Elsevier

The Lancet

Volume 390, Issue 10114, 23 December 2017–5 January 2018, Pages 2790-2802
The Lancet

Articles
PET-guided treatment in patients with advanced-stage Hodgkin's lymphoma (HD18): final results of an open-label, international, randomised phase 3 trial by the German Hodgkin Study Group

https://doi.org/10.1016/S0140-6736(17)32134-7Get rights and content

Summary

Background

The intensive polychemotherapy regimen eBEACOPP (bleomycin, etoposide, doxorubicin, cyclophosphamide, vincristine, procarbazine, and prednisone in escalated doses) is very active in patients with advanced-stage Hodgkin's lymphoma, albeit at the expense of severe toxicities. Individual patients might be cured with less burdensome therapy. We investigated whether metabolic response determined by PET after two cycles of standard regimen eBEACOPP (PET-2) would allow adaption of treatment intensity, increasing it for PET-2-positive patients and reducing it for PET-2-negative patients.

Methods

In this open-label, randomised, parallel-group phase 3 trial, we recruited patients aged 18–60 years with newly diagnosed, advanced-stage Hodgkin's lymphoma 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 using 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 described; rituximab was given intravenously at a dose of 375 mg/m2 (maximum total dose 700 mg). The primary objectives were to show superiority of the experimental treatment in the PET-2-positive cohort, and to show non-inferiority of the experimental treatment in the PET-2-negative cohort in terms of the primary endpoint, progression-free survival. We defined non-inferiority as an absolute difference of 6% in the 5-year progression-free survival estimates. Primary analyses in the PET-2-negative cohort were per protocol; all other analyses were by intention to treat. This trial was registered with ClinicalTrials.gov, number NCT00515554.

Findings

Between May 14, 2008, and July 18, 2014, we recruited 2101 patients, of whom 137 were found ineligible before randomisation and a further 19 were found ineligible after randomisation. 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 associated with 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 × eBEACOPP or 6 × eBEACOPP in PET-2-negative patients. Ten treatment-related deaths occurred: four in the PET-2-positive cohort (one [<1%] in the 8 × eBEACOPP group, three [1%] in the 8 × R-eBEACOPP group) and six in the PET-2-negative group (six [1%] in the 8 × eBEACOPP or 6 × eBEACOPP group).

Interpretation

The favourable 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 reducing treatment-related risks for patients with negative PET-2. We recommend this PET-2-guided treatment strategy for patients with advanced-stage Hodgkin's lymphoma.

Funding

Deutsche Krebshilfe, Swiss State Secretariat for Education and Research, and Roche Pharma AG.

Introduction

Patients with advanced-stage Hodgkin's lymphoma can be cured with modern chemotherapy regimens.1, 2 The intensive eBEACOPP regimen (bleomycin, etoposide, doxorubicin, cyclophosphamide, vincristine, procarbazine, and prednisone in escalated doses) developed by the German Hodgkin Study Group (GHSG) has produced excellent tumour control in the entire group of patients with advanced-stage Hodgkin's lymphoma.3, 4, 5 Favourable outcomes are, however, accompanied by a high incidence of severe acute and long-term toxicities, which can have a major effect on patients' lives even many years after treatment.6, 7, 8 Within the heterogeneous group of patients diagnosed with advanced-stage Hodgkin's lymphoma, a low individual risk of treatment failure might allow the use of a less intensive treatment to avoid toxicities. However, none of the established staging systems based on the Ann Arbor classification in combination with various clinical risk factors can reliably predict the individual risk of treatment failure.

The introduction of functional imaging using 18F-fluoro-2-deoxy-D-glucose (18F-FDG) PET for metabolic response assessment has opened up the possibility of a more individualised treatment approach.9 18F-FDG-PET response after two cycles of doxorubicin, bleomycin, vinblastine, and dacarbazine (ABVD) chemotherapy appears to overcome the prognostic effect of even the International Prognostic Score.10, 11, 12, 13 We thus hypothesised that interim PET imaging after two cycles of the GHSG standard regimen eBEACOPP (PET-2) might discriminate between low-risk and high-risk patients. Based on this hypothesis, the GHSG HD18 study aimed to answer two questions.

