that INRT needs a complete pre- and post-chemotherapy imaging in treatment position, whereas ISRT may compensate for suboptimal imaging by a slight enlargement of the target volume (from individual lymph-nodes to lymphatic sites). Retrospective data on clinical outcomes support the safety and efficacy of both INRT (5) and ISRT 6, 7, planned with either standard 3D technique or IMRT. On the technical side, various IMRT solutions have been implemented over the years, generally showing superior target coverage and sparing of organs at risk (OAR; mainly heart and coronary arteries) 8, 9, 10. However, the heart-sparing effect of IMRT at high-intermediate dose is usually achieved at the price of a larger amount of thoracic tissues receiving low or very low doses (breasts, lungs). Given this particular dose distribution, we may question the appropriateness of IMRT in young HL patients, giving the potential increase in radiation-induced malignancies by low-dose exposure of larger volumes (11). Second cancers are indeed a leading cause of death in HL long-term survivors (12), and studies based on radiobiological risk estimations have been conducted in recent years based on individual patient dose-volume histograms (DVH). We previously developed a VMAT class solution for lymphoma patients with supradiaphragmatic presentations treated with INRT (9), with multiarc beam arrangements and optimization parameters on breast and lungs. Results of a subsequent study based on radiobiological models showed that the risks of breast cancer induction between 3D-CRT and optimized multiarc VMAT were similar (13). These preliminary findings were in contrast with those obtained by a pioneering study with a comparable design (14) but pursuing different planning solutions (3D-CRT vs IMRT vs RapidArc). Likewise, in later reports, VMAT appeared to be associated with higher estimates of second cancer risk 15, 16.

The present study was thus designed with the aim of further investigating the potential risks of late toxicity (second cancers, cardiovascular diseases) associated with a multiarc VMAT technique optimized for supradiaphragmatic HL patients.

Section snippets

Patients

We included in the study 42 consecutive patients (15 males and 27 females) affected with stages I-IIA mediastinal HL treated with ABVD (doxorubicin, bleomycin, vinblastine, and dacarbazine) chemotherapy followed by 30-Gy INRT or ISRT. Four patients (4 of 42 patients [9.5%]) presented with axillary involvement but were excluded from the analysis, as the subgroup was too small for any comparison. The remaining 38 patients (13 males and 25 female) were divided into 3 groups according to disease

Results

Dosimetric data of target volumes and OARs (3D-CRT and VMAT) are reported in Table 2. Table 3 shows the means ± SD OED values for lung, breast (only female patients), and thyroid cancers according to treatment technique and anatomical presentation. A significant difference between 3D-CRT and VMAT was evident in favor of 3D-CRT (P=.025) for lung cancer, especially in mediastinal (P=.001) or mediastinal plus unilateral neck (P=.03) presentations. No differences between the 2 treatment techniques

Discussion

The aim of this study was to assess the risk of developing second cancer and cardiovascular disease associated with an optimized VMAT planning solution in patients with early stage mediastinal HL versus standard 3D-CRT, while considering the potential impact of different anatomical presentations. We applied the INRT/ISRT concepts, including only lymphatic sites originally involved by macroscopic disease at presentation into the treatment volume. We excluded patients with axillary involvement,

Conclusions

This study showed that in stage I-II HL patients with mediastinal but not axillary involvement (with or without neck, and with a low rate of bulky disease), optimized multiarc VMAT was on average superior to 3D-CRT in terms of PTV coverage and in lowering the risk of cardiac toxicity; no differences were observed between 3D-CRT and VMAT for thyroid and breast cancer induction, while VMAT resulted in a higher risk of lung cancer induction. Results were influenced by the different anatomical

