# Diffuse Large B-Cell Lymphoma: Consolidative Radiation After Chemoimmunotherapy

## Introduction

Diffuse large B-cell lymphoma (DLBCL) represents the most common subtype of non-Hodgkin lymphoma, accounting for about 30% of all cases. The introduction of rituximab to the CHOP chemotherapy regimen (R-CHOP) has significantly improved patient outcomes, prompting a reevaluation of the role of consolidative radiation therapy (RT) in treatment. This discussion explores the evidence supporting and opposing the use of consolidative RT in the era of rituximab-based chemoimmunotherapy.

## Historical Context

### Pre-Rituximab Era

Before rituximab became standard, CHOP chemotherapy alone for limited-stage DLBCL often resulted in suboptimal local disease control. The SWOG 8736 trial demonstrated that three cycles of CHOP followed by involved-field radiation therapy (IFRT) was superior to eight cycles of CHOP alone, with a 5-year progression-free survival (PFS) of 77% versus 64%, respectively. Consequently, radiation therapy was considered an essential component of treatment for limited-stage disease during this period.

### Rituximab Revolution

The addition of rituximab to CHOP markedly improved complete response rates and overall survival. Six to eight cycles of R-CHOP became the standard of care for advanced-stage DLBCL. This advancement raised the critical question of whether consolidative radiation therapy still provides additional benefit after adequate chemoimmunotherapy.

## Evidence for Consolidative RT

### SWOG S0014

In patients with limited-stage DLBCL who had one or more International Prognostic Index (IPI) risk factors, the SWOG S0014 study administered three cycles of R-CHOP followed by IFRT at doses between 40 and 46 Gy. This approach yielded excellent outcomes, with a 5-year PFS of 88% and overall survival (OS) of 92%. However, as a single-arm study without a chemotherapy-alone comparator, definitive conclusions about the added value of RT remain limited.

### UNFOLDER Trial (Arm Comparison)

The UNFOLDER trial randomized patients with limited-stage DLBCL to receive six cycles of R-CHOP with or without consolidative radiation therapy. The arm receiving RT demonstrated improved event-free survival (EFS). An interim analysis revealed a higher number of adverse events in the non-RT arm, leading to early closure of that group. This trial supports the benefit of RT in this setting.

### Retrospective and NCDB Analyses

Several large retrospective studies and analyses of the National Cancer Database (NCDB) have suggested that consolidative RT improves overall survival in limited-stage DLBCL, even with rituximab-based therapy. The benefit is most pronounced in patients presenting with bulky disease (tumors larger than 7.5 cm), incomplete response to chemotherapy, or involvement of extranodal sites.

![Summary of key trials evaluating consolidative radiation in limited-stage DLBCL showing PFS outcomes across treatment strategies](images/dlbcl-rt-trials.jpg)

## Evidence Against Routine Consolidative RT

### FLYER Trial

The FLYER trial focused on favorable limited-stage DLBCL patients aged 18 to 60 years with an IPI of 0 and non-bulky disease. It compared four cycles of R-CHOP plus two doses of rituximab against six cycles of R-CHOP, with no radiation therapy in either arm. Both groups achieved a 3-year PFS exceeding 95%, suggesting that chemotherapy alone may be sufficient for very favorable patients.

### LYSA/GOELAMS Trial (IELSG-37)

This trial employed a PET-directed approach, randomizing patients who achieved a complete metabolic response (CMR) defined by Deauville scores 1 to 3 after R-CHOP to either consolidative RT or observation. No significant difference in PFS was observed between the two arms among PET-negative patients, supporting the omission of RT in those with a complete metabolic response.

### R-CHOP x 6 Without RT

Trials such as RICOVER-60 have demonstrated that six cycles of R-CHOP chemotherapy alone can achieve 3-year PFS rates above 85% in limited-stage disease. This suggests that extended chemotherapy may compensate for the omission of radiation therapy in certain patient populations.

## PET-Adapted Strategy

### Complete Metabolic Response (Deauville 1-3)

For patients with non-bulky limited-stage DLBCL who achieve a complete metabolic response on PET imaging, radiation therapy may be safely omitted. These patients require close surveillance with clinical follow-up and imaging according to established guidelines to monitor for relapse.

### Partial Metabolic Response (Deauville 4-5)

In contrast, patients with a partial metabolic response, indicated by Deauville scores of 4 or 5, are strongly recommended to receive consolidative radiation therapy, typically 30 to 40 Gy directed to the involved site. Residual PET-avid disease after adequate chemotherapy carries a high risk of local failure without RT. Biopsy of residual PET-avid masses should be considered to confirm the presence of viable tumor before proceeding with radiation.

## Dose and Technique

### Dose Recommendations (ILROG)

The International Lymphoma Radiation Oncology Group (ILROG) recommends delivering 30 to 36 Gy in 1.5 to 2 Gy fractions for patients achieving complete response. For those with partial response or residual disease, higher doses of 40 to 50 Gy are advised. Involved-site radiation therapy (ISRT) principles guide treatment, with pre-chemotherapy PET/CT scans used to delineate target volumes accurately.

### Treatment Planning

ISRT fields are based on the extent of disease before chemotherapy but are modified according to post-chemotherapy anatomy. Advanced techniques such as intensity-modulated radiation therapy (IMRT) or volumetric modulated arc therapy (VMAT) are preferred for mediastinal or anatomically complex volumes. Deep inspiration breath hold techniques are employed to minimize radiation exposure to critical structures in mediastinal disease.

![ISRT treatment plan for consolidative radiation to a residual mediastinal mass following R-CHOP for DLBCL](images/dlbcl-consolidative-rt-plan.jpg)

## Special Situations

### Bulky Disease

Bulky disease at presentation, defined as tumors larger than 7.5 to 10 cm, strongly indicates the need for consolidative radiation therapy. These patients have higher local failure rates even if they achieve a complete metabolic response. Radiation doses of 30 to 36 Gy are typically delivered to the initially bulky site to improve local control.

### Testicular DLBCL

In testicular DLBCL, prophylactic contralateral scrotal irradiation at doses of 25 to 30 Gy is recommended to prevent relapse, as there is a high risk of contralateral testicular recurrence without radiation. Additionally, intrathecal prophylaxis is indicated due to the risk of central nervous system involvement.

### Extranodal Sites

Patients with extranodal involvement, such as bone, sinus, orbit, and other primary sites, may benefit from consolidative radiation therapy. In gastrointestinal DLBCL, radiation is used selectively for localized residual disease after chemotherapy.

![Algorithm for PET-adapted consolidative radiation decision-making in limited-stage DLBCL after R-CHOP](images/dlbcl-pet-adapted-rt.jpg)

## Key Clinical Pearls

Consolidative radiation therapy improves local control in limited-stage DLBCL even in the rituximab era, particularly for patients with bulky disease or incomplete response to chemotherapy. PET-adapted strategies enable selective omission of radiation in patients who achieve a complete metabolic response after R-CHOP. Conversely, consolidative radiation is strongly recommended for those with PET-positive residual disease following chemotherapy. Standard radiation doses range from 30 to 36 Gy for patients with complete metabolic response and 40 to 50 Gy for those with residual disease, following ISRT principles. In testicular DLBCL, contralateral scrotal irradiation is necessary regardless of treatment response to reduce relapse risk.

## References

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3. Lamy T, Damaj G, Soubeyran P, et al. R-CHOP with or without radiotherapy in non-bulky limited-stage diffuse large B-cell lymphoma (IELSG-37): a randomised, open-label, phase 3 trial. *Lancet Oncol*. 2023;24(7):781-793.  
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