Cardiotoxicity model-based patient selection for Hodgkin lymphoma proton therapy

Hodgkin lymphoma (HL) is a highly curable hematological malignancy. Consolidation radiation therapy techniques have made significant progresses to improve organ-at-risk sparing in order to reduce late radiation-induced toxicity. Recent technical breakthroughs notably include intensity modulated proton therapy (IMPT), which has demonstrated a major dosimetric benefit at the cardiac level for mediastinal HL patients. However, its implementation in clinical practice is still challenging, notably due to the limited access to proton therapy facilities. In this context, the purpose of this study was to estimate the benefit of IMPT for HL proton therapy for diverse cardiac adverse events and to propose a general frame for mediastinal HL patient selection strategy for IMPT based on cardiotoxicity reduction, patient clinical factors, and IMPT treatment availability. This retrospective dosimetric study included 30 mediastinal HL patients treated with VMAT. IMPT plans were generated on the initial simulation scans. Dose to the heart, to the left ventricle and to the valves were retrieved to calculate the relative risk (RR) of ischemic heart disease (IHD), congestive heart failure (CHF) and valvular disease (VD). Composite relative risk reduction (cRRR) of late cardiotoxicity, between VMAT and IMPT, were calculated as the weighted mean of relative risk reduction for IHD, CHF and VD, calculated across a wide range of cardiovascular risk factor combinations. The proportion of mediastinal HL patients who could benefit from IMPT was estimated in European countries, based on the country population and on the number of active gantries, to propose country-specific cRRR thresholds for patient selection. Compared with VMAT, IMPT significantly reduced average mean doses to the heart (2.36 Gy vs 0.99 Gy, <i>p</i> &lt; 0.01), to the left ventricle (0.67 Gy vs 0.03, <i>p</i> &lt; 0.01) and to the valves (1.29 Gy vs. 0.06, <i>p</i> &lt; 0.01). For a HL patient without cardiovascular risk factor other than anthracycline-based chemotherapy, the relative risks of late cardiovascular complications were significantly lower after IMPT compared with VMAT for ischemic heart disease (1.07 vs 1.17, <i>p</i> &lt; 0.01), for congestive heart failure (2.84 vs. 3.00, <i>p</i> &lt; 0.01), and for valvular disease (1.01 vs. 1.06, <i>p</i> &lt; 0.01). The median cRRR of cardiovascular adverse events with IMPT was 4.8%, ranging between 0.1% and 30.5%, depending on the extent of radiation fields and on the considered cardiovascular risk factors. The estimated proportion of HL patients currently treatable with IMPT in European countries with proton therapy facilities ranged between 8.0% and 100% depending on the country, corresponding to cRRR thresholds ranging from 24.0% to 0.0%. While a statistically significant clinical benefit is theoretically expected for ischemic heart disease, cardiac heart failure and valvular disease for mediastinal HL patients with IMPT, the overall cardiotoxicity risk reduction is notable only for a minority of patients. In the context of limited IMPT availability, this study proposed a general model-based selection approach for mediastinal HL patient based on calculated cardiotoxicity reduction, taking into consideration patient clinical characteristics and IMPT facility availability.

霍奇金淋巴瘤（Hodgkin Lymphoma, HL）是一种治愈率极高的血液系统恶性肿瘤。为降低放射诱导的晚期毒性，巩固放射治疗技术在危及器官保护方面已取得显著进展。近期的技术突破尤以调强质子治疗（intensity modulated proton therapy, IMPT）为代表，该技术已被证实可在纵隔霍奇金淋巴瘤患者的心脏层面实现显著的剂量学优势。然而，受限于质子治疗设施的可及性不足，其在临床实践中的推广仍面临诸多挑战。在此背景下，本研究旨在评估调强质子治疗针对霍奇金淋巴瘤患者的各类心脏不良事件获益，并基于心脏毒性降低、患者临床特征及调强质子治疗的可及性，提出一套用于纵隔霍奇金淋巴瘤患者选择调强质子治疗的通用框架。本回顾性剂量学研究共纳入30例接受容积调强弧形治疗（Volumetric Modulated Arc Therapy, VMAT）的纵隔霍奇金淋巴瘤患者。研究基于患者初始定位扫描图像生成调强质子治疗计划，提取心脏、左心室及瓣膜的受照剂量，进而计算缺血性心脏病（ischemic heart disease, IHD）、充血性心力衰竭（congestive heart failure, CHF）及瓣膜性心脏病（valvular disease, VD）的相对风险（Relative Risk, RR）。以多种心血管危险因素组合为基础，分别计算缺血性心脏病、充血性心力衰竭及瓣膜性心脏病的相对风险降低率，再通过加权平均得到容积调强弧形治疗与调强质子治疗间的晚期心脏毒性综合相对风险降低率（Composite Relative Risk Reduction, cRRR）。基于各国人口及在用质子治疗机架数量，本研究估算了欧洲各国可从调强质子治疗中获益的纵隔霍奇金淋巴瘤患者比例，进而提出针对不同国家的患者选择综合相对风险降低率阈值。与容积调强弧形治疗相比，调强质子治疗可显著降低心脏、左心室及瓣膜的平均受照剂量：心脏平均剂量分别为2.36 Gy与0.99 Gy（p < 0.01），左心室平均剂量分别为0.67 Gy与0.03 Gy（p < 0.01），瓣膜平均剂量分别为1.29 Gy与0.06 Gy（p < 0.01）。对于仅接受过蒽环类药物化疗、无其他心血管危险因素的霍奇金淋巴瘤患者，调强质子治疗相较于容积调强弧形治疗，可显著降低其晚期心血管并发症的相对风险：缺血性心脏病相对风险分别为1.07与1.17（p < 0.01），充血性心力衰竭相对风险分别为2.84与3.00（p < 0.01），瓣膜性心脏病相对风险分别为1.01与1.06（p < 0.01）。调强质子治疗对应的心血管不良事件中位综合相对风险降低率为4.8%，范围介于0.1%至30.5%之间，具体数值取决于照射野范围及所考虑的心血管危险因素。基于现有质子治疗设施情况，欧洲各国可接受调强质子治疗的霍奇金淋巴瘤患者比例估算为8.0%至100%，对应的患者选择综合相对风险降低率阈值范围为24.0%至0.0%。尽管理论上调强质子治疗可为纵隔霍奇金淋巴瘤患者在缺血性心脏病、充血性心力衰竭及瓣膜性心脏病方面带来具有统计学意义的临床获益，但整体心脏毒性风险降低仅在少数患者中较为显著。在调强质子治疗可及性有限的背景下，本研究提出了一种基于模型的通用患者选择方法，该方法通过计算心脏毒性降低幅度，综合考虑患者临床特征及调强质子治疗设施的可及性，用于纵隔霍奇金淋巴瘤患者的治疗选择。