Two presentations at the American Society for Radiation Oncology (ASTRO) Annual Meeting offered more evidence that omitting radiation therapy leads to higher rates of recurrence for patients with early-stage Hodgkin lymphoma.1,2 Both studies involve work by the German Hodgkin Study Group among patients with early-stage favorable Hodgkin lymphoma.
Taken together and in context with previous studies, they show the value of combined-modality treatment and definitively answer the question of whether radiation can be omitted for these patients without increasing the risk of recurrence, noted George Mikhaeel, MD, Professor of Radiation Oncology and Consultant Clinical Oncologist at Guy’s Cancer Centre in London, and discussant of the ASTRO science highlights session on hematologic cancers. “In all of the studies that have been done, there is a difference in outcome when radiotherapy is included, and we now have data on 3,702 patients. So, hopefully, that is the end of this question and it will not be asked again,” Dr. Mikhaeel stated.
Progression-Free Survival Benefit
The HD16 trial reported by Eich et al1 enrolled 1,150 patients, ranging in age from 18 to 75 years, with newly diagnosed, early-stage, favorable-risk Hodgkin lymphoma. To qualify, these patients had none of the following risk factors: extranodal lesions, bulky mediastinal involvement, elevated erythrocyte sedimentation rate, and three or more involved nodal areas.
Patients were randomly assigned into the standard treatment arm or the positron-emission tomography (PET)-guided arm. Those in the standard arm received combined-modality treatment with two cycles of doxorubicin, bleomycin, vinblastine, and dacarbazine (ABVD) chemotherapy. This was followed by PET (which, by protocol, did not alter treatment) and then 20 Gy of involved-field radiation therapy (IFRT). This “has been the standard treatment for the German Hodgkin Study Group,” Dr. Mikhaeel reported.
Does PET positivity predict a higher likelihood of relapse [in patients with early-stage Hodgkin lymphoma]? The answer is yes.— George Mikhaeel, MD
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Patients in the PET-guided arm received two courses of chemotherapy followed by PET. “In the PET-guided arm, if you were PET-negative, radiotherapy was omitted. If you were PET-positive, 20 Gy of [involved-field radiotherapy] was given,” Dr. Mikhaeel explained. PET status after two chemotherapy cycles (PET-2) was based on central review; patients with a Deauville score of 1 or 2 were considered PET-2–negative and those with a Deauville score of 3 to 5 were considered PET-2–positive.
At a median follow-up of 47 months, the estimated 5-year progression-free survival for PET-2–negative patients in the standard treatment arm was 93.4% with chemotherapy and radiation vs 86.1% with chemotherapy alone. “There was a statistically significant difference in progression-free survival, with a reduction of 7.3% and a hazard ratio of 1.78,” Dr. Mikhaeel said. “There is a loss of progression-free survival if you omit radiotherapy.”
Those results answered the study’s first question: Can radiation be omitted for PET-negative patients. “The answer is a strong no—not without loss of progression-free survival or increased relapse,” Dr. Mikhaeel said.
“The second question was, does PET positivity predict a higher likelihood of relapse,” Dr. Mikhaeel noted. “The answer is yes,” he said, if PET positivity is defined as having a Deauville score of 4 or higher.
When the definition of PET-2 positivity was restricted to patients with a Deauville score of 4 or higher, the estimated 5-year progression-free survival was 93.1% among PET-2–negative patients vs 80.9% among PET-2–positive patients. Using a Deauville score cutoff of 3 to define positivity, the difference was less pronounced: 93.2% 5-year progression-free survival for PET-2–negative patients vs 88.4% for PET-2–positive patients and was not statistically significant.
The study findings make a strong case for changing the definition of PET positivity from Deauville 3 to Deauville 4, according to Dr. Mikhaeel. “The prognosis for Deauville 3 was the same as for Deauville 2,” he said, and prognosis only became worse at a score of Deauville 4.
Where Relapses Occur
The second study presented found that most of the recurrences among patients in the HD16 study who were PET-negative and who did not receive radiation therapy were in-field recurrences. Those patients had an in-field recurrence rate of 8.7% vs 2.1% for patients receiving combined therapy (P = .0003).
