In a phase III German Hodgkin Study Group trial (GHSG HD17) reported in The Lancet Oncology, Peter Borchmann, MD, and colleagues found that positron-emission tomography (PET)-guided omission of consolidation radiotherapy was associated with noninferior progression-free survival among patients with early-stage unfavorable Hodgkin lymphoma in complete metabolic response after induction chemotherapy.

Peter Borchmann, MD

Study Details

In the open-label trial, 1,096 eligible patients with newly diagnosed disease from sites in Germany, Switzerland, Austria, and The Netherlands were randomly assigned between January 2012 and March 2017 to receive standard combined-modality treatment (n = 546) or PET4-guided treatment, ie, PET scan after four cycles of chemotherapy (n = 550). The per-protocol population consisted of 428 patients in the standard combined-modality treatment group and 477 in the PET4-guided treatment group.

Treatment consisted of standard combined-modality treatment with the 2 + 2 regimen of two  21-day cycles of escalated (e)BEACOPP (cyclophosphamide at 1,250 mg/m² on day 1; doxorubicin at 35 mg/m² on day 1; etoposide at 200 mg/m² on days 1–3; procarbazine at 100 mg/m² on days 1–7; prednisone at 40 mg/m² days 1–14; vincristine at 1.4 mg/m² on day 8 (maximum dose of 2 mg per cycle; and bleomycin at 10 mg/m² on day 8) and two 28-day cycles of ABVD (doxorubicin at 25 mg/m², bleomycin at 10 mg/m², vinblastine at 6 mg/m², and dacarbazine at 375 mg/m², all given on days 1 and 15), followed by 30 Gy of involved-field radiotherapy. PET4-guided treatment consisted of 2 + 2 chemotherapy followed by 30 Gy of involved-node radiotherapy only in patients with positive PET at the end of four cycles of chemotherapy.

In this final trial analysis, the primary objective was to show noninferiority of the PET4-guided strategy in per-protocol analysis of the primary endpoint of progression-free survival. Noninferiority was defined as an absolute difference of 8% in the 5-year progression-free survival estimates between the two groups.

Progression-Free Survival

At a median follow-up of 46.2 months (interquartile range = 32.7–61.2 months), estimated 5-year progression-free survival in the per-protocol population was 97.3% (95% confidence interval [CI] = 94.5%–98.7%) in the standard combined-modality treatment group vs 95.1% (95% CI = 92.0%–97.0%) in the PET4-guided treatment group (hazard ratio [HR] = 0.523, 95% CI = 0.226–1.211), with the between-group difference of 2.2% (95% CI = –0.9% to 5.3%), excluding the noninferiority margin of 8%.

In analysis restricted to 274 patients in the standard-treatment group vs 323 patients in the PET4 treatment group who were PET4-negative, estimated 5-year progression-free survival was 97.7% vs 95.5%, with a between-group difference of 1.7%. In analysis of the prognostic effect of PET4 on progression-free survival among 646 patients comparing those in either group with a positive PET4 vs those in the standard treatment group with negative PET4, estimated 5-year progression-free survival was significantly better in the PET4-negative group (HR = 3.03, P = .024).

Toxicity

In the intention-to-treat population, the most common grade 3 or 4 acute hematologic adverse events were leukopenia (83% in the standard treatment group vs 84% in the PET4 treatment group) and thrombocytopenia (26% vs 33%); the most frequent acute nonhematologic adverse events were infection (6% vs 8%) and nausea/vomiting (7% vs 6%).

Among 429 patients in the standard treatment group and 155 in the PET4 treatment group who received consolidation radiotherapy, grade 3 or 4 acute radiotherapy-associated toxicity occurred in 9% vs 3%, with the most common being dysphagia (6% vs 2%) and mucositis (2% vs 0%). Serious adverse events occurred in 29% vs 30% of patients in the intention-to-treat population. One treatment-related death occurred, due to infection in a patient in the PET4 treatment group. Second primary malignancies were reported in seven vs eight patients.  

The investigators concluded, “PET4-negativity after treatment with 2 + 2 chemotherapy in patients with newly diagnosed early-stage unfavorable Hodgkin lymphoma allows omission of consolidation radiotherapy without a clinically relevant loss of efficacy. PET4-guided therapy could thereby reduce the proportion of patients at risk of the late effects of radiotherapy.”

Andreas Engert, MD, of University Hospital Cologne, is the corresponding author for The Lancet Oncology article.

Disclosure: The study was funded by Deutsche Krebshilfe. For full disclosures of the study authors, visit thelancet.com.