Abstract
Purpose
Radiotherapy (RT) is often used as a combined modality therapy for patients with Hodgkin (HL) and aggressive Non-Hodgkin Lymphoma (aNHL). RT options include photon intensity-modulated radiotherapy (IMRT) or proton therapy (PT). As PT is a limited and costly resource, it is important to identify cases in which PT may best benefit in order to offer providers and patients the best possible information for decision-making. Accordingly, the purpose of this study was to assess the difference in OAR sparing between photon IMRT and pencil-beam scanning (PBS) based on disease location using the Ann Arbor (AA) staging system.
Materials and Methods
A cohort was established including all patients with HL or aNHL (n = 156) treated with RT at a single institution from 2007 to 2020. Two plans (IMRT and PBS) were developed for each patient using consistent planning techniques with a prescribed dose of 30 Gy. Disease anatomic classification was classified using AA, and OAR differences were assessed based on disease location. Mediastinal involvement was divided between upper, middle, and lower (UML). OAR doses were comparatively assessed by the AA site looking at absolute (AS) and relative sparing (RS) using patient plan pairs using the Wilcoxon signed-rank test.
Results
PBS reduced the mean heart dose with the largest AS (6.4 Gy) for patients with UML mediastinal involvement. Greatest AS and RS for lung V20 was seen for patients with bilateral axillary involvement (20.9% AS, 53.5% RS), and for mean breast dose greatest sparing was seen for those with bilateral hilar disease (5.1 Gy AS, 58.6% RS).
Conclusion
The use of PBS resulted in a substantial decrease in the mean dose to OARs, the magnitude of which depended on the location in which disease was present. This work advances that the anatomic location of involvement is an important influence on the relative benefit of PT.
Keywords: Lymphoma, Proton therapy, Hodgkin lymphoma, Non-Hodgkin lymphoma
Introduction
Radiation therapy (RT) has indications for both Hodgkin (HL) and non-Hodgkin lymphoma (nHL). Due to favorable prognoses, a primary concern for lymphoma patients is survivorship, and therefore the mitigation of potential late effects introduced by treatment modalities. Late effects, such as secondary cancers and cardiovascular disease, have been associated with radiation doses to normal tissue and organs at risk (OARs) in lymphoma survivors.1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17 As RT modalities have evolved, along with an aim at reducing late toxicities, indications for RT have become narrower. Doses have been reduced by utilizing a combined modality therapy approach.18 Additionally, targeted methods that reduce field size and irradiated volumes, such as involved-node RT and involved-site RT have become the standard.18, 19, 20
More advanced photon RT techniques such as intensity-modulated radiotherapy (IMRT) and volumetric-modulated arc therapy have demonstrated improved target conformity and reduced OAR doses in lymphoma patients compared to 3D.21, 22, 23, 24 Proton therapy (PT) offers certain dosimetric advantages due to intrinsic beam characteristics, such as rapid distal fall-off and minimal lateral penumbra. When compared to advanced photon techniques, PT has shown to further reduce doses to OARs and normal tissue in lymphoma patients, and therefore further reducing potential late effects.25, 26, 27, 28, 29, 30, 31, 32, 33 However, PT is a more costly treatment, and access is limited compared to conventional RT.
Unlike many other cancers, HL and nHL can appear anywhere in the body, and therefore utilize the Ann Arbor staging system, which further classifies the disease by anatomical site and extent. Due to the heterogeneity of disease presentation combined with increased cost and limited access to PT, indications for lymphoma PT based on anatomic location should be carefully considered. In this study, we sought to compare differences in patient OAR sparing by the Ann Arbor site for IMRT and pencil beam scanning (PBS) PT to provide clinicians with an evidence-based approach for determining which patients are likely to benefit the most from PT.
Methods
Patient selection
A cohort was established containing all patients (N = 156) with HL or aggressive (a) nHL treated at the University of Florida Health Proton Therapy Institute between 2007 and 2020. The patients were retrospectively enrolled under a protocol approved by the Institutional Review Board at the University of Florida (IRB202003234). All patients had an IMRT and PBS-PT plan pair generated for analysis.
