Two Cycles of ABVD Followed by Involved Field Radiotherapy with 20 Gray (Gy) is the New Standard of Care in the Treatment of Patients with Early Stage Hodgkin Lymphoma: Final Analysis of the Randomized German Hodgkin Study Group (GHSG) Trial HD10
Authors: R. P. Mueller, H. T. Eich, A. Plutschow, J. Debus, M. Bamberg, K. Wilborn, M. Eble, H. Muller-Hermelink, V. Diehl, A. Engert
Institutions: Radioonkologie, Klinikum der Universitaet zu Koeln, Koeln, Germany; Medical Oncology, Klinikum der Universitaet zu Koeln, Koeln, Germany; Radioonkologie, Universitat Heidelberg, Heidelberg, Germany; Radioonkologie, Universitat Tubingen, Tubingen, Germany; Pius-Hospital Oldenburg, Oldenburg, Germany; Radioonkologie, Universitat Aachen, Aachen, Germany; Pathologie, Universitat Wurzburg, Wurzburg, Germany; Universitat zu Koeln, Koeln, Germany
- Strategies for the treatment of Hodgkin's Lymphoma (HL) continue to be studied and optimized with the intent of reducing long term side effects and preserving treatment efficacy.
- Major study groups have shifted from use of extended field radiotherapy (EFRT) to involved field radiotherapy (IFRT) due to the recognition of greater late effects such as heart disease, pulmonary dysfunction, and the development of secondary malignancies in patients treated with higher doses or larger fields.
- At present, a brief course of systemic chemotherapy followed by IFRT is considered as standard therapy for patients with early stage favorable HL.
- German Hodgkin Study Group (GHSG) Trial HD7 trial demonstrated that 2xABVD prior to radiation improved freedom from tumor progression for early stage favorable HL.
- However, there has been continuous discussion about the best treatment for patients with early favorable Hodgkin lymphoma.
- Open questions include the choice between combined modality treatment and chemotherapy only, the number of chemotherapy cycles needed and the optimal radiation dose.
- The GHSG thus conducted a randomized study for patients with early