# Hodgkin Lymphoma: Omission of Radiation in PET-Negative Early-Stage Disease

## Introduction

The standard treatment for early-stage Hodgkin lymphoma (HL) has traditionally involved combined modality therapy (CMT), which consists of chemotherapy followed by radiation. While this approach has been effective, the excellent long-term survival rates of HL patients have shifted attention toward the late effects of radiation therapy. These late effects include cardiac disease, secondary malignancies, and pulmonary toxicity, all of which can significantly impact patients' quality of life years after treatment. The development of interim PET/CT imaging has allowed for response-adapted treatment strategies, aiming to omit radiation in patients who achieve a complete metabolic response, thereby potentially reducing these long-term risks.

## Rationale for Radiation Omission

Long-term mortality in HL survivors is increasingly attributed to treatment-related toxicity rather than disease relapse. Specifically, the risk of cardiac disease rises two- to seven-fold after mediastinal radiation, and women irradiated before age 30 face a five- to ten-fold increased risk of secondary breast cancer. Interim PET imaging after chemotherapy can identify patients with a low residual disease burden, as indicated by PET-negative status, who may safely forgo consolidative radiation without compromising overall survival.

## Landmark Trials

Several pivotal trials have investigated the omission of radiation in PET-negative early-stage HL. The RAPID trial conducted by the NCRI enrolled patients with early-stage, non-bulky HL who received three cycles of ABVD chemotherapy followed by an interim PET scan. Patients who were PET-negative were randomized to receive involved-field radiation therapy (IFRT) at 30 Gy or no further treatment. The trial demonstrated a three-year progression-free survival (PFS) of 94.6% in the radiation group versus 90.8% in the no-radiation group. Although the non-inferiority boundary was not met, indicating a small but statistically significant PFS advantage with radiation, overall survival was equivalent between the two arms.

The HD16 trial by the German Hodgkin Study Group focused on favorable early-stage HL patients treated with two cycles of ABVD followed by PET. PET-negative patients were randomized to 20 Gy IFRT or observation alone. At five years, PFS was 93.4% for the combined modality therapy group compared to 86.1% for the PET-guided omission group. Similar to RAPID, omission of radiation was associated with a higher relapse rate but no difference in overall survival, confirming a small but real PFS cost to omitting radiation.

The H10 trial, a collaboration between EORTC, LYSA, and FIL, included patients with both favorable and unfavorable early-stage HL. After two cycles of ABVD, PET-negative patients were randomized to involved-node radiation therapy (INRT) or additional cycles of ABVD alone. In the unfavorable group, non-inferiority was not demonstrated for chemotherapy alone, and the futility boundary was crossed, favoring combined modality therapy. In the favorable group, chemotherapy alone approached but did not meet the non-inferiority threshold. These results reinforce the benefit of radiation in reducing relapse risk, particularly in unfavorable disease.

| Trial | Population | Chemo | RT Arm | PFS (RT vs. no RT) | OS Difference |
|---|---|---|---|---|---|
| RAPID | Non-bulky, stage IA-IIA | 3x ABVD | 30 Gy IFRT | 94.6% vs. 90.8% (3 yr) | None |
| HD16 | Favorable, stage I-II | 2x ABVD | 20 Gy IFRT | 93.4% vs. 86.1% (5 yr) | None |
| H10 (favorable) | Favorable, stage I-II | 3x ABVD | 30 Gy INRT | Non-inferiority not met | None |
| H10 (unfavorable) | Unfavorable, stage I-II | 4x ABVD | 30 Gy INRT | Futility crossed (favors CMT) | None |

![Forest plot summarizing progression-free survival outcomes from RAPID, HD16, and H10 trials comparing radiation omission vs. consolidative RT in PET-negative early-stage Hodgkin lymphoma](images/hl-pet-negative-trials.jpg)

## Interpreting PET Response

The Deauville score is the standard method for assessing PET response in HL. Scores of 1 or 2 indicate a complete metabolic response, with uptake at or below the mediastinal blood pool. A score of 3, where uptake is above the mediastinal level but at or below liver uptake, is generally considered PET-negative. Scores of 4 or 5 indicate PET-positive disease, suggesting residual active lymphoma and a need for radiation. PET scans are typically performed after two to three cycles of ABVD chemotherapy, with imaging scheduled at least 10 to 14 days after the last chemotherapy dose to reduce false positives. While standardized uptake value (SUV) thresholds can provide additional information, the Deauville scoring system remains the preferred method for response assessment.

## Clinical Decision Framework

Several factors influence the decision to omit or include radiation therapy after chemotherapy in early-stage HL. Radiation omission is favored in patients with a Deauville score of 1 or 2 following adequate chemotherapy, non-bulky disease at presentation, younger age (particularly under 30 years due to higher lifetime risk of late effects), female sex (given the increased breast cancer risk with mediastinal radiation), and when patients prefer to avoid radiation after informed discussion. Conversely, consolidative radiation is generally recommended for patients with a Deauville score of 3, bulky disease at presentation even if PET-negative, unfavorable risk features such as elevated erythrocyte sedimentation rate (ESR), multiple nodal sites, or extranodal involvement, as well as for male or older patients where the risk of late effects is lower. Patients with initial stage II disease involving multiple sites may also benefit from radiation.

![Decision algorithm for PET-adapted radiation therapy in early-stage Hodgkin lymphoma based on Deauville score and risk factors](images/hl-pet-adapted-algorithm.jpg)

## Chemotherapy Intensification as an Alternative

In some protocols, additional cycles of chemotherapy are used as an alternative to radiation. For example, the favorable arm of the H10 trial administered three extra cycles of ABVD instead of radiation. However, this approach raises concerns about cumulative bleomycin-related pulmonary toxicity. Escalation to more intensive regimens such as BEACOPP is not standard for early-stage favorable HL. Although the HD18 trial demonstrated the role of BEACOPP in advanced-stage disease, its increased toxicity limits its use as a substitute for radiation in early-stage patients.

## Shared Decision-Making

The absolute difference in progression-free survival when omitting radiation ranges from approximately 3 to 7 percent. This modest increase in relapse risk must be balanced against the potential for decades of late-effect toxicity associated with radiation. Importantly, salvage therapy for relapsed early-stage HL, including autologous stem cell transplantation, achieves high cure rates. Patients should be counseled that while omitting radiation slightly increases the risk of relapse, it does not compromise overall survival based on current follow-up data.

![Infographic illustrating the tradeoff between slightly higher relapse risk vs. reduced long-term toxicity when omitting radiation in PET-negative Hodgkin lymphoma](images/hl-rt-omission-tradeoff.jpg)

## Key Clinical Pearls

Multiple randomized trials, including RAPID, HD16, and H10, have consistently demonstrated a small progression-free survival advantage for consolidative radiation therapy in PET-negative early-stage Hodgkin lymphoma, but no difference in overall survival. Radiation omission is a reasonable option in patients with PET-negative, non-bulky, favorable early-stage disease after thorough informed consent. The Deauville score remains the standard for PET response assessment, with scores of 1 and 2 indicating complete metabolic response. Patients presenting with bulky disease may still warrant consolidative radiation even if interim PET is negative. Finally, the availability of highly effective salvage therapies for relapsed early-stage HL provides a safety net that supports the option of omitting initial radiation in selected patients.

## References

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3. Andre MPE, Girinsky T, Federico M, et al. Early positron emission tomography response-adapted treatment in stage I and II Hodgkin lymphoma: final results of the randomized EORTC/LYSA/FIL H10 trial. *J Clin Oncol*. 2017;35(16):1786-1794.  
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