Treatment planning
Patient imaging and contours
Patient simulation scans were performed on a Philips Big Bore computed tomography (CT) (Philips Healthcare, Amsterdam, Netherlands). Planning was performed on a 4D averaged CT image set. Gross tumor volumes and clinical target volumes (CTV) were defined by the radiation oncologist. Planning target volumes were formed as a 5 mm expansion of the CTV. OAR contours were reviewed and verified by the radiation oncologist.
Treatment machines
IMRT plans were designed using an Elekta LINAC (Elekta, Stockholm, Sweden) with a 1 cm multi-leaf collimator. PBS-PT plans were designed using the IBA ProteusONE PBS gantry (Ion Beam Applications SA, Louvain-la-Neuve, Belgium).
Beam arrangement
A typical beam arrangement for IMRT plans included 5-7 beams total, with 2 of the beams being posterior oblique. Anterior beams were separated by 20-30 degrees. Collimator rotation was utilized when necessary for optimal field shape modulation. Typical beam arrangement for PBS-PT plans included 2 anterior beams near the patient midline, separated by 20°-30° degrees. Typical beam arrangements for both IMRT and PBS-PT plans are shown in Figure 1.
Figure 1.
Demonstration of commonly used beam arrangements. The same patient is shown for both the PBS-PT beam arrangement (top) and the IMRT beam arrangement (bottom). Abbreviations: PBS, pencil beam scanning; PT, proton therapy.
For patients with cervical disease, couch and gantry rotation was typically utilized to avoid treating through the chin/mandible. For both IMRT and PBS-PT, patients with disease extending into the abdomen or extremities often require additional isocenters and beams.
Plan design and optimization
IMRT and PBS-PT plans were designed, optimized, and calculated in the RayStation version 11A (RaySearch Laboratories AB, Stockholm, Sweden) treatment planning system. All plans utilized ring structures for dose control, and optimization structures were used on OARs, such as structures that define portions of OARs cropped away from target volumes or OAR expansion structures. For IMRT plans, 6X beams were predominantly used, but 10X was utilized for posterior beams treating through large separations. For PBS-PT plans, targets were robustly optimized with an isotropic shift uncertainty of 3 mm applied to each beam individually with the systematic density uncertainty set to 3.5%. Dose calculation was performed using the Monte Carlo algorithm with a maximum allowed statistical uncertainty of 0.5%. Contouring, optimization, and beam computation settings were kept as consistent and reasonably allowed for both IMRT and PBS-PT plans to ensure reliable evaluation. OARs and dose-limiting structures began with 1% of the relative priority assigned to target structures. If further sparing was required for a structure, priority could be raised up to a maximum of 5% the relative priority of targets. All final dose calculations were performed on a dose calculation grid with a resolution of 2 × 2 × 2 mm3. If minimum target coverage was not met following optimization, the dose was scaled to minimum target coverage defined within the prescription.
Prescription
All plans were prescribed to 30 Gy, 15 fractions of 200 cGy. Minimum target coverage for IMRT plans was 100% of the prescription dose covering 95% of planning target volume. Minimum target coverage for PBS-PT plans was 100% of the prescription dose covering 99% of CTV. IMRT plans were ensured to have at least 100% of the prescription dose covering 99% of the CTV as well.
Ann Arbor staging
Patients were classified into cohorts by the Ann Arbor site, and the following sites were analyzed: mediastinal, cervical, para-aortic, hilar, axillary, infraclavicular, and spleen involvement. Mediastinal disease was further classified as upper, middle, and lower (UML) mediastinal. Upper mediastinal was defined as disease that goes down to the left pulmonary artery, middle mediastinal as disease that extends below the left pulmonary artery and to the inferior aspect of the aortic valve, and lower mediastinal as disease that extends below the level of the aortic valve.34
Sub-cohorts were further divided for analysis of OAR sparing. Common presentations for mediastinal lymphomas included patients with upper and middle (UM) mediastinal disease or patients with UML mediastinal disease. Hilar, axillary, and infraclavicular disease was separated by left, right, unilateral, and bilateral presentation. Due to the asymmetry of the heart and cardiac substructures, side-specific analysis of OAR dose was performed for these OARs. For OARs assumed to be symmetric, such as lungs and breast, disease was classified simply as bilateral or unilateral.
