Clinical Investigation
Modern Radiation Therapy for Hodgkin Lymphoma: Field and Dose Guidelines From the International Lymphoma Radiation Oncology Group (ILROG)

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Radiation therapy (RT) is the most effective single modality for local control of Hodgkin lymphoma (HL) and an important component of therapy for many patients. These guidelines have been developed to address the use of RT in HL in the modern era of combined modality treatment. The role of reduced volumes and doses is addressed, integrating modern imaging with 3-dimensional (3D) planning and advanced techniques of treatment delivery. The previously applied extended field (EF) and original involved field (IF) techniques, which treated larger volumes based on nodal stations, have now been replaced by the use of limited volumes, based solely on detectable nodal (and extranodal extension) involvement at presentation, using contrast-enhanced computed tomography, positron emission tomography/computed tomography, magnetic resonance imaging, or a combination of these techniques. The International Commission on Radiation Units and Measurements concepts of gross tumor volume, clinical target volume, internal target volume, and planning target volume are used for defining the targeted volumes. Newer treatment techniques, including intensity modulated radiation therapy, breath-hold, image guided radiation therapy, and 4-dimensional imaging, should be implemented when their use is expected to decrease significantly the risk for normal tissue damage while still achieving the primary goal of local tumor control. The highly conformal involved node radiation therapy (INRT), recently introduced for patients for whom optimal imaging is available, is explained. A new concept, involved site radiation therapy (ISRT), is introduced as the standard conformal therapy for the scenario, commonly encountered, wherein optimal imaging is not available. There is increasing evidence that RT doses used in the past are higher than necessary for disease control in this era of combined modality therapy. The use of INRT and of lower doses in early-stage HL is supported by available data. Although the use of ISRT has not yet been validated in a formal study, it is more conservative than INRT, accounting for suboptimal information and appropriately designed for safe local disease control. The goal of modern smaller field radiation therapy is to reduce both treatment volume and treatment dose while maintaining efficacy and minimizing acute and late sequelae. This review is a consensus of the International Lymphoma Radiation Oncology Group (ILROG) Steering Committee regarding the modern approach to RT in the treatment of HL, outlining a new concept of ISRT in which reduced treatment volumes are planned for the effective control of involved sites of HL. Nodal and extranodal non-Hodgkin lymphomas (NHL) are covered separately by ILROG guidelines.

Introduction

The purpose of these guidelines is to provide a consensus position on the modern approach to the delivery of radiation therapy (RT) in the treatment of Hodgkin lymphoma (HL) and to outline a new concept of involved site radiation therapy (ISRT) in which reduced treatment volumes are planned for the effective control of involved sites of disease. The present guidelines represent a consensus viewpoint of the Steering Committee of the International Lymphoma Radiation Oncology Group (ILROG). The guidelines are based on the best available evidence and the experience of ILROG members (1).

RT has been widely used in the management of malignant lymphomas and was responsible for many of the early cures of HL. Although RT continues to play an important role as a single modality for some HL patients, in most HL patients, RT is used in combination with chemotherapy. Combination chemotherapy has evolved with increasing efficacy to play a major role in the management of HL. RT continues to have an important place in ensuring locoregional control and improving overall outcome in the combined modality treatment programs for HL. With effective curative treatment regimens, there is increasing concern about the late effects of treatment and the quality of “survivorship.” Therefore, it is of paramount importance in the delivery of RT to maintain high rates of long-term local control while minimizing radiation exposure to surrounding normal tissues. Furthermore, it is recognized that most recurrences in patients treated for HL occur in sites of previous involvement, and that RT reduces local recurrence. Advances in imaging, treatment planning, and RT delivery have made it possible to better define and further decrease RT fields in many situations. The current guidelines for involved field RT based on anatomic landmarks and encompassing adjacent uninvolved lymph nodes (2) are no longer appropriate for modern, more focused RT delivery aimed at reducing normal tissue exposure.

In this article, we highlight the application of advances in the technologic expertise available in the delivery of RT. These developments include the routine use of cross-sectional imaging for RT planning, accurate dosimetry using modern algorithms that adjust for tissue inhomogeneities, complex beam shaping with multileaf collimation, and intensity modulated beam delivery in the treatment of HL.

The purpose of this document is to provide radiation oncologists treating HL with guidelines for imaging and treatment planning. The focus is on adult patients with localized HL and on bulky sites in advanced-stage and residual/relapsed/refractory disease in all stages.

Section snippets

Treatment Volume Principles

Modern RT planning in lymphoma incorporates the current concepts of volume determination as outlined in the International Commission on Radiation Units and Measurements (ICRU) Report 83 (3). It is based on defining a gross tumor volume (GTV) and a clinical target volume (CTV) that is expanded to a planning target volume (PTV). The PTV is then used to define beam coverage. This approach allows direct comparison with the diagnostic imaging, increasing the accuracy with which lymph node volumes

Radiation Therapy as Primary Treatment

As a single modality in HL, RT is relevant for early-stage lymphocyte-predominant Hodgkin lymphoma (LPHL). It may also be relevant in selected cases of early-stage classic HL in patients who are not candidates for primary chemotherapy because of having serious comorbidities.

