Omitting Mediastinal Radiotherapy in Some Patients With Primary Mediastinal B-Cell Lymphoma After Immunochemotherapy
In the largest prospective study of patients with primary mediastinal B-cell lymphoma, radiation therapy was omitted in complete responders to immunochemotherapy without compromising outcomes. These findings were presented at the 2023 ASCO Annual Meeting.1
“Mediastinal radiotherapy may be safely omitted in patients with a complete metabolic response after front-line immunochemotherapy containing rituximab and doxorubicin. This is in keeping with the results of single-institution retrospective studies,” said Emanuele Zucca, MD, a consultant and Head of the Lymphoma Unit at the Oncology Institute of Southern Switzerlan d in Bellinzona.
The IELSG37 trial was planned with a noninferiority design to test whether radiotherapy could be omitted in patients who achieved a complete metabolic response after immunochemotherapy. Although the event rate did not reach the assumed level, the findings support the omission of radiotherapy in patients achieving a complete metabolic response after immunochemotherapy, he said.
Mediastinal radiotherapy may be safely omitted in patients [with primary mediastinal B-cell lymphoma] who have a complete metabolic response after front-line immunochemotherapy containing rituximab and doxorubicin.— Emanuele Zucca, MD
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Primary mediastinal B-cell lymphoma is clinically and biologically distinct from other types of aggressive lymphoma, usually occurs in younger adults, and may have a good prognosis barring relapse after front-line chemoimmunotherapy—in which case prompt response to treatment is critical. “This has led many of us to use radiotherapy as a way to consolidate chemoimmunotherapy response, though radiotherapy increases the risk of second cancers and cardiovascular disease,” he said.
The omission of radiotherapy has been controversial, and the study addressed the question of whether this practice is safe in patients who respond to chemoimmunotherapy. The answer is clear, according to Dr. Zucca: “This study shows chemoimmunotherapy alone is an effective treatment for primary mediastinal B-cell lymphoma.”
The IELSG37 trial, which enrolled patients with newly diagnosed primary mediastinal B-cell lymphoma (median patient age, 35) from 13 countries, compared mediastinal radiotherapy and observation only in patients who had complete remission of lymphoma on positron-emission tomography (PET) or computed tomography (CT) scans after standard immunochemotherapy with an anthracycline and rituximab–containing regimen. A complete metabolic response was defined as a Deauville score of 1 to 3, according to the Lugano classification.
Induction immunochemotherapy was completed and response assessed in 530 patients; 268 (50.6%) had a complete metabolic response and were randomly allocated to observation (n = 132) or consolidation radiation therapy at 30 Gy (n = 136). Most patients had bulky disease or elevated lactate dehydrogenase levels. The Deauville score was 2 for about 52% of patients and 3 for 45%. As expected, few patients had complete disappearance of any residual uptake.
Investigators assumed a 30-month progression-free survival probability of 85% in both arms, with alpha at 0.05, 80% power, and a hazard ratio (HR) of 1.77 as the noninferiority margin. After two planned and one unplanned interim analyses revealed fewer events than expected, a recalculation of the sample size showed the trial was no longer feasible. The independent data monitoring committee recommended that the analysis for the primary endpoint should be conducted after more than 80% of patients completed at least 30 months of follow-up.
- In the largest trial ever conducted in primary mediastinal B-cell lymphoma, mediastinal radiotherapy was omitted in patients who responded to front-line immunochemotherapy.
- There appeared to be no negative impact on progression-free or overall survival with the omission of radiotherapy.
- At 30 months, more than 96% of both arms were progression-free, and more than 90% were alive.
- The omission of radiotherapy may spare many patients, who are often young women, long-term cardiac toxicity and secondary cancers.
This analysis occurred when 97% of patients had more than 30 months of follow-up; median follow-up was about 5 years in both arms. “In a disease where relapses are almost never seen after 2 years, these data are very mature for progression-free survival,” Dr. Zucca noted.
At 30 months, the progression-free survival rate was 98.5% with radiotherapy and 96.2% with observation, for an unadjusted difference of 2.3% (P = .274). When investigators adjusted the calculation according to stratification factors, the absolute difference dropped to 1.2%, with a number needed to treat of 126 to prevent one relapse. The overall survival rate was more than 99% for both arms, reflecting no additional benefit from radiotherapy, Dr. Zucca reported.
“When we calculated the statistical power according to the actual event rate, we found a statistical power of 86.1% to detect an absolute progression-free survival difference at 30 months of more than 6%. This figure is clearly below the 10% difference that was initially taken as acceptable for the noninferiority margin,” he added.
The most common side effects of standard immunochemotherapy were hair loss; fatigue; sore mouth and throat; and transient neutropenia, thrombocytopenia, and anemia. “Longer follow-up is needed to ascertain late toxicities, but so far, three severe cardiac events and three secondary cancers have been reported, all in patients randomly assigned to radiotherapy,” Dr. Zucca concluded.
DISCLOSURE: Dr. Zucca reported financial relationships with BeiGene, Bristol Myers Squibb, Curis, Incyte, Ipsen, Janssen, Eli Lilly, Merck, Miltenyi Biomedicine, and Roche.
1. Zucca E, Davies A, Kryachok I, et al: Observation vs radiotherapy in primary mediastinal B-cell lymphoma patients with complete response to standard immunochemotherapy: The IELSG37 randomized trial. 2023 ASCO Annual Meeting. Abstract LBA7505. Presented June 6, 2023.
ASCO expert Corey Speers, MD, PhD, Professor of Radiation Oncology at the University Hospitals Seidman Cancer Center, Cleveland, provided thoughts on the IELSG37 trial at a press briefing. “The investigators should be congratulated for running the largest ever trial in primary mediastinal B-cell...