Combined modality treatment (CMT) consisting of chemotherapy and small-field radiotherapy has long been considered the standard of care for patients with early-stage, favorable Hodgkin lymphoma (HL), but the potential late toxicities of radiotherapy have prompted researchers to question whether certain patients could be treated with chemotherapy alone.
In the German Hodgkin Study Group’s HD16 trial, investigators attempted to use a PET-guided treatment strategy to identify patients who could avoid radiotherapy without sacrificing efficacy. Their findings, published in the Journal of Clinical Oncology, suggest that patients with a negative PET scan after two cycles of chemotherapy (PET-2) have worse survival without radiation, while patients with a positive scan have worse progression-free survival (PFS), even with CMT.
“PET-2 … allows for identifying patients who are at high risk for treatment failure; however, [we] clearly missed our primary goal of showing noninferiority of the PET-2–guided omission of radiotherapy,” Michael Fuchs, MD, from the University of Cologne in Germany, and co-authors wrote. “We therefore recommend proceeding with consolidation radiotherapy as a standard of care for patients achieving a metabolic response after two cycles [of chemotherapy].”
The phase III HD16 trial recruited 1,150 adults with newly diagnosed, early-stage, favorable HL between November 2009 and December 2015. Patients were randomized 1:1 to receive either:
- CMT: 2 cycles of ABVD (doxorubicin, bleomycin, vinblastine, dacarbazine) and involved-field radiotherapy (IFRT) at 20 Gy
- PET-2–guided treatment: 2 cycles of ABVD for all patients and IFRT at 20 Gy only for those with positive PET-2 findings (defined as Deauville score ≥3)
After excluding patients who withdrew consent or dropped out before review of PET-2, the per-protocol population included 952 patients: 464 in the CMT group and 488 in the PET-2–guided treatment group.
A total of 628 patients were found to be PET-2-negative: 328 received CMT and 300 had ABVD alone. With a median follow-up of 47 months (range = 30-65 months), the five-year PFS rate was significantly higher in patients who received CMT, compared with those who received chemotherapy alone: 93.4% versus 86.1% (hazard ratio [HR] = 1.78; 95% CI 1.02-3.12; p=0.04).
“The difference in PFS primarily resulted from a significant increase in disease recurrences within the hypothetical radiation field without IFRT,” the authors explained, with an in-field recurrence rate of 2% versus 9% (p=0.0003) and no relevant difference in out-field recurrences.
However, there was no significant difference in five-year overall survival (OS) between the two treatment groups: 98.1% with CMT and 98.4% with PET-2–guided treatment.
Looking at the 693 patients who were assigned to receive IFRT after a negative PET-2 scan (n=353) or a positive PET-2 scan (n=340), the researchers observed that PET-2–positive patients were more likely to have bulky disease (p<0.001). After a median follow-up of 46 months (range not reported), the five-year PFS was 93.2% in the PET-2–negative subgroup, compared with 88.4% in the PET-2–positive subgroup (HR=1.71; 95% CI 1.00-2.93; p=0.47). Rates of five-year OS were similar: 98.2% versus 97.9%, respectively (HR=0.71; 95% CI 0.24-2.13; p=0.55).
The authors then repeated the analysis using a cutoff of Deauville score 4 for PET-2-positivity to further assess the prognostic effect of PET-2, but again, five-year PFS was higher among patients with PET-2–negative scans (Deauville score 1-3) than PET-2–positive scans: 93.1% versus 80.9% (HR=2.94; 95% CI 1.63-5.31; p=0.001).
“A positive PET scan after two cycles of ABVD represents a risk factor for PFS among patients … treated with standard CMT,” the authors noted, particularly when a higher cutoff for PET positivity is used.
While the results prompted the re-searchers to recommend radiotherapy consolidation after two cycles of ABVD, they acknowledged that IFRT may carry a risk for certain late toxicities. “Uncertainty around the risk-to-benefit ratio of the CMT strategy for individual patients must be addressed in a shared decision-making process,” they wrote. “However, we feel safe to conclude that the hypothetical benefit of the chemotherapy-alone treatment strategy does not outweigh the immediate loss of tumor control with all its consequences.”
The authors noted several potential limitations of this analysis, including the use of a conservative definition of PET-2 negativity, a higher proportion of PET-2–positive patients in the experimental group, and the inability to evaluate late effects, which may occur up to 20 years after radiotherapy treatment.
The authors report no relevant conflicts of interest.
Fuchs M, Goergen H, Kobe C, et al. Positron emission tomography–guided treatment in early-stage favorable Hodgkin lymphoma: final results of the international, randomized phase III HD16 trial by the German Hodgkin Study Group. J Clin Oncol. 2019 September 10. [Epub ahead of print]