Statistical analysis of dose to organs at risk
Patient plans were exported from RayStation and imported into ProKnow Systems (Elekta ProKnow, Sanford, FL, United States) for data collection and cohort analysis. Dose volume histogram data was extracted from ProKnow and statistical testing was performed in JMP Pro version 17 (JMP Statistical Discovery LLC, Cray, NC, United States). IMRT and PBS-PT plan pairs within a cohort were compared using a Wilcoxon signed-rank test. Statistical significance was recognized for P < .05.
Results
For all metrics reported, both in tables and figures, the Ann Arbor site designation is reported as site involvement beyond mediastinal (e.g., the left hilar cohort is defined as patients with mediastinal disease that extends to the left hilar).
Heart and cardiac substructures
OAR dosimetry for the heart and cardiac substructures is presented in Table 1 and Figure 2. For mean heart dose, the presence of lower mediastinal disease increases the absolute sparing seen in patients treated with PBS-PT from 4.0 to 6.4 Gy, a 60% increase in sparing. Patients with left hilar disease did experience overall higher mean heart doses compared to those with right hilar disease, but the absolute and relative sparing was similar. As disease progresses laterally, as demonstrated with the cohort of patients with both left hilar and left infraclavicular disease, there is no prominent increase in overall mean heart doses and heart dose sparing observed relative to patients with only hilar disease present. These trends remain true for the heart V5 metric, with a large increase in sparing for patients with lower mediastinal disease and higher overall V5 for patients with disease to the left of the mediastinum. For the left anterior descending (LAD) artery, overall mean doses are also much higher for patients with lower mediastinal disease, but absolute and relative sparing is lower when compared to patients with only UM mediastinal disease. The greatest increase in LAD sparing is for patients with bilateral hilar disease, with a 42% increase over patients with only left hilar disease and a 76% increase over patients with only right hilar disease. For the left ventricle, the highest overall V5 values, as well as the highest overall absolute sparing, is seen for patients with lower mediastinal disease present, as well as patients with left hilar disease.
Table 1.
Summary of OAR dose data for heart and cardiac substructures.
| Cohort | N = 39 | N = 94 | N = 9 | N = 6 | N = 15 | N = 6 |
|---|---|---|---|---|---|---|
| Site | ||||||
| UM | UML | Left Hilar | Right Hilar | Bilateral Hilar | Left Hilar + Left ICV | |
| Heart mean dose (Gy) | ||||||
| IMRT | 9.1 (4.1) | 15.3 (4.5) | 16.2 (5.63) | 14.2 (3.4) | 15.5 (4.8) | 16.3 (5.9) |
| PBS | 5.1 (3.0) | 8.9 (3.7) | 10.5 (4.1) | 8.7 (3.1) | 11.3 (3.8) | 11.1 (3.2) |
| AS | 4.0 | 6.4 | 5.7 | 5.5 | 4.2 | 5.2 |
| RS (%) | 44.7 | 41.6 | 35.5 | 38.7 | 26.8 | 31.8 |
| Heart V5 (%) | ||||||
| IMRT | 43.3 (21.9) | 70.8 (19.5) | 76.2 (26.0) | 62.6 (14.03) | 71.5 (23.1) | 66.3 (18.9) |
| PBS | 23.9 (15.0) | 40.3 (16.6) | 50.9 (19.8) | 38.5 (13.4) | 53.6 (16.8) | 48.8 (11.1) |
| AS | 19.4 | 30.5 | 25.3 | 24.1 | 17.9 | 17.5 |
| RS (%) | 44.9 | 43.0 | 33.2 | 38.5 | 25.1 | 26.4 |
| LAD mean dose (Gy) | ||||||
| IMRT | 9.9 (6.5) | 15.8 (8.8) | 17.9 (6.3) | 12.0 (6.3) | 15.2 (6.5) | 19.6 (5.4) |
| PBS | 6.3 (6.8) | 12.9 (9.8) | 14.8 (7.0) | 9.5 (7.8) | 10.8 (7.1) | 16.9 (6.2) |
| AS | 3.6 | 2.9 | 3.1 | 2.5 | 4.4 | 2.7 |
| RS (%) | 36.0 | 18.1 | 17.4 | 20.9 | 29.1 | 13.7 |
| LV V5 (%) | ||||||
| IMRT | 25.8 (25.9) | 56.4 (31.3) | 70.6 (32.3) | 46.6 (18.1) | 55.6 (33.7) | 46.6 (30.5) |
| PBS | 7.8 (12.9) | 19.7 (19.1) | 35.7 (19.5) | 14.6 (13.4) | 25.5 (17.1) | 18.5 (12.4) |
| AS | 18.0 | 36.7 | 34.9 | 32.0 | 30.1 | 31.1 |
| RS (%) | 69.8 | 65.1 | 49.4 | 68.7 | 54.2 | 62.8 |
Abbreviations: OAR, organ-at-risk; IMRT, intensity-modulated radiation therapy; PBS, pencil beam scanning; Gy, Gray; UM, upper + middle mediastinal; UML, upper + middle + lower mediastinal; ICV, infraclavicular; LAD, left anterior descending; LV, left ventricle; AS, absolute sparing; RS, relative sparing.
