Jury Still Out on Interim PET for Response-Adapted Therapy in Hodgkin Lymphoma


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Oliver Press, MD, PhD

The prognostic value of interim PET imaging is not very controversial—it’s a great tool for determining which patients are going to do well with their treatment and which aren’t. But whether outcomes are improved by changing treatment based on the interim PET scan results remains controversial.

—Oliver Press, MD, PhD

Interim positron-emission tomography (PET) scans provide good prognostic information in patients with Hodgkin lymphoma, but more research is needed to determine whether patients benefit when the findings are used to alter treatment, according to Oliver Press, MD, PhD, Professor at the University of Washington School of Medicine and Chair of Lymphoma Research at the Fred Hutchinson Cancer Research Center, both in Seattle.

Interim PET—performed during induction therapy, after one to four cycles of treatment—remains a hot-button issue, he told attendees of the Pan Pacific Lymphoma Conference held in Kohala Coast, Hawaii. “There are some very strong but diametrically opposed views that people in this room have about this topic,” he said.

Use for Prognostication

Studies have validated the prognostic value of interim PET in this setting. For example, a pooled analysis found that the PET result after two cycles of chemotherapy was highly predictive of progression-free survival in patients with advanced disease.1 “Using this very powerful prognostic tool, other prognostic factors really weren’t very relevant, including the international prognostic score … after adjusting for the PET scan results,” Dr. Press noted.

A retrospective study comparing visual inspection of PET scans with the 5-point Deauville scale with a change in maximal standardized uptake value cutoff of 70% suggests that the latter may yield better discrimination.2 “This is probably the way the field is moving,” he said. “But the consensus is that we are not quite ready yet to move away from the visual scale, that we really need larger studies and prospective studies. And most importantly, this requires really tight standardization in how the scans are done.”

Response-Adapted Therapy in Early-Stage Disease

At least eight trials are studying the use of interim PET for response-adapted therapy in early-stage Hodgkin lymphoma, according to Dr. Press. In one trial, patients were randomized after two cycles of chemotherapy to standard therapy or to PET response-adapted therapy.3 The respective 1-year rates of progression-free survival were 100% and 94% among patients with favorable disease and 97.3% and 94.7% among patients with unfavorable disease.

The data safety monitoring committee concluded that response-adapted therapy was unlikely to meet noninferiority criteria and halted the trial. It also concluded that PET did not meet the goal of identifying patients who did not need radiation therapy.

“This was a very controversial study and very controversial decision by the data safety monitoring board. It led to a lot of debate,” Dr. Press noted. “A lot of people feel that they made this decision too soon, that progression-free survival is not the right endpoint, that overall survival is most important. And a lot of people felt the trial should stay open.”

A second trial in which patients underwent PET after three cycles of chemotherapy had similar findings.4 Among PET-negative patients, the 3-year rate of progression-free survival was 94.5% with radiation therapy and 90.8% without it—a nonsignificant difference in intent-to-treat analysis. However, these investigators concluded that “excellent outcomes” were possible without radiation ­therapy.

“These were obviously two trials with similar results and opposite conclusions about interim PET and its role, and the role of radiation therapy. So the jury is out, I would say, on early-stage disease and interim PET,” Dr. Press commented.

Use in Advanced-Stage Disease

Many trials are also evaluating the use of interim PET to guide therapy in advanced-stage Hodgkin lymphoma. In the Southwest Oncology Group (SWOG) S0816 trial, patients have a PET scan after two cycles of chemotherapy; those with negative results are given standard therapy and those with positive results are given escalated therapy.5 Recently updated findings, with median follow-up of about 28 months, show that 2-year progression-free survival is 62% in PET-positive patients and 82% in PET-negative patients.

“Everybody would probably agree that the results look promising for the PET-positive patients,” Dr. Press commented, “but people might argue about whether the 82% progression-free survival is good enough in the PET-negative patients.” Although results thus far suggest a benefit of switching to escalated therapy in the PET-positive group, “we really do need truly randomized studies to definitely prove the value of this response-adapted approach, and we need longer follow-up on this trial,” he said.

A similar trial undertaken in Europe also found that PET-positive patients switched to escalated therapy had a 1-year failure-free survival rate of 76.5%, and PET-negative patients who continued on standard therapy had a rate of 96.2%.6

Putting It All Together

“The prognostic value of interim PET imaging is not very controversial—it’s a great tool for determining which patients are going to do well with their treatment and which aren’t. But whether changing your treatment based on what the interim PET scan shows improves outcomes remains at least somewhat controversial,” Dr. Press concluded.

At present, the National Comprehensive Cancer Network endorses PET response-adapted therapy in Hodgkin lymphoma.7 “So they have embraced the preliminary results very firmly,” he said. “I agree that it seems promising, but this does seem to be just a little bit out ahead of the data. Many people want the truly randomized studies, where half the patients get standard treatment, half the patients get a response-adapted treatment, and then you compare the outcomes and make the final decisions.”

An international consensus group has developed a more reserved statement.8 The forthcoming statement finds a lack of conclusive evidence warranting a change in treatment based solely on the results of interim PET. “My tendency would be to agree with this consensus group,” Dr. Press concluded. ■

Disclosure: Dr. Press reported no potential conflicts of interest.

References

1. Gallamini A, Hutchings M, Rigacci L, et al: Early interim 2-[18F]fluoro-2-deoxy-D-glucose positron emission tomography is prognostically superior to international prognostic score in advanced-stage Hodgkin’s lymphoma: A report from a joint Italian-Danish study. J Clin Oncol 25:3746-3752, 2007.

2. Rossi C, Kanoun S, Berriolo-Riedinger A, et al: Interim 18F-FDG PET SUVmax reduction is superior to visual analysis in predicting outcome early in Hodgkin lymphoma patients. J Nucl Med 55:569-573, 2014.

3. Raemaekers JM, André MP, Federico M, et al: Omitting radiotherapy in early positron emission tomography-negative stage I/II Hodgkin lymphoma is associated with an increased risk of early relapse: Clinical results of the preplanned interim analysis of the randomized EORTC/LYSA/FIL H10 trial. J Clin Oncol 32:1188-1194, 2014.

4. Radford J, Barrington S, Counsell N, et al: Involved field radiotherapy versus no further treatment in patients with clinical stages IA and IIA Hodgkin lymphoma and a ‘negative’ PET scan after 3 cycles ABVD: Results of the UK NCRI RAPID trial. 2012 ASH Annual Meeting. Abstract 547. Presented December 10, 2012.

5. Press OW, LeBlanc M, Rimsza LM, et al: A phase II trial of response-adapted therapy of stage III-IV Hodgkin lymphoma using early interim FDG-PET imaging: US Intergroup S0816. Hematol Oncol 31(suppl 1):Abstract 124, 2013.

6. Gallamini A, Tarella C, Patti C, et al: Multicentre clinical study with early treatment intensification in high-risk Hodgkin Lymphoma (HL) patients with a positive FDG-PET scan after two ABVD courses: GITIL HD0607 study. Ann Oncol 22(suppl 4):O167, 2011.

7. National Comprehensive Cancer Network: NCCN Clinical Practice Guidelines in Oncology (NCCN Guidelines®). Hodgkin Lymphoma, version 2.2014. Available at www.nccn.org/professionals/physician_gls/pdf/hodgkins.pdf. Accessed August 12, 2014.

8. Barrington SF, Mikhaeel NG, Kostkoglu L, et al: Conclusion on interim PET/CT from consensus conference (Lugano, Menton). J Clin Oncol. 2014. In press.

 



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