Expert Insights: Lymphoma
Trends in Proton and Carbon Ion Therapy to Assist Clinical Choices and Research Pursuits
Parsing out the Tools of the Trade: Photons, Protons, and Deep-Inspiration Breath Hold for Mediastinal Lymphoma
Yolanda D. Tseng, MD
Department of Radiation Oncology, University of Washington
Seattle Cancer Care Alliance Proton Therapy Center
Radiation technology has improved for both photon and proton therapy. With photons, improvements have come by way of intensity-moduated radition therapy / volumetric modulated arc therapy, and with protons by way of pencil-beam scanning (PBS). Motion management strategies, including deep-inspiration breath hold (DIBH), which have had the added benefit of displacing the heart inferiorly and maximally expanding the lungs. Nevertheless, selecting the optimal technique, or combination of techniques, to minimize the dose to patients with mediastinal lymphoma may be challenging given the unique anatomy of each patient and their target volume, which is based on the prechemotherapy extent of disease (e.g., involved-site radiotherapy).
In a comparative dosimetry study from Ntentas and colleagues,1 21 patients with Hodgkin lymphoma were treated with DIBH and PBS proton therapy. 3D conformal and partial arc volumetric modulated photon therapy plans were created for each patient to identify patient characteristics in which PBS was associated with improved sparing of the breast, heart, and lung tissue. The cohort had a mixed distribution of disease, including those with axillary involvement (43%) and disease that extended below the 7th thoracic vertebral body (T7) (48%). Overall, the greatest reductions in dose with PBS compared to either photon techniques was observed in distinct subgroups, including 1) patients whose clinical target volume extends down to the level of the heart, below T7 (lower mean heart dose), 2) female patients with axillary disease (lower mean breast dose), and 3) patients with larger planning target volumes (lower mean lung and normal tissue doses).
One caveat is that many proton centers do not yet have volumetric image-guided radiotherapy. Moreover, use of DIBH may not be routine at all proton centers. This raises consideration of whether these results are generalizable to patients treated while free breathing. Or, put another way, must patients be treated with DIBH to realize these dosimetric benefits?
For patients with lower mediastinal lymphoma (LML), at least, the answer may be no. In a separate study from Everett and colleagues,2 four comparative plans were created for 21 patients with LML, comparing proton therapy (double-scatter or uniform scanning) and IMRT with and without DIBH. In these patients with LML, proton therapy, with or without DIBH, was associated with significantly lower mean dose to the heart and left ventricle compared to IMRT with DIBH. While DIBH improved lung dosimetry over free breathing for protons and IMRT, there was little impact on mean heart dose.
Together, these two studies help define patient disease characteristics that may predict for whom proton therapy will yield significant dosimetric benefits. Determining the clinical impact, however, still requires integration of other patient characteristics, including age, sex, treatment history, and comorbidities, as outlined in the International Lymphoma Radiation Oncology Group (ILROG) consensus guidelines on proton therapy for patients with mediastinal lymphomas.3
1. Ntentas G, Dedeckova K, Andrlik M, et al. Clinical Intensity Modulated Proton Therapy for Hodgkin Lymphoma: Which Patients Benefit the Most? Practical Radiation Oncology. 2019;9: 179-187.
2. Everett AS, Hoppe BS, Louis D, et al. Comparison of Techniques for Involved-Site Radiation Therapy in Patients With Lower Mediastinal Lymphoma. Practical Radiation Oncology. 2019. doi: 10.1016/j.prro.2019.05.009 [Epub ahead of print].
3. Dabaja BS, Hoppe BS, Plastaras JP, et al. Proton therapy for adults with mediastinal lymphomas: the International Lymphoma Radiation Oncology Group guidelines. Blood. 2018;132: 1635-46].
Quantifying the Dosimetric Benefits of Proton Therapy in Patients with Hodgkin Lymphoma
Yolanda D. Tseng, MD
There remains an unmet need to improve radiation therapy (RT) delivery in patients with mediastinal lymphoma, who are commonly young and cured of their cancer. Recognition that late cardiac toxicity and secondary cancer risks are dose-dependent has prompted use of advanced radiation techniques such as proton therapy, intensity-modulated radiation therapy (IMRT)/volumetric modulated arc therapy, and deep-inspiration breath hold (DIBH). Early dosimetric studies have demonstrated superior sparing of organs at risk (OAR) with proton therapy compared with photons. However, with wider adoption of DIBH, there has been renewed interest in evaluating the dosimetric benefit of proton therapy compared to photons with DIBH.
Rechner and colleagues  compared the life years lost (LYL) attributable to RT-associated late effects based on dose to OARs. Proton (PBS) and IMRT plans were created with and without DIBH for 22 patients with early-stage Hodgkin lymphoma. Compared to IMRT in free breathing (FB), use of DIBH, proton therapy, and the combination significantly reduced the LYL, but no significant differences were observed between IMRT in DIBH and proton therapy in FB. Many proton therapy centers have not routinely used DIBH given the lack of volumetric image-guided radiation (e.g., cone-beam computed tomography). While this study quantifies how dose-sparing influences the risk of late toxicity, there are potential limitations with the proton treatment planning. In particular, anterior-posterior and posterior-anterior fields were used for all patients, despite knowledge that PA fields may increase the dose to the heart and posterior tissues.
Given these findings, who may benefit from proton therapy? Recently, the International Lymphoma Research Oncology Group (ILROG) published consensus recommendations of who may derive the greatest benefit from proton therapy . They included (1) patients with mediastinal disease that extends below the origin of the left main stem coronary artery and is anterior to, posterior to, or on the left side of the heart, (2) young female patients for whom proton therapy can reduce the breast dose, and (3) heavily pretreated patients who are at higher risk for RT-related toxicity to the bone marrow, heart, and lungs. These guidelines recognize that the effect of RT dose to the breast, heart, or lung tissues is modulated by clinical factors such as patient age and prior treatment. Therefore, while patient-specific comparative plans should be used to quantify the dosimetric benefits of proton therapy, radiation oncologists must also consider whether these differences are clinically significant based on patient and treatment factors.
1. Rechner LA, Maraldo MV, Vogelius IR, et al. . Life years lost attributable to late effects after radiotherapy for early stage Hodgkin lymphoma: The impact of proton therapy and/or deep inspiration breath hold. Radiotherapy and Oncology 2017;125:41-47.
2. Dabaja BS, Hoppe BS, Plastaras JP, et al. . Proton therapy for adults with mediastinal lymphomas: the International Lymphoma Radiation Oncology Group guidelines. Blood 2018;132:1635.