Some Patients with DLBCL Can Skip Radiation: 'It's a Win'

Alexander M. Castellino, PhD

December 08, 2019

ORLANDO, Florida — New results suggest that radiotherapy can be skipped by some patients with diffuse large B-cell lymphoma (DLBCL).

Patients with non-bulky DLBCL (stage I or II disease) typically receive chemotherapy with abbreviated R-CHOP (rituximab, cyclophosphamide, doxorubicin [hydroxydaunomycin], vincristine [Oncovin, Eli Lilly], and prednisolone), and this is followed by radiation therapy.

But the new results suggest that patients with an interim positron emission tomography (iPET)-negative scan may forego radiation therapy altogether.

The finding comes from the Intergroup National Clinical Trials Network (NCTN) study S1001 reported here at the American Society of Hematology (ASH) 2019 annual meeting.

The study showed that 89% of patients with stage I/II DLBCL maintained excellent outcomes after four cycles of R-CHOP with PET-directed therapy. Only 11% of patients with an interim PET-positive scan required radiation therapy.

"Together with the FLYER results in younger patients, this NCTN trial has established four cycles of R-CHOP alone as a new standard approach to limited-stage disease for a majority of patients," said lead author Daniel O. Persky, MD, of the division of hematology/oncology at the University of Arizona in Tucson.

"Radiation treatment, like all cancer treatments, has side effects," Persky said in a press statement. "It can be painful and cause rashes or burns, as well as fatigue. It can also increase patients' risk of developing other cancers. If we can spare people the pain — and time and cost — of radiation and give a simpler course of treatment, it's a win."

The FLYER study, presented at the ASH 2018 meeting and reported then by Medscape Medical News, showed that 3-year progression-free survival with four cycles of CHOP was noninferior to six cycles of CHOP.

Change in Clinical Practice

Medscape Medical News approached several lymphoma experts for comments about this study, and all agreed that it has significant clinical implications.

This study (S1001) is "the largest US study of limited stage DLBCL in the rituximab era, and it confirms the results of the earlier FLYER study that for patients with limited stage DLBCL the outcomes will be excellent, and for most patients four cycles of R-CHOP chemotherapy are sufficient and they do not require radiation," said Catherine M. Diefenbach, MD, director of the clinical lymphoma program at the Perlmutter Cancer Center, NYU Langone Health, New York City.

"S1001 was a large phase 2 trial. The level of evidence provided by studies of this nature is lower than that provided by randomized trials, but these data are consistent with the phase 3 FLYER trial and support a change in practice," commented Peter Martin, MD, chief of the lymphoma program at Weill Cornell Medicine and NewYork-Presbyterian, New York City.

When the FLYER study was presented last December at ASH 2018, many clinicians were ready to make the switch to less intensive therapy for stage I/II DLBCL, but some were reluctant, Martin noted. "For those of us who changed our practice over the past year, the S1001 study results provide additional data that four cycles of R-CHOP are sufficient for the vast majority of these patients. For those who maybe felt a little uncomfortable with the FLYER data, the S1001 trial may help by providing additional data and also adding a framework for interpretation of interim PET/CT," he said.

Detailed Results From S1001

THE S1001 study enrolled patients with non-bulky (<10 cm) untreated DLBCL.

Patients received standard R-CHOP therapy and underwent an iPET scan on day 15 to 18 of cycle 3. The PET scan was reviewed centrally in real time and patients with an iPET-negative scan (Deauville scale 1-3) received an additional cycle of R-CHOP.

Patients with an iPET-positive scan (Deauville 4-5) went on to receive radiation: 36 Gy of involved field radiation therapy (IFRT) and an additional boost up to 9 Gy to FDG-avid areas within 5 weeks of the third cycle of R-CHOP followed by ibritumomab tiuxetan (Zevalin, Acrotech Biopharma) 3 to 6 weeks after completing IFRT (IFRT-Zevalin). The final PET scan was done 12 weeks after treatment was completed.

In the Q&A session, a question was posed as to why a higher-than-normal radiation dose was used in patients following an iPET-positive scan. Patients with an iPET-positive scan are at a higher risk for relapse and hence the higher dose, Persky explained. 

Results were reported for 132 patients. They had a median age of 62 years, 62% had stage I disease, the median largest diameter was 3.5 cm, and 43% had extranodal involvement.

An iPET scan was reviewed for 128 patients, of which 110 were iPET-negative. Interim PET scan was positive in 18 patients, but four were treated as iPET-negative due to infection (Deauville X).

Of the 14 patients with a truly iPET-positive scan, 12 patients received IFRT-Zevalin. Partial responses were converted to complete responses in 8 patients (67%) after IFRT-Zevalin for an overall complete response rate of 92%.   

With median follow up of 4.5 years, disease progression was seen in 5 patients and 2 patients died from lymphoma.

S1001 reported a 5-year progression-free survival estimate of 87% and an overall estimate of 90%. Patients with iPET-negative and iPET-positive scans had similar outcomes (iPET-negative versus iPET-positive):

  • 5-year PFS: 88% vs 86%

  • 5-year OS: 91% vs 93%

Longer Follow-Up Required

In commenting on the study, Diefenbach pointed out a caveat. "This lymphoma [stage I/II], unlike more aggressive DLBCL, tends to relapse late. So I would like to see a further follow-up at 7 or 8 years to confirm this excellent disease control," she said.

Martin agreed, and added his own perspective. "The number of patients with interim PET-positive disease was quite small in S1001," he said (only 14 patients had a truly positive iPET scan). Although these patients had excellent outcomes following radiation therapy, some caution may be warranted, he added.

Longer follow-up will be required to evaluate the rate of late relapse in both iPET-positive and iPET-negative patients and to estimate the rates of secondary myelodysplastic syndromes/acute myeloid leukemia in those receiving radiation therapy, he noted.

PET-Directed Approach in Clinical Decision Making

"These results validate the results of the earlier FLYER study that a PET-directed approach may be used to guide clinical decision making," Diefenbach told Medscape Medical News.

However, we cannot generalize "no radiation required" for early stage DLBCL, she noted. "We can say that for patients with limited stage non-bulky DLBCL who had no risk factors, if they are interim PET-negative (Deauville 3 or lower) after three cycles of R-CHOP that they should receive a fourth cycle of R-CHOP but do not require radiation," she said.

Diefenbach and Martin, neither of whom were involved with the S1001 study, both agreed that the validation of the FLYER study should require updating of the guidelines to response-adapted approaches in low-risk DLBCL.

Persky is a consultant for Sandoz and Bayer. He is also on the Independent Data Monitoring Committee for MorphoSys and Debiopharm. Diefenbach and Martin have disclosed no relevant financial relationships.

American Society of Hematology (ASH) 2019 Annual Meeting: Abstract 349. Presented December 8, 2019.

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