Carlson, Robert H.
NEW YORK—While the use of FDG-PET ([18F]-fluoro-2-deoxy-D-glucose positron emission tomography) scans to evaluate patients with Hodgkin lymphoma (HL) before and after treatment is standard and of proven value, using interim scans between cycles of chemotherapy to evaluate response and plan future treatment remains controversial. And it remained so after a debate on the subject here at the International Congress on Hematological Malignancies, even though both debaters made strong efforts to prove their opposing points.
Among his arguments in favor of interim FDG-PET, Craig Moskowitz, MD, Clinical Director of the Division of Hematologic Oncology and Attending Surgeon in the Lymphoma and ABMT Services at Memorial Sloan-Kettering Cancer Center, pointed to several recent European studies that showed improved outcomes for both early and late-stage HL when therapy was guided by interim FDG-PET.
Nancy Bartlett, MD, Komen Professor of Medical Oncology at Washington University School of Medicine, though, disagreed, saying that FDG-PET-directed therapy should not be used outside of a clinical trial because escalation therapies are too toxic and of no proven benefit.
Moskowitz said that in his opinion no study in Hodgkin lymphoma in 2013 should exclude use of interim FDG-PET scans. He argued that in early-stage disease use reduces therapy; in advanced-stage disease there is a reduction on increase in therapy; in relapsed/refractory disease it determines eligibility for transplant; and in evaluation of target agents it determines response rates.
Starting with recent history of the use of PET in HL, Moskowitz said the first important literature was from a joint Italian/Danish prospective evaluation of the prognostic value of interim PET (Gallamini et al: JCO 2007;25:3746-3752). With a median follow-up of 2.19 years, the study showed PET prognostically superior to the International Prognostic Score (IPS) in patients with advanced-stage HL treated with conventional ABVD (doxorubicin, bleomycin, vinblastine, and dacarbazine) therapy.
“PET-2 overshadows the prognostic value of IPS and emerges as the single most important tool for planning of risk-adapted treatment in advanced HL,” the researchers concluded.
Bringing the story up to date, Moskowitz called the 2012 American Society of Hematology Annual Meeting a “home run for PET in Hodgkin Lymphoma.” He reviewed the UK RAPID Trial (Radford et al: Abstract 547) presented at that meeting, which compared involved-field radiotherapy vs. no further treatment in patients with clinical stages IA and IIA HL and a “negative” PET scan (score 1 or 2 on the five-point Deauville scale) after three cycles of ABVD. The study showed that patients with a negative PET scan after three cycles of ABVD have an excellent prognosis without any further treatment.
“We conclude that in stages IA/IIA HL, radiation therapy is unnecessary in the 75 percent of patients who become PET negative after three cycles of ABVD,” the RAPID authors wrote. “Such a response-adapted approach based on centrally reviewed PET imaging reduces treatment time and costs, improves tolerability, and most importantly removes the burden of early and late toxicity of radiotherapy from the PET-negative population.”
Another presentation at the meeting (Hay et al: Abstract 548), on treatment of stage I-II-A non-bulky HL, analyzed results from three studies, the German Hodgkin Study Group HD10 and HD11 and the NCIC Clinical Trials Group HD.6.
Those authors reported that time to progression was superior and progression-free survival trended to be superior in patients treated with combined-modality therapy, and that involved-field radiation therapy was especially important in patients who do not attain complete responses after two cycles of ABVD. “These data support more recent strategies evaluating response-adapted approaches for use of involved-field radiation therapy,” the authors wrote.
And a third paper at the ASH meeting on stage I/II HL, an interim analysis of the HD10 study on early PET-driven treatment adaption (André et al: Abstract 549), concluded that early relapse in non-irradiated patients was significantly higher than in patients receiving standard combined-modality therapy, even in this selected group of patients with an early negative PET.
Moskowitz said he was particularly impressed with a study presented at the meeting on advanced-stage high-risk disease (Gallamini et al: Abstract 550), the first interim analysis of the GITIL/FIL HD0607 Clinical Trial. Among their conclusions, the authors said the findings suggested that an early switch from ABVD to escalated BEACOPP can be done safely in PET-2 positive patients, and that a centralized online PET scan review system is feasible and allows a real time decision-making process.
Not Outside Clinical Trials
Before stating her arguments against the use of interim FDG-PET scans in Hodgkin lymphoma, Bartlett began with the disclaimer that she has designed trials for several years that incorporated interim PET to guide therapy in HL.
Nonetheless, she proved up to the assignment of the “no” stance, saying that with the data available there is no role for interim PET-directed therapy outside of a clinical trial because escalation therapies are too toxic and have no proven benefit; and because in PET-early stage patients there is still a five to 10 percent difference in progression-free survival with chemotherapy only vs. combined-modality therapy.
“Our hope was that we could have our cake and eat it too—that PET would tell us who would need radiation and who didn't—but the differences are similar to what we saw before we ever started doing interim PET,” she said.
Clinicians should, therefore, “consider the ‘middle ground’ in early-stage disease: If after four to six cycles [of chemotherapy] PET is positive, then go to radiotherapy. Meanwhile, we need to search for better biologic prognostic markers, and more effective, less toxic treatments.”
One problem Bartlett has with interim FDG-PET is its predictive value. She said that in most studies the positive predictive value is about 50 percent, meaning that a substantial number of patients are overtreated if treatment is escalated. And the negative predictive value has been about 90 percent, meaning under treatment of a small percentage of patients if treatment is de-escalated.
“Importantly, that negative predictive value of 90 percent in most series in early-stage patients includes combined-modality therapy, so the question is, if you're only getting chemotherapy, what is the negative predictive value of the PET scan?” she asked.
Ideal vs. Real World
Bartlett noted that data evaluating the utility of interim PET all come from prospective clinical trials using two to three expert readers for each scan, with rules of adjudication if they disagree. And only “approved” scan sites are allowed, with strictly uniform timing, machines, and dose.
In addition, she said, Moskowitz even touted the quality of one of the European trials he cited by saying the reader for all the scans was one of the world's foremost experts. “In the real world it's a little difficult to obey all these rules—that's unrealistic to expect. In the US, outside the setting of a trial, we cannot mandate the location and interpretation of PET, which is in contrast to most counties.”
© 2013 Lippincott Williams & Wilkins, Inc.