Progression-free survival of early interim PET-positive patients with advanced stage Hodgkin’s lymphoma treated with BEACOPPescalated alone or in combination with rituximab (HD18): an open-label, international, randomized phase 3 study ... German HSG

Progression-free survival of early interim PET-positive patients with advanced stage Hodgkin’s lymphoma treated with BEACOPPescalated alone or in combination with rituximab (HD18): an open-label, international, randomized phase 3 study ... German HSG
Data suggests the use of interim PET assessment during chemotherapy is superior to baseline international prognostic scoring in terms of predicting long-term treatment outcome in patients with Hodgkin’s lymphoma (HL). PET-2 (PET scan after 2 cycles of chemotherapy) has shown a high positive predictive value for patients with advanced HL given ABVD chemotherapy (doxorubicin, bleomycin, vinblastine, dacarbazine). Further, the results of uncontrolled studies suggest there might be a benefit of treatment intensification for patients with advanced HL given ABVD; however, there is no evidence from controlled trials on the prognostic or predictive value of PET-2 for patients given ABVD or BEACOPP.
In this open-label, international, randomized phase 3 trial, patients aged 18-60 years with advanced stage HL were recruited. All patients initially received two courses of BEACOPPescalated. Those patients without progress with PET-positive disease after two courses of BEACOPPescalated (PET2) were randomly assigned (1:1) to receive standard treatment, additional six courses of BEACOPPescalated or six courses of R-BEACOPPescalated.
Consolidating radiotherapy with 30Gy was recommended if a follow up PET showed positive residual disease.
From May 2008-2011, 1100 patients were enrolled, with 440 patients having a positive PET-2 and were randomly assigned to either BEACOPPescalated (220) or R- BEACOPPescalated (220). With a median follow-up of 33 months for PFS, estimated PFS was 91.4% for the BEACOPPescalated group and 93% for those in the R- BEACOPPescalated group (p=0.99).
The chemotherapy regimen itself might have affected the PET-2 imaging results. In contrast to studies with ABVD, patients in this trial received relevant doses of corticosteroids. Additionally, all patients received G-CSF, which can cause false PET-positive findings in the bone marrow and spleen. However, these GCSF effects can usually be discriminated from active lymphoma tissue. The time interval of 3-7 days between the last day of treatment and the PET-2 imaging was relatively short. Finally PET after two courses of BEACOPPescalated took place about two weeks earlier than after treatment with ABVD (6 vs. 8 weeks, respectively).
Additionally, the use of consolidating radiotherapy for patients with PET-8 positive residual disease at the end of chemotherapy (34% of PET-2 positive patients) might have contributed to the unexpectedly good PFS and accordingly, poor positive predictive value of PET-2 in this trial.
However, with regard to the absence of any positive predictive value of PET in this trial, the most important reason is the likelihood and frequency of progression-free survival events, which affects the power of predictive factors generally. Current randomized studies report failure rate of about 30% for ABVD in patients with stage III and IV disease. Thus, the number of PFS events in patients with advanced stage HL given ABVD is about three times higher than after treatment with BEACOPPescalated followed by radiotherapy to PET-8 positive residual disease in the HD18 study.
The analysis does not allow any conclusions on the negative predictive value of PET-2. Although the positive predictive value of PET-2 is poor in this study, a negative PET-2 might still allow the reduction of chemotherapy in PET-2 negative patients.
The addition of rituximab to BEACOPPescalated did not improve the PFS of PET-2 positive patients with advanced stage HL. However, PFS survival for PET-2 positive patients was much better than expected, exceeding even the outcome of PET-2-unselected patients in the previous HD15 trial. Thus, PET-2 cannot identify patients at high risk for treatment failure in the context of the German Hodgkin Study Group standard treatment for advanced stage HL: BEACOPP escalated.