# Hodgkin Lymphoma: Involved-Site Radiation Therapy (ISRT)

## Introduction

Radiation therapy has played a crucial role in the treatment of Hodgkin lymphoma (HL) for more than six decades. Over time, the approach to radiation fields has evolved significantly, moving from extended-field radiation therapy (EFRT) to involved-field radiation therapy (IFRT), and now to involved-site radiation therapy (ISRT). This progression reflects an ongoing effort to reduce long-term toxicities while preserving excellent disease control. Currently, ISRT, which is endorsed by the International Lymphoma Radiation Oncology Group (ILROG), represents the standard of care in radiation treatment for HL.

## Historical Evolution of Radiation Fields

Initially, extended-field radiation therapy (EFRT) was employed, which included not only the clinically involved lymph node regions but also uninvolved nodal areas, such as the mantle field and inverted-Y fields. Although EFRT achieved high cure rates, it was associated with unacceptable long-term toxicities, including cardiac disease, secondary malignancies, and hypothyroidism. With the advent of combined modality therapy, EFRT was largely abandoned.

In response, involved-field radiation therapy (IFRT) was developed to target only the involved nodal regions as defined by the Ann Arbor classification system. IFRT became the standard in clinical trials such as HD10, HD11, and RAPID. However, IFRT faced criticism because its field borders were based on anatomical nodal regions rather than the individual patient’s disease extent.

To address this, involved-node radiation therapy (INRT) was introduced, which focused radiation solely on the involved lymph node(s) with small margins. INRT required pre-chemotherapy PET/CT imaging performed in the treatment position, which was often unavailable, limiting its widespread use. INRT served as a conceptual predecessor to ISRT.

In 2014, the ILROG published consensus guidelines for involved-site radiation therapy (ISRT). ISRT is a practical adaptation of INRT principles designed for situations where pre-chemotherapy imaging in the treatment position is not available. It uses pre-chemotherapy imaging fused with planning CT scans to accurately define target volumes.

![Evolution of radiation field design in Hodgkin lymphoma from extended-field to involved-site radiation therapy](images/hl-field-evolution.jpg)

## ISRT Volume Definitions

The pre-chemotherapy gross tumor volume (GTV-pre) includes all sites of initial disease identified on pre-chemotherapy PET/CT scans. This encompasses involved lymph nodes as well as any extranodal extension. The clinical target volume (CTV) is derived by modifying the GTV-pre according to post-chemotherapy anatomy. In the cranio-caudal direction, the CTV respects the pre-chemotherapy extent of disease, while in the axial plane, it may be reduced to the post-chemotherapy volume if adjacent organs at risk allow. Importantly, the CTV does not include uninvolved nodal regions.

The planning target volume (PTV) accounts for uncertainties in patient setup and organ motion, typically involving a 5 to 10 mm expansion from the CTV. For mediastinal disease, four-dimensional CT (4D-CT) may be necessary to account for respiratory motion during treatment.

## Dose and Fractionation

For patients with favorable early-stage HL, the recommended radiation dose is 20 Gy delivered in 10 fractions, as established by the HD10 trial, following an adequate chemotherapy response. This is typically combined with two cycles of ABVD chemotherapy. In early-stage unfavorable disease, a higher dose of 30 Gy in 15 fractions is used after four cycles of ABVD, based on the HD11 trial. If residual PET-avid disease remains, a boost to 30-36 Gy may be considered.

In advanced-stage HL, consolidation radiation doses range from 30 to 36 Gy, targeting sites of initial bulky disease or residual PET-positive areas. However, the role of radiation in this setting is diminishing due to the increasing use of PET-adapted chemotherapy strategies.

| Stage / Setting | Chemotherapy | RT Dose | Key Trial |
|---|---|---|---|
| Favorable early-stage | ABVD x 2 cycles | 20 Gy / 10 fx | HD10 |
| Unfavorable early-stage | ABVD x 4 cycles | 30 Gy / 15 fx | HD11 |
| Advanced-stage (bulky/residual PET+) | ABVD x 6 or escalated BEACOPP | 30–36 Gy / 15–18 fx | HD15, HD18 |
| PET-negative after chemo (early) | ABVD x 3 | Consider omission (see Lecture 55) | RAPID |