Data presented is the mean value for the given dose metric for the specified cohort, with the standard deviation provided in parentheses.
Figure 2.
Distributions of heart and cardiac substructure dose metrics for IMRT and PBS-PT plans within the sub-cohorts. Mean heart dose (top left), heart V5 (top right), left anterior descending artery mean dose (bottom left), and left ventricle V5 (bottom right). Abbreviations: IMRT, intensity-modulated radiation therapy; PBS, pencil beam scanning; PT, proton therapy.
Lungs
OAR dosimetry for the lungs is presented in Supplemental Table 1 and Figure 3. For lung sparing, the presence of lower mediastinal increases sparing, as mean lung dose decreases in PBS-PT plans by 6.3 Gy, compared to 4.4 Gy for patients without lower mediastinal disease. The addition of spleen involvement increases mean dose sparing even further, reaching 7.0 Gy. The presence of bilateral disease that extends further lateral from the mediastinum also shows increased sparing in the PBS-PT plans, with bilateral infraclavicular and bilateral axillary disease resulting in mean doses reduced by 7.9 and 7.4 Gy compared to the IMRT plans, respectively. Lung V20 values demonstrate similar correlations. For patients with spleen, bilateral hilar, bilateral infraclavicular, and bilateral axillary disease, the largest decrease in V20 for patients treated with PBS-PT relative to IMRT was observed, with a reduction of 17.0%, 14.7%, 19.1%, and 20.9%. For lung V5, patients with lower mediastinal and bilateral infraclavicular disease experienced the greatest sparing with PBS-PT relative to IMRT, with a reduction of 50.8% and 50.9%.
Figure 3.
Distributions of lung dose metrics for IMRT and PBS-PT plans within the sub-cohorts. Mean dose to lungs (top) and Lungs V20 (bottom). Abbreviations: IMRT, intensity-modulated radiation therapy; PBS, pencil beam scanning; PT, proton therapy.
Breasts
The analysis of breast tissue sparing was limited to female patients, and the OAR dosimetry is presented in Supplemental Table 2 and Figure 4. Mean breast dose, as well as sparing for patients treated with PBS-PT, was higher in patients with lower mediastinal disease present. PBS-PT sparing of mean dose to the breasts increased from 2.1 to 3.7 Gy for patients with lower mediastinal disease. Patients with axillary disease had the highest overall mean breast dose, as well as the highest absolute sparing for PBS-PT plans relative to IMRT plans, with an absolute decrease of 5.3 Gy.
Figure 4.
Distributions of breast mean dose for IMRT and PBS-PT plans within the sub-cohorts. Abbreviations: IMRT, intensity-modulated radiation therapy; PBS, pencil beam scanning; PT, proton therapy.