Research in context

Evidence before this study

Early interim 18F-fluoro-2-deoxy-D-glucose (18F-FDG PET) after two cycles of chemotherapy (PET-2) has shown a high positive and negative predictive value in patients with advanced-stage Hodgkin's lymphoma receiving ABVD (doxorubicin, bleomycin, vinblastine, and dacarbazine). Treatment modification based on PET-2 results might improve the outcome. We searched MEDLINE between Jan 1, 2000, and Jan 1, 2017, with the search terms “interim PET” or “PET-2” and “Hodgkin*” to identify studies that assessed the predictive effect of early interim functional imaging with PET-2. The results from both uncontrolled and controlled studies suggest that PET-2 has a high positive predictive value in advanced-stage Hodgkin's lymphoma after upfront ABVD, and that treatment intensification might be of moderate benefit in these patients. The negative predictive value in patients receiving upfront ABVD seems to be less robust. We found no evidence from controlled trials on the prognostic or predictive value of PET-2 for patients receiving BEACOPP (bleomycin, etoposide, doxorubicin, cyclophosphamide, vincristine, procarbazine, and prednisone) besides the HD18 study.

Added value of this study

A positive PET after two cycles of BEACOPP in escalated doses (eBEACOPP) did not identify a high-risk patient cohort in our phase 3 trial, neither in patients treated with a total of eight or six cycles. The negative predictive value of PET-2, however, allowed reduction from eight to four cycles of eBEACOPP without loss of tumour control. As a result from the reduced treatment intensity, the incidence of severe adverse events was significantly reduced and overall survival was significantly improved.

Implications of all the available evidence

PET-2 positivity does not identify a high-risk patient cohort when the current GHSG standard treatment is used. However, PET-2 negativity allows the reduction to a highly effective, short, and very safe treatment of only four cycles of eBEACOPP. To our knowledge, the survival outcomes of patients in the HD18 study exceed any data from controlled trials reported so far. Because a large number of contributing centres from different countries and all levels of care generated the presented data, the results of HD18 should be widely applicable in countries with access to 18FDG-PET for response assessment.

First, we wanted to assess whether treatment intensification with the addition of the anti-CD20 antibody rituximab to standard eBEACOPP would improve progression-free survival in presumably high-risk patients with positive PET-2. However, a pre-planned interim analysis showed no difference in progression-free survival at 3 years, futility was concluded, and results were published early.14

Second, assuming a favourable outcome in presumably low-risk patients with negative PET-2, we asked whether a substantial treatment reduction from eight to only four cycles of eBEACOPP would be possible without compromising progression-free survival in this patient group. With this treatment reduction, we intended to reduce the burden of therapy for our patients.

Here we report the final analysis of the GHSG HD18 study.

Section snippets

Study design and patients

This open-label, multicentre, international, randomised phase 3 trial was done in 301 hospitals and private practices in Germany, Switzerland, Austria, the Netherlands, and the Czech Republic. The trial was designed by the GHSG steering committee and approved by the ethics committees of all participating centres.

We recruited patients aged 18–60 years with newly diagnosed, histology-proven, classical or nodular lymphocyte-predominant Hodgkin's lymphoma in advanced stages (that is, clinical stage

Results

Between May 14, 2008, and July 18, 2014, we enrolled 2101 patients, of whom 137 were not randomised (figure 1). Another 19 patients were excluded from the randomised comparisons owing to ineligibility for randomisation that had not been detected earlier (figure 1). 1945 patients were randomised according to protocol and comprise the randomised ITT set. Of these, 434 patients with positive PET-2 were randomly assigned to either 8 × eBEACOPP (n=217) or 8 × R-eBEACOPP (n=217), and another 506 were

Discussion

Two major findings have emerged from the GHSG HD18 trial for patients with newly diagnosed advanced-stage Hodgkin's lymphoma. First, a negative PET scan after initial therapy with two cycles of eBEACOPP allows a reduction of treatment cycles from eight to four without a negative effect on progression-free survival. The reduction is associated with markedly improved tolerability and thereby a significantly improved overall survival. Second, a positive PET scan after two cycles of eBEACOPP does

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