Borchmann P, et al. - The purpose of this study is to examine whether metabolic response ascertained by PET after two cycles of standard regimen eBEACOPP (bleomycin, etoposide, doxorubicin, cyclophosphamide, vincristine, procarbazine, and prednisone in escalated doses) (PET-2) would allow adaption of treatment intensity, increasing it for PET-2-positive patients and decreasing it for PET-2-negative patients. The outcome revealed that the favorable outcome of patients treated with eBEACOPP could not be improved by adding rituximab after positive PET-2. PET-2 negativity allows reduction to only four cycles of eBEACOPP without loss of tumour control. PET-2-guided eBEACOPP provides outstanding efficacy for all patients and increases overall survival by decreasing treatment-related risks for patients with negative PET-2. They prescribe this PET-2-guided treatment strategy for patients with advanced-stage Hodgkin's lymphoma.

Methods

• For this study, they designed an open-label, randomised, parallel-group phase 3 trial.
• They enrolled patients aged 18-60 years with newly diagnosed, advanced-stage Hodgkin's lymphoma.
• This study was conducted in 301 hospitals and private practices in Germany, Switzerland, Austria, the Netherlands, and the Czech Republic.
• After central review of PET-2, patients were assigned (1:1) to one of two parallel treatment groups on the basis of their PET-2 result.
• Patients with positive PET-2 were randomised to receive six additional cycles of either standard eBEACOPP (8 × eBEACOPP in total) or eBEACOPP with rituximab (8 × R-eBEACOPP).
• Those with negative PET-2 were randomised between standard treatment with six additional cycles of eBEACOPP (8 × eBEACOPP) or experimental treatment with two additional cycles (4 × eBEACOPP).
• A protocol amendment in June, 2011, introduced a reduction of standard therapy to 6 × eBEACOPP; after this point, patients with positive PET-2 were no longer randomised and were all assigned to receive 6 × eBEACOPP and patients with negative PET-2 were randomly assigned to 6 × eBEACOPP (standard) or 4 × eBEACOPP (experimental).
• Randomisation was done centrally utilizing the minimisation method including a random component, stratified according to centre, age (<45 vs ≥ 45 years), stage (IIB, IIIA vs IIIB, IV), international prognostic score (0-2 vs 3-7), and sex. eBEACOPP was given as previously depicted; rituximab was given intravenously at a dose of 375 mg/m² (maximum total dose 700 mg).
• The primary objectives were to exhibit superiority of the experimental treatment in the PET-2-positive cohort, and to demonstrate non-inferiority of the experimental treatment in the PET-2-negative cohort in terms of the primary endpoint, progression-free survival.
• They characterized non-inferiority as an absolute difference of 6% in the 5-year progression-free survival estimates.
• Primary investigations in the PET-2-negative cohort were per protocol; all other examination were by intention to treat.

Results

• They enlisted total 2101 patients between May 14, 2008, and July 18, 2014.
• Out of 2101 patients, 137 were found ineligible before randomization and a further 19 were found ineligible after randomization.
• Among 434 randomised patients (217 per arm) with positive PET-2, 5-year progression-free survival was 89·7% (95% CI 85·4-94·0) with eBEACOPP and 88·1% (83·5–92·7) with R-eBEACOPP (log-rank p=0·46).
• Patients with negative PET-2 randomly assigned to either 8 × eBEACOPP or 6 × eBEACOPP (n=504) or 4 × eBEACOPP (n=501) had 5-year progression-free survival of 90·8% (95% CI 87·9–93·7) and 92·2% (89·4-95·0), respectively (difference 1·4%, 95% CI -2·7 to 5·4). 4 × eBEACOPP was related to fewer severe infections (40 [8%] of 498 vs 75 [15%] of 502) and organ toxicities (38 [8%] of 498 vs 91 [18%] of 502) than were 8 × e