Discussion
We present a dosimetric analysis comparing PT versus IMRT with the important lens of anatomic disease location. PBS-PT demonstrated significant sparing relative to IMRT for all OAR metrics in all patient cohorts. Patients with lower mediastinal disease present had a higher mean heart dose on average, which also led to greater sparing in the PBS-PT plans. The presence of left hilar disease did increase the mean heart dose compared to right hilar disease, though absolute and relative sparing was similar. Considering the higher initial doses, however, the sparing seen for patients with disease to the left of the mediastinum may be more clinically significant. Heart V5, LAD mean dose, and left ventricle V5 showed correlations to mean heart dose, with the presence of lower mediastinal and left hilar disease resulting in higher overall dose and greater sparing from the PBS-PT plans. The LAD, however, had a large increase in sparing when bilateral hilar disease is present. Lung dose metrics and sparing were highly impacted by the extent to which the disease had spread from the mediastinum, both laterally and inferiorly. Disease in the lower mediastinum increased lung dose and therefore lung sparing seen in PBS-PT plans, and disease continuing further down to the spleen saw even greater sparing compared to the IMRT plans. The same occurred with lateral spread, with bilateral axillary and bilateral infraclavicular disease demonstrating the greatest reduction in mean lung dose and V20 for PBS-PT plans. Breast dose sparing showed similarity to heart and lung dose, with lower mediastinal disease increasing mean breast dose and increasing the absolute and relative sparing in PBS-PT plans. Axillary disease resulted in the highest mean breast dose, as well as the highest absolute decrease relative to IMRT plans.
The high survival rate of patients treated for HL and aNHL combined with large radiation treatment volumes results in a particular concern for minimizing radiation toxicities and late effects. Cardiotoxicity is one of the primary concerns for HL and aNHL survivors. A study by van Nimwegen et al. found that after a 20-year follow-up on patients treated for HL, they were 4 to 6 times more likely to experience heart failure or congestive heart failure. Mediastinal RT was found to increase congestive heart disease with a hazard ratio of 2.7 and heart failure with a relative risk of 2.7.3 Normal tissue complication probability models are often used to estimate cardiotoxicity risk, but the current models are based on photon RT and have been shown to be unreliable when attempting to correlate metrics such as mean heart dose with dose to cardiac substructures.35 Recommending patients for PBS-PT over IMRT based on cardiotoxicity should be informed by disease site specification but may also require further work on appropriate toxicity models for PT.
Radiation dose to the lungs can lead to both pulmonary toxicities as well as secondary cancers. Fox et al found that HL RT resulting in a mean lung dose greater than 13.6 Gy and a lung V20 > 33.5% were significantly predictive of radiation-induced pneumonitis.36 A study by Schaapveld et al found an excess absolute risk of 24.6 lung cancer cases for 10 000 person-years in a cohort of 3905 HL patients with a median follow-up of 19.1 years.2 Based on the Schneider et al model, which uses the linear quadratic formula for prediction of secondary cancers, Konig et al found that secondary lung cancers could be reduced by 54.4% for HL patients treated with PT compared to IMRT.37, 38
The primary concern for breast dose resulting from mediastinal RT is the risk of secondary cancers. The study by Schaapveld et al found that the greatest excess absolute risk following treatment for HL was breast cancer at 54.3 cases for 10,000 person-years, while Konig et al. found that secondary breast cancers could be reduced by 56.4% for HL patients treated with PT compared to IMRT.2, 38
There are limitations to this work. While each patient served as their own control, patients were not simulated twice to achieve the best possible positioning for a PBS versus IMRT plan, introducing bias. Such bias could most influence breast dose between supine positioning with arms down for protons versus a butterfly IMRT technique with arms up. However, the data generated still can inform providers and decision-makers for what cases sparing may be most notable between the 2 modalities. Similarly, the differences that may be achieved for heart sparing between those different positions would not be expected to be substantial. Another limitation is the lack of deep inspiration breathe hold (DIBH) analysis, which is frequently performed when utilizing IMRT. A review performed by the PTCOG Lymphoma Subcommittee concluded that free breathing (FB) proton treatments are superior to IMRT with DIBH for heart, lung, breast, and integral dose sparing, however, a more nuanced analysis is necessary. While our data conclusively found that PBS-PT was dosimetrically superior to IMRT, the use of a 4D averaged CT for IMRT planning may overestimate the benefits of PBS-PT compared to IMRT with the use of DIBH. For this work that is retrospective in nature, it was not practice nor standard for our center to undergo both DIBH and free-breathing simulations. A final limitation to consider is the heterogeneous breakdown of disease involvement such that 94 patients had UML disease but only 5 patients had bilateral axillary involvement. As these patients were treated over a 13-year period, such heterogeneity would be influenced by selection bias for referral for RT: the indications and availability of chemotherapy-alone strategies began and flourished in that time period.