## Treatment Planning Considerations

Regarding radiation techniques, three-dimensional conformal radiation therapy (3D-CRT) is acceptable for simple volumes such as unilateral neck involvement. However, intensity-modulated radiation therapy (IMRT) or volumetric modulated arc therapy (VMAT) is preferred for mediastinal disease to reduce doses to the heart and lungs. Deep inspiration breath hold (DIBH) is strongly recommended during mediastinal ISRT to further minimize cardiac and pulmonary exposure.

Key organs at risk include the heart, lungs, thyroid, breast tissue in young women, and the spinal cord. Efforts should be made to keep the mean heart dose below 5 Gy when feasible, while minimizing the volume of heart receiving 20 Gy (V20) and 30 Gy (V30). For the lungs, the goal is to keep V20 under 30% and the mean lung dose below 13.5 Gy. Thyroid dose should be documented, and patients should be counseled about long-term monitoring for hypothyroidism. In young women, breast tissue dose should be minimized using IMRT or, when available, proton therapy. The spinal cord maximum dose should remain below 36 Gy.

Proton therapy offers potential advantages by reducing radiation dose to the heart, lungs, and breasts, which is particularly beneficial for young patients with mediastinal disease. However, proton therapy is not universally available, and comparative trials are ongoing to better define its role.

![ISRT treatment plan for mediastinal Hodgkin lymphoma using VMAT with deep inspiration breath hold showing cardiac dose sparing](images/hl-isrt-dibh-plan.jpg)

## Special Considerations

Bulky disease is defined as a mass larger than 10 cm or a mediastinal mass ratio greater than 0.33. Such cases carry a higher risk of local failure, and consolidative ISRT is recommended even in advanced-stage disease, with doses ranging from 30 to 36 Gy.

When the spleen is involved at diagnosis, the entire spleen is included in the CTV. If the spleen normalizes in size after chemotherapy, the post-chemotherapy splenic volume is used for planning.

For involvement of the Waldeyer ring, only the involved portion, such as the tonsil, is included in the radiation volume rather than the entire ring. Careful planning is necessary to avoid unnecessary radiation to the salivary glands and oral mucosa.

![Axial CT slice demonstrating ISRT volume delineation for cervical and mediastinal Hodgkin lymphoma with pre-chemotherapy PET fusion](images/hl-isrt-contouring.jpg)

## Key Clinical Pearls

Involved-site radiation therapy (ISRT) is now the standard radiation field for Hodgkin lymphoma, having replaced involved-field radiation therapy (IFRT) according to ILROG guidelines. Pre-chemotherapy PET/CT imaging is essential for accurate target delineation and should be obtained before any treatment whenever possible. For mediastinal disease, the use of deep inspiration breath hold (DIBH) combined with IMRT or VMAT techniques is critical to reduce radiation doses to the heart and lungs. The typical radiation dose is 20 Gy for favorable early-stage disease, as supported by the HD10 trial, and 30 Gy for unfavorable early-stage disease. Long-term survivorship care must focus on screening for cardiac complications, monitoring thyroid function, and assessing the risk of secondary malignancies.

## References

1. Specht L, Yahalom J, Illidge T, et al. Modern radiation therapy for Hodgkin lymphoma: field and dose guidelines from the International Lymphoma Radiation Oncology Group (ILROG). *Int J Radiat Oncol Biol Phys*. 2014;89(4):854-862.  
2. Engert A, Plutschow A, Eich HT, et al. Reduced treatment intensity in patients with early-stage Hodgkin's lymphoma (HD10). *N Engl J Med*. 2010;363(7):640-652.  
3. Eich HT, Diehl V, Gorgen H, et al. Intensified chemotherapy and dose-reduced involved-field radiotherapy in patients with early unfavorable Hodgkin's lymphoma: final analysis of the German Hodgkin Study Group HD11 trial. *J Clin Oncol*. 2010;28(27):4199-4206.  
4. 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(16):1635-1646.