Safe to Skip Radiotherapy With Negative PET in Hodgkin Lymphoma

Nancy A. Melville

June 15, 2020

The majority of patients with early stage unfavorable Hodgkin lymphoma respond well enough to a current standard regimen of 4 cycles of chemotherapy, and can skip the additional radiotherapy that is normally included in the combined modality treatment, say experts reporting the final results from an international phase 3 randomized trial dubbed HD17.  

"Most patients with this disease will not need radiotherapy any longer," concluded first author Peter Borchmann, MD, assistant medical director in the Department of Hematology/Oncology at the University Hospital of Cologne, Germany.

Borchmann was speaking online as part of the virtual edition of the European Hematology Association (EHA) 25th Annual Congress 2020.

"Importantly, the mortality of patients with early stage unfavorable Hodgkin lymphoma in the HD17 study did not differ from the normal healthy German population, and this is the first time we have had this finding in one of our studies," he emphasized.   

Borchmann added that positron emission tomography (PET) imaging is key in deciding which patients can skip radiation.  

"We conclude from the HD17 trial that the combined modality concept can and should be replaced by a PET-guided omission of radiotherapy for patients with newly diagnosed early stage unfavorable Hodgkin lymphoma," he said.

"The vast majority of early stage unfavorable Hodgkin lymphoma patients can be treated with the brief and highly effective 2+2 chemotherapy alone," he added.

Therefore, he continued, "PET-guided 2+2 chemotherapy is the new standard of care for the German Hodgkin study group," which conducted the trial.

The use of both chemotherapy and radiation has long been a standard approach to treatment, and this combined modality treatment is highly effective, Borchmann explained. But it can cause long-term damage, and the known longer-term negative effects of radiotherapy, such as cardiovascular disease and second malignancies, are a particular concern because patients with early stage Hodgkin lymphoma are relatively young, with a median age of around 30 years at disease onset.

An expert approached for comment said that the momentum to skip radiotherapy when possible is an ongoing issue, and importantly, this study adds to those efforts.

"The treatment of Hodgkin lymphoma has moved for many years now to less radiation therapy, and this trend will continue with the results of this study," commented John G. Gribben, MD, director of the Stem Cell Transplantation Program and medical director of the North East London Cancer Research Network Centre at Barts Cancer Center of Excellence and The London School of Medicine, UK.

"We have moved to lower doses and involved fields with the intent of decreasing toxicity, and particularly long-term toxicity from radiotherapy," he told Medscape Medical News. 

HD17 Study Details  

For the multicenter, phase 3 HD17 trial, Borchmann and colleagues turned to PET to identify patients who had and had not responded well to chemotherapy (PET-negative and PET-positive) and to determine if those who had responded well could safely avoid radiotherapy without compromising efficacy.

“We wanted to determine if we could reduce the treatment intensity by omission of radiotherapy in patients who respond very well to the systemic treatment, so who have a complete metabolic remission after the chemotherapy,” Borchmann said.

The 2+2 treatment approach includes 2 cycles of eBEACOPP (bleomycin, etoposide, doxorubicin, cyclophosphamide, vincristine, procarbazine, and prednisone) and 2 subsequent cycles of ABVD (doxorubicin, bleomycin, vinblastine, and dacarbazine).

The trial enrolled 1100 patients with newly diagnosed Hodgkin lymphoma between January 2012 and March 2017. Of these, 979 patients had confirmed PET results, with 651 (66.5%) found to be PET-negative, defined as having a Deauville score (DS) of less than 3 (DS3); 238 (24.3%) were DS3 and 90 (9.2%) were DS4.

The study met its primary endpoint of noninferiority in progression-free survival (PFS) at 5 years, with a PFS of 95.1% in the PET-guided group (n = 447) compared with 97.3% in the standard combined-modality treatment group (n = 428), over a median observation time of 45 months, for a difference of 2.2% (P = .12).

"We found that the survival levels were very high and we can safely conclude the noninferiority of the PET-guided approach in PET-negative patients," Borchmann said.

A further analysis showed that the 597 PET-negative patients who did not receive radiotherapy due to their PET status had 5-year PFS that was noninferior to the combined modality group (95.9% vs 97.7%, respectively; P = .20).

And among 646 patients who received the 2+2 regimen plus radiotherapy, of those confirmed as PET-positive (n = 328), the estimated 5-year PFS was significantly lower (94.2%) compared with those determined to be PET-negative (n = 318; 97.6%; hazard ratio, 3.03).

A cut-off of DS4 for positivity was associated with a stronger effect, with a lower estimated 5-year PFS of 81.6% vs 98.8% for DS3 patients and 97.6% for DS < 3 (P < .0001).

"Only DS4 has a prognostic impact, but not DS3," Borchmann said. "DS4 positivity indicates a relevant risk for treatment failure, however, there are few patients in this risk group (9.2% in this trial)."

The 5-year overall survival rates in an intent-to-treat analysis were 98.8% in the standard combined modality group and 98.4% in the PET-guided group.

With a median observation time of 47 months, there have been 10 fatal events in the trial out of 1100 patients, including two Hodgkin lymphoma-related events and one treatment-related death.

"Overall, Hodgkin lymphoma or treatment-related mortality rates were extremely low," Borchmann said.

The study was funded by Deutsche Krebshilfe. Borchmann and Gribben have reported no relevant financial relationships.

EHA 2020 Congress. Presented June 12, 2020. Abstract S101.

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