There have been multiple studies performed on the use of PT for increased OAR sparing in the treatment of HL and aNHL. While these studies have analyzed dose metrics comparing PBS-PT and IMRT for the heart, cardiac substructures, lungs, and breast, none of the literature thus far has analyzed the site-specific sparing based on the Ann Arbor staging system.25, 33, 39, 40, 41, 42 When recommending PT for HL and aNHL, ideally this clinical recommendation will be informed by both the potential for reduction in OAR toxicities, as well as a consideration for cost-effectiveness, due to the limited availability of PT. Previous work by Mailhot Vega et al established thresholds for cost-effectiveness as well as reductions in coronary heart disease based on the mean heart dose for mediastinal lymphoma patients treated with PBS-PT.43 The previous work establishes thresholds for a reduction in proton mean heart dose in relative to the photon mean heart dose for a given patient, and these thresholds are stratified by initial photon plan mean heart dose, patient age, and patient gender. Mailhot Vega et al provides mean heart dose reductions associated with proton cost-effectiveness for a willingness to pay of $100K/quality-adjusted life years. Our cost-effectiveness acceptability estimates based on anatomic location of disease and reduction of coronary heart disease are presented in Table 2. These reflect the proportion of cases that would have been deemed cost-effective per the prior Mailhot Vega analysis. Highest acceptance of proton cost-acceptability was associated with UML mediastinal involvement in addition to hilar involvement.
Table 2.
Percentage proton cost-acceptability by anatomic sites of involvement.
| Site | Men |
Women |
||
|---|---|---|---|---|
| Age 30 (y) | Age 60 (y) | Age 30 (y) | Age 60 (y) | |
| UM | 48% | 59% | 9% | 29% |
| UML | 73% | 80% | 38% | 54% |
| Left Hilar | 50% | 50% | 33% | 33% |
| Right Hilar | 50% | 50% | 25% | 50% |
| Bilateral Hilar | 29% | 57% | 13% | 25% |
| Left Hilar + Left ICV | 100% | 100% | 20% | 20% |
Abbreviations: UM, upper + middle mediastinal; UML, upper + middle + lower mediastinal; ICV, infraclavicular.
Current national guidelines for lymphoma therapy remain agnostic to anatomic site. These analyses provide data that can inform stakeholders with estimates for expected OAR doses—offset by the expected toxicities that chemotherapy-alone strategies engender, typically associated with increased anthracycline and alkylating agent dosages. Similarly, ASTRO’s policy for PT has evolved within the last decade to include patients with mediastinal lymphomas; yet insurance companies remain a third party within the patient-physician relationship for shared decision-making. These analyses provide data for clinician stakeholders who have clinical disease information with possible benefits of PT based on disease location.
Ethics
The study protocol was approved by the University of Florida Institutional Review Board (IRB202003234). All participants provided informed consent to participate in this study.
Funding
RBMV received salary support from a KL2 award through 3UL1TR001427-07S1 and currently receives salary support as a Robert A. Winn Excellence in Clinical Trials: Career Development Award recipient. This study received funding through a 2021 PTCOG Award.
CRediT authorship contribution statement
Keaton Reiners: Conceptualization, Data Curation, Formal Analysis, Methodology, Software, Writing – Original Draft, Writing – Review and Editing. Emma Viviers: Writing – Review and Editing, Data curation. Nataly Getman: Writing – Review and Editing, Formal Analysis. Kevin Kirby: Writing – Review and Editing, Formal Analysis. Perry B. Johnson: Writing – Review and Editing. Nancy P. Mendenhall: Writing – Review and Editing. Yawei Zhang: Writing – Review and Editing. Raymond B. Mailhot Vega: Project administration, Resources, Supervision, Writing – Original Draft, Writing – Review and Editing, Funding Acquisition.
Declaration of Conflicts of Interest
The authors declare the following financial interests/personal relationships, which may be considered as potential competing interests: NPM is the Editor-in-Chief of IJPT, and PBJ is an Associate Editor for IJPT. If there are other authors, they declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper.
Data availability
The authors agree to share anonymized data upon reasonable request by researchers.
Footnotes
Supplementary data associated with this article can be found in the online version at doi:10.1016/j.ijpt.2026.101307.
Appendix A. Supplementary material
Supplementary material
.
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