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A document and literature search was carried out in the following databases: Medline and ClinicalTrial.gov, for the terms “radiotherapy”, “haematologic malignancies”, “Hodgkin lymphoma”, “non-Hodgkin lymphoma”, “CAR T cells”, “multiple myeloma”, “solitary plasmocytoma”, “intensity-modulated radiotherapy”, “extracranial stereotactic body radiation therapy” and “proton therapy references”.
Haemopathological malignancies include a wide range of diseases and radiation therapy indications have been assessed over the past 20 years. Currently, radiation therapy is indicated for localized disease (solitary plasmocytoma), as an adjuvant (Hodgkin lymphoma), in palliative settings, or after systemic treatment in relapsed patients (chimeric antigen receptor [CAR] T-cells) with a low recurrence burden, which can therefore be considered “oligorecurrence”. Radiation therapy, through total body irradiation, has important indications, thanks to its immunomodulatory and/or myeloablative effects. Moreover, recent technological developments have made possible significant improvement in safety, contributing to radiation therapy being positioned in the treatment strategy of several indications.
Given the effectiveness of systemic treatments in hematologic malignancies, the oligometastasis stage is of little importance. A curative intent after local radiation therapy, even advanced stage, is possible, both with residual disease for advanced Hodgkin lymphoma, aggressive non-Hodgkin lymphoma, or solitary plasmocytoma, and even without evidence of disease after chemotherapy for Hodgkin or non-Hodgkin lymphoma. The role of new treatments, such as CAR T cells, allows us to consider radiation therapy after systemic treatment of relapsed diseases with low volume recurrence, which can be considered oligorecurrence.
Les hémopathies malignes ont la particularité qu’elles peuvent généralement être guéries, même en présence de métastases au moment du diagnostic, contrairement aux tumeurs malignes solides. Les traitements systémiques, y compris la chimiothérapie, les thérapies ciblées et l’immunothérapie, sont la base du traitement et donnent d’excellents résultats. Les progrès considérables réalisés dans la prise en charge de ces maladies au cours des 20 dernières années ont redéfini le rôle de la radiothérapie en tant que traitement mineur dans de nombreuses situations cliniques. Nous proposons une revue de la littérature des données montrant que la radiothérapie a toujours un rôle dans les situations de thérapie curative, de sauvetage et palliative.
Une recherche documentaire et bibliographique a été effectuée sur les bases de données suivantes : ClinicalTrial.gov et Medline (à l’aide du moteur de recherche PubMed), pour les termes “radiotherapy”, “hematologic malignancies”, “Hodgkin lymphoma”, “non-Hodgkin lymphoma”, “CAR T cells”, “multiple myeloma”, “solitary plasmocytoma”, “intensity-modulated radiotherapy”, “extracranial stereotactic body radiation therapy” et “proton therapy references”.
Les hémopathies malignes comprennent un large éventail de maladies. Les indications de la radiothérapie ont été évaluées au cours des 20 dernières années. Actuellement, la radiothérapie est indiquée pour les maladies localisées, comme traitement adjuvant (lymphome de Hodgkin), dans les situations palliatives ou après un traitement systémique chez les patients en situation de rechute (cellules CAR-T) avec un faible taux de récidive, qui peut donc être considéré comme une “oligorécidive”. La radiothérapie corporelle totale, a des indications importantes, grâce à ses effets immunomodulateurs et/ou myéloablatifs. En outre, les développements technologiques récents ont permis une amélioration significative de la tolérance, contribuant à positionner la radiothérapie dans la stratégie de traitement de plusieurs indications.
Compte tenu de l’efficacité des traitements systémiques pour les hémopathies malignes, le stade de l’oligométastase a peu d’importance. Un objectif curatif après une radiothérapie locale, même à un stade évolué, est possible, à la fois avec une maladie résiduelle dans le cas d’une maladie de Hodgkin évoluée, d’un lymphome non hodgkinien agressif ou d’un plasmocytome solitaire, et même sans preuve de maladie après une chimiothérapie dans le cas d’un lymphome de Hodgkin, d’un lymphome non hodgkinien et d’une leucémie aiguë lymphoblastique. Le rôle des nouveaux traitements, tels que les lymphocytes T modifiés (chimeric antigen receptor [CAR] T cells), nous permet d’envisager la radiothérapie après le traitement systémique des patients en situation de récidive de faible volume, qui peut être considérée comme une oligométastase.
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Citation Excerpt :
Likewise, the transition from three dimensional conformal radiotherapy to highly conformal radiotherapy techniques, such as intensity modulated radiotherapy and volumetric modulated arc therapy, has led to a reduction in the dose delivered to the heart but with an increased exposure of breasts and lungs to low doses, with a potential increase in the risk of second cancers.54 However, second generation studies have tested new volumetric modulated arc therapy solutions to tailor the radiotherapy treatment to the clinical needs of each patient in terms of heart sparing while limiting the exposure of other organs (ie, primarily breasts and lungs).55 The most recent innovation in radiotherapy planning and delivery is proton therapy.
