Reduced-intensity chemotherapy and PET-guided radiotherapy in patients with advanced stage Hodgkin's lymphoma (HD15 trial): A randomised, open-label, phase 3 non-inferiority trial

University Hospital of Cologne, Department of Internal Medicine I, Köln, Germany.
The Lancet (Impact Factor: 45.22). 04/2012; 379(9828):1791-9. DOI: 10.1016/S0140-6736(11)61940-5
Source: PubMed

ABSTRACT The intensity of chemotherapy and need for additional radiotherapy in patients with advanced stage Hodgkin's lymphoma has been unclear. We did a prospective randomised clinical trial comparing two reduced-intensity chemotherapy variants with our previous standard regimen. Chemotherapy was followed by PET-guided radiotherapy.
In this parallel group, open-label, multicentre, non-inferiority trial (HD15), 2182 patients with newly diagnosed advanced stage Hodgkin's lymphoma aged 18-60 years were randomly assigned to receive either eight cycles of BEACOPP(escalated) (8×B(esc) group), six cycles of BEACOPP(escalated) (6×B(esc) group), or eight cycles of BEACOPP(14) (8×B(14) group). Randomisation (1:1:1) was done centrally by stratified minimisation. Non-inferiority of the primary endpoint, freedom from treatment failure, was assessed using repeated CIs for the hazard ratio (HR) according to the intention-to-treat principle. Patients with a persistent mass after chemotherapy measuring 2·5 cm or larger and positive on PET scan received additional radiotherapy with 30 Gy; the negative predictive value for tumour recurrence of PET at 12 months was an independent endpoint. This trial is registered with Current Controlled Trials, number ISRCTN32443041.
Of the 2182 patients enrolled in the study, 2126 patients were included in the intention-to-treat analysis set, 705 in the 8×B(esc) group, 711 in the 6×B(esc) group, and 710 in the 8×B(14) group. Freedom from treatment failure was sequentially non-inferior for the 6×B(esc) and 8×B(14) groups as compared with 8×B(esc). 5-year freedom from treatment failure rates were 84·4% (97·5% CI 81·0-87·7) for the 8×B(esc) group, 89·3% (86·5-92·1) for 6×B(esc) group, and 85·4% (82·1-88·7) for the 8×B(14) group (97·5% CI for difference between 6×B(esc) and 8×B(esc) was 0·5-9·3). Overall survival in the three groups was 91·9%, 95·3%, and 94·5% respectively, and was significantly better with 6×B(esc) than with 8×B(esc) (97·5% CI 0·2-6·5). The 8×B(esc) group showed a higher mortality (7·5%) than the 6×B(esc) (4·6%) and 8×B(14) (5·2%) groups, mainly due to differences in treatment-related events (2·1%, 0·8%, and 0·8%, respectively) and secondary malignancies (1·8%, 0·7%, and 1·1%, respectively). The negative predictive value for PET at 12 months was 94·1% (95% CI 92·1-96·1); and 225 (11%) of 2126 patients received additional radiotherapy.
Treatment with six cycles of BEACOPP(escalated) followed by PET-guided radiotherapy was more effective in terms of freedom from treatment failure and less toxic than eight cycles of the same chemotherapy regimen. Thus, six cycles of BEACOPP(escalated) should be the treatment of choice for advanced stage Hodgkin's lymphoma. PET done after chemotherapy can guide the need for additional radiotherapy in this setting.
Deutsche Krebshilfe and the Swiss Federal Government.

  • Source
    [Show abstract] [Hide abstract]
    ABSTRACT: It has been shown that [18F]fluorodeoxyglucose (FDG)-positron emission tomography (PET) provides robust and reproducible data for early metabolic response assessment in various malignancies. This led to the initiation of several prospective multicenter trials in malignant lymphoma and adenocarcinoma of the esophagogastric junction, in order to investigate whether the use of PET-guided treatment individualization results in a survival benefit. In Hodgkin lymphoma and aggressive non-Hodgkin lymphoma, several trials are ongoing. Some studies aim to investigate the use of PET in early identification of metabolic non-responders in order to intensify treatment to improve survival. Other studies aim at reducing toxicity without adversely affecting cure rates by safely de-escalating therapy in metabolic responders. In solid tumors the first PET response-adjusted treatment trials have been realized in adenocarcinoma of the esophagogastric junction. These trials showed that patients with an early metabolic response to neoadjuvant chemotherapy benefit from this treatment, whereas metabolic non-responders should switch early to surgery, thus reducing the risk of tumor progression during chemotherapy and the risk of toxic death. The trials provide a model for designing response-guided treatment algorithms in other malignancies. PET-guided treatment algorithms are the promise of the near future; the choice of therapy, its intensity, and its duration will become better adjusted to the biology of the individual patient. Today's major challenge is to investigate the impact on patient outcome of personalized response-adapted treatment concepts.
    Cancer Imaging 09/2012; 12(2):324-35. DOI:10.1102/1470-7330.2012.9006 · 1.29 Impact Factor
  • The Lancet 04/2012; 379(9828):1767-8. DOI:10.1016/S0140-6736(12)60153-6 · 45.22 Impact Factor
  • Source
    [Show abstract] [Hide abstract]
    ABSTRACT: Hodgkin lymphoma (HL) has become one of the most easily curable malignancies in oncology. More than 80% of patients can be cured with risk-adapted treatment that includes chemotherapy and radiotherapy. This progress is mainly due to the development of multi-agent chemotherapy and improved radiation techniques; however, severe, life-threatening treatment-related side effects occur, which include organ toxicity and secondary malignancies. Thus, the treatment approaches must be carefully balanced between optimal disease control and the risk of long-term sequelae. Although this article is meant to provide an overview of the current treatment approaches for patients with HL, in many instances conflicting results from various clinical trials are available, and a personal judgment is inevitable. Here, we focus on evidence from large clinical trials with solid conclusions.
    Nature Reviews Clinical Oncology 06/2012; 9(8):450-9. DOI:10.1038/nrclinonc.2012.91 · 15.70 Impact Factor
Show more