Controversies on the prognostic value of interim FDG‐PET in advanced‐stage Hodgkin lymphoma

Abstract

Hodgkin lymphoma, even in advanced-stage, is a highly curable malignancy, but treatment is associated with short-term toxicity and long-term side effects. Early predictive markers are required to identify those patients who do not require the full-length standard therapy (and thus qualify for therapy de-escalation) and those patients who will not be cured by standard therapy (and thus qualify for therapy escalation). Multiple trials have assessed the value of 18 F-fluoro-2-deoxy-D-glucose positron emission tomography (FDG-PET) after a few cycles of chemotherapy (also known as 'interim FDG-PET') in predicting outcome in advancedstage Hodgkin lymphoma. Furthermore, multiple interim FDG-PET-adapted trials, in which patients with positive interim FDG-PET scans are assigned to escalated therapies, and patients with negative interim FDG-PET scans are assigned to de-escalated therapies, have recently been published or are currently ongoing, with generally heterogeneous results. The present article reports the currently available evidence (and controversies) on the prognostic value of interim FDG-PET in advanced-stage Hodgkin lymphoma in patients with positive and negative interim FDG-PET findings following continuation of standard chemotherapy or escalated/de-escalated therapy. Hodgkin lymphoma is one of the most frequently occurring malignancies in young adults aged 20-40 yr, whereas a second incidence peak is observed in people aged >55 yr (1). Early-stage Hodgkin lymphoma is usually treated with two to three cycles of adriamycin, bleomycin, vinblastine and dacarbazine (ABVD) followed by radiation therapy (RT), whereas there is less consensus on the optimal treatment of advanced-stage Hodgkin lymphoma, in which six to eight cycles of ABVD or six to eight cycles of a more intense regimen of bleomycin, etoposide, doxorubicin, cyclophosphamide, vincristine, procarbazine and prednisone (BEACOPP) are proposed (2). An important question in treating Hodgkin lymphoma is whether intensified chemotherapy should be applied upfront or reserved for patients with resistance to first-line therapy. In advancedstage Hodgkin lymphoma, the administration of six to eight cycles of ABVD has been reported to result in a long-term progression-free survival (PFS) of approximately 75% (3-6), whereas with upfront BEACOPP chemotherapy, the long-term PFS is approximately 85% (7-10). However, upfront BEACOPP chemotherapy is associated with an increased toxicity profile compared to ABVD therapy (7, 10). Furthermore, whether upfront BEACOPP will result in an improved overall survival (OS) compared to ABVD chemotherapy has not been consistently proven, with heterogeneous results among studies (7,8,(10)(11)(12). Therefore, there are strong arguments to reserve intensified treatments as second-line therapy for patients in whom standard firstline ABVD treatment fails, rather than exposing the entire population to an intensified treatment as would happen in case of upfront BEACOPP chemotherapy.To reduce toxicity and maximise patient outcome, id...

PET-adapted therapy for advanced Hodgkin lymphoma – systematic review

“…Previous systematic reviews regarding PET adapted therapy in HL have been published [32][33][34]. The strength of our systematic review, lies within the fact that it was based on a comprehensive search, according to a defined protocol and search terms.…”

Reply: Interim PET in Hodgkin Lymphoma: Is It So Useless?

“…Consequently, the studies by Gallamini et al (12,13) are methodologically seriously biased. The predictive value of interim 18 F-FDG PET/CT was generally lower in other comparable studies (21), and 2 recent studies (22,23) including advanced-stage lymphoma as part of their patient population showed interim 18 F-FDG PET/CT to have minor or no value in predicting prognosis. Three recent studies (24-26) on treatment intensification in interim 18 F-FDG PET/CT-positive patients were published, all lacking a randomized control arm with nonintensified treatments.…”

“…Consequently, the true benefit of treatment intensification in these patients could not be assessed. In addition, comparisons with historical studies that suffered from inadequate methodology and heterogeneous results are futile (21). We individually criticized all 3 of these studies for these issues (27)(28)(29).…”

PET-adapted approaches to primary therapy for advanced Hodgkin lymphoma

“…17 Early interim PET-CT response assessment performed after two cycles of ABVD (PET-2), has been demonstrated to be a powerful predictor of outcome, although both negative and positive predictive value have varied in cohort studies and retrospective analyses. 18–25 Standardization of response assessment with FDG PET has been important to prospective study design, and our subsequent understanding of results from PET-guided treatment strategies. While the cut-off levels of uptake defining a negative or positive interim scan have varied between trials, these criteria have allowed identification of patients who could be considered for studies aiming to improve outcome of high-risk patients by intensification of their treatment (escalation) and to minimize exposure to toxic drugs without compromising the efficacy of therapy for low-risk patients (de-escalation).…”