In potentially curable cancers, long-term survival depends not only on the successful treatment of the malignancy but also on the risks associated with treatment-related toxicity, especially cardiotoxicity. Malignant lymphomas affect patients at any age, with acute and late toxicity risks that could have a severe effect on morbidity, mortality, and quality of life. Although our understanding of chemotherapy-associated and radiotherapy-associated cardiovascular disease has advanced considerably, new drugs with potential cardiotoxicity have been introduced for the treatment of lymphomas. In this Review, we summarise the mechanisms of treatment-related cardiac injury, available clinical data, and protocols for optimising cardioprotection in lymphomas. We discuss ongoing research strategies to advance our knowledge of the molecular basis of drug-induced and radiation-induced toxicity. Additionally, we emphasise the potential for personalised follow-up and early detection, including the role of biomarkers and novel diagnostic tests, highlighting the role of the cardio-oncology team.
Proton Therapy in Supradiaphragmatic Lymphoma: Predicting Treatment-Related Mortality to Help Optimize Patient Selection
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In some patients with Hodgkin lymphoma (HL), proton beam therapy (PBT) may reduce the risk of radiation-related cardiovascular disease (CVD) and second cancers (SC) compared with photon radiation therapy (RT). Our aim was to identify patients who benefit the most from PBT in terms of predicted 30-year absolute mortality risks (AMR₃₀) from CVD and SC, taking into account individual background, chemotherapy, radiation, and smoking-related risks.
Eighty patients with supradiaphragmatic HL treated with PBT between 2015 and 2019 were replanned using optimal photon RT. To identify patients predicted to derive the greatest benefit from PBT compared with photon RT, doses and AMR₃₀ from CVD and SC of the lung, breast, and esophagus were compared for all patients and across patient subgroups.
For patients with mediastinal disease below the origin of the left main coronary artery (n = 66; 82%), PBT reduced the mean dose to the heart, left ventricle, and heart valves by 1.0, 2.7, and 3.6 Gy, respectively. Based on U.S. mortality rates, PBT reduced CVD AMR₃₀ by 0.2%, from 5.9% to 5.7%. The benefit was larger if the mediastinal disease overlapped longitudinally with the heart by ≥40% (n = 23; 29%). PBT reduced the mean dose to the heart, left ventricle, and heart valves by 3.2, 5.6, and 5.1 Gy, respectively, and reduced CVD AMR₃₀ by 0.8%, from 7.0% to 6.2%. For patients with axillary disease (n = 25; 31%), PBT reduced the mean lung dose by 2.8 Gy and lung cancer AMR₃₀ by 0.6%, from 2.7% to 2.1%. Breast and esophageal doses were also lower with PBT, but the effects on AMR₃₀ were negligible. The effect of smoking on CVD and lung cancer AMR₃₀ was much larger than radiation and chemotherapy and the differences between radiation modalities.
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Radiotherapy for Hodgkin lymphomas has evolved a lot over time, but still plays an important role, almost always in addition to chemotherapy, for the management of the early stages. The major objective is to preserve the quality of life of patients who will be cured from this disease in the vast majority of cases. Also, the personalization of the indications for the purpose of de-escalating toxicity is very refined and is essentially based on the pre- and pertherapeutic assessment by FDG-PET. The indications for radiotherapy are more limited for non-Hodgkin lymphomas, but the same principles are found, regardless of the histological type. We present the update of the recommendations of the French society of oncological radiotherapy for radiotherapy of lymphomas, which remains a very evolving field in terms of therapeutic strategy and evaluation.
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: Conflict of interest: FL has received research support, travel grants, and teaching honoraria from Elekta and IBA and is a Board Member of C-Rad. The other authors state there are no conflicts of interest with the material included in the study.

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Clinical InvestigationOptimized Volumetric Modulated Arc Therapy Versus 3D-CRT for Early Stage Mediastinal Hodgkin Lymphoma Without Axillary Involvement: A Comparison of Second Cancers and Heart Disease Risk

Purpose

Methods and Materials

Results

Conclusions

Introduction

Section snippets

Patients

Results

Discussion

Conclusions

Ann Oncol

Radiother Oncol

Int J Radiat Oncol Biol Phys

Int J Radiat Oncol Biol Phys

Int J Radiat Oncol Biol Phys

Int J Radiat Oncol Biol Phys

Int J Radiat Oncol Biol Phys

Blood

Pract Radiat Oncol

Int J Radiat Oncol Biol Phys

Ann Oncol

Int J Radiat Oncol Biol Phys

Z Med Phys

Int J Radiat Oncol Biol Phys

Int J Radiat Oncol Biol Phys

Clinical Investigation
Optimized Volumetric Modulated Arc Therapy Versus 3D-CRT for Early Stage Mediastinal Hodgkin Lymphoma Without Axillary Involvement: A Comparison of Second Cancers and Heart Disease Risk