In most clinical situations that require RT as the primary modality, the GTV should be readily visualized during simulation. In this situation, the clinical target volume (CTV) should be more generous because microscopic or

Radiation Therapy as Part of a Combined Modality Approach

In early-stage classic HL, RT is often part of the treatment program after adequate systemic chemotherapy in all age groups. RT improves freedom from treatment failure even in patients with negative positron emission tomography (PET) scans 4, 5 and allows treatment with fewer chemotherapy cycles (6). In a recent systematic review, combined modality treatment was found to improve tumor control and overall survival in patients with early-stage HL (7). In patients with advanced-stage disease,

Volume Definitions for Planning Radiation Therapy for Lymphoma

These principles apply whether ISRT or involved node radiation otherapy (INRT) is applied (see below). The difference between them is the quality and accuracy of the prechemotherapy imaging, which determine the margins needed to allow for uncertainties in the contouring of the CTV.

Radiation Therapy Dose Considerations

The determinants of dose prescription for HL include the histologic subtype (classic HL vs LPHL) and clinical risk factors.

For patients with early-stage classic HL in CR after chemotherapy, the dose to the CTV is determined on the basis of the results of the German Hodgkin Studies HD 10 and 11 6, 11. For patients with favorable characteristics according to the German criteria, the dose is 20 Gy, whereas for patients with unfavorable characteristics it is 30 Gy.

For patients with early-stage

Role of imaging in radiation therapy planning

Lymphoma staging and response assessment is based on 3D imaging, with CT supplemented by functional imaging using 18F-fluorodeoxyglucose (FDG)-PET. Optimally, these images should be acquired with the patient in the radiation treatment position and with the involvement of the radiation oncologist (Fig. 1).

The use of diagnostic contrast-enhanced CT is essential to delineate nodal stations and differentiate nodes from vessels. In centers where PET/CT can be done with contrast medium, this can

Dose Constraints

Previous experience comes from patients treated over the past 5 decades, where extended fields and higher doses resulted in significant risks of morbidity and mortality. Hence, it is important to use the ISRT treatment technique described below and to choose the treatment plan that is estimated to lead to the lowest risk of long-term complications for the individual patient. Consideration should be given to factors such as sex, age, and comorbidities.

An integral part of calculating conformal

Involved Site Radiation Therapy in Early-Stage HL

The concept of ISRT was developed on the basis of the INRT concept. INRT was introduced and implemented by the European Association for Research and Treatment of Cancer (EORTC) Lymphoma Group and is detailed later in the document 18, 19.

In both INRT and ISRT, the prechemotherapy GTV determines the CTV, and the irradiated volume is significantly smaller than with IFRT. However, ISRT accommodates cases in which optimal prechemotherapy imaging is not available to the radiation oncologist. In these

Involved Node Radiation Therapy in Early-Stage Classic HL

The concept of INRT for early-stage classic HL was developed and implemented by the EORTC and replaced the traditional larger IFRT that was used in previous studies by the EORTC and other groups. The INRT technique reduces the treated volume to a minimum, but to be safe, optimal imaging both before and after chemotherapy is needed 18, 20. INRT can therefore be regarded as a special case of ISRT wherein optimal imaging is available. It has been demonstrated that PET/CT is the most accurate

Irradiation of Residual Mass After Full Chemotherapy for Advanced Disease

In advanced disease (classic HL and LPHL), many centers treat patients with chemotherapy alone (especially in the absence of bulky disease) and only if a CR is not achieved will RT be used. The target in this situation is the residual mass (GTV) after chemotherapy.

Once the GTV has been contoured, the planning procedure is as described previously. A margin is added to account for uncertainties and motion. Usually a margin of 1 cm is sufficient, but in the chest and upper abdomen a larger margin

Irradiation of Early-Stage LPHL

When RT is used as the only treatment modality, the CTV must be designed to encompass suspected subclinical disease. However, no advantage has been demonstrated with EFRT as opposed to more limited treatment fields (23). The CTV should incorporate the GTV and include as a minimum adjacent lymph nodes in that site and a generous margin dictated by the clinical situation. The scenario is similar to RT for localized indolent NHL.

Larger Field RT

The role of larger field RT is now limited essentially to salvage treatment in patients in whom chemotherapy is unsuccessful and who are unable to embark on more intensive salvage treatment schedules. Such salvage cases are usually addressed on a case-to-case basis and it is not feasible to produce guidelines, given the diversity of individual cases. As such, there are no data to support the use of extended fields that can cause toxicity and compromise the safety of subsequent therapy such as

Refractory and Relapsed HL

Salvage RT plays an important role in local control for patients who have primary refractory disease dominated by a local site. Salvage RT is also important for patients who experience relapse after achieving a CR with initial therapy, where RT is generally used as part of combined modality therapy along with salvage chemotherapy followed by high-dose chemotherapy and autologous stem cell transplantation (ASCT).

A small group of patients with localized disease and no systemic symptoms enjoy

Conclusion

Modern RT for HL is a highly individualized treatment restricted to limited treatment volumes. Modern imaging and RT techniques should be used to limit the amount of normal tissue being irradiated, thus minimizing the risk of long-term complications. The newly defined fields of ISRT represent a significant reduction in the volume included in the previously used IFRT. Radiation oncologists treating HL should be involved as part of the multidisciplinary team in the initial management plan and

Acknowledgment

The authors thank Ms. Jessi Shuttleworth for coordinating the ILROG guidelines committee.

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Supported by the Connecticut Sports Foundation and the Global Excellence Program of the Capital Region of Denmark.

Conflict of interest: none.

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