“In contrast, there was no relevant difference regarding [out-of-field] recurrences (3.7% vs 4.7%; P = .55),” according to the study abstract.2 Knowing the site of recurrence confirms that it can potentially be prevented with radiotherapy, Dr. Mikhaeel noted.
The authors of this study concluded: “The therapy-associated side effects of [involved-field radiotherapy] were marginal, and the incidence of second malignancies was not increased thus far. [Involved-field radiotherapy] should continue to be considered standard after two cycles of ABVD to avoid intensive and toxic salvage therapies such as autologous stem cell transplantation.”
Putting the Data in Context
“It is important,” Dr. Mikhaeel noted, “to put the findings of the HD16 trial within the context of other trials.” They include the United Kingdom’s RAPID trial, published in The New England Journal of Medicine3 and the EORTC/LYSA/FIL H10 study, published in the Journal of Clinical Oncology.4 “They have slight differences, but they have accrued a large number of patients,” Dr. Mikhaeel noted, with follow-up and progression-free survival rates at 3 to 5 years. ABVD was used in both studies, and the EORTC study also had an escalation arm using bleomycin, etoposide, doxorubicin, cyclophosphamide, vincristine, procarbazine, and prednisone (BEACOPP).
All three studies showed improved progression-free survival when radiotherapy was used in addition to chemotherapy. In the RAPID study, the difference in progression-free survival was 6.3%. In the H10 study, the difference was 11.9% among patients with the most favorable stage of disease and 2.5% in the group with unfavorable disease, but in this group patients in the chemotherapy-alone arm received more cycles of chemotherapy than in the combined-modality arm. In the HD16 study presented at the meeting, the difference was 7.3%.
Showing a slide with the progression-free survival results from all three studies, Dr. Mikhaeel remarked, “If you wanted one single slide to put in your tumor board for discussion, take a photo of that slide and show it every time there are arguments about radiotherapy.” He added a reminder that these results are for early favorable-group patients receiving 20 Gy.
Effect on Standard of Care
How should these findings affect the standard of care? Dr. Mikhaeel said that ABVD × 2, plus 20 Gy would be standard for patients with early-stage favorable Hodkgin lymphoma. “What remains a little unclear is what to do with the PET-positive patients, and that is because in this study [HD16], they had a progression-free survival of 80%,” he said. “We might look at the EORTC study again. The outcome of the escalation arm was quite remarkable. It improved progression-free survival from 77.4% to 90.6 %.”
For patients “suitable for chemotherapy escalation, you might do a PET after 2 cycles of ABVD,” he said, and then if the Deauville score is 1 to 3, give radiotherapy, but if the Deauville score is 4 to 5, “consider escalation to BEACOPP to bring the progression-free survival back to 90%.” For patients not suitable for chemotherapy escalation, the standard treatment “is still quite good,” he said. ■
DISCLOSURE: Dr. Mikhaeel reported no conflicts of interest.
1. Eich HT, Baues C, Fuchs M, et al: PET-guided treatment of early-stage favorable Hodgkin lymphoma: Final results of the international, randomized phase 3 trial HD16 by the GHSG. 2019 ASTRO Annual Meeting. Abstract 1. Presented September 15, 2019.
2. Baues C, Goergen H, Fuchs M, et al: Consolidating involved field radiotherapy prevents early and local recurrences in early-stage Hodgkin lymphoma. 2019 ASTRO Annual Meeting. Abstract 66. Presented September 16, 2019.
3. Radford J, Illidge T, Counsell N, et al: Results of a trial of PET-directed therapy for early-stage Hodgkin’s lymphoma. N Engl J Med 372:1598-1607, 2015.
4. André MPE, Girinsky T, Federico M, et al: Early positron emission tomography response-adapted treatment in stage I and II Hodgkin lymphoma: Final results of the randomized EORTC/LYSA/FIL H10 trial. J Clin Oncol 35:1786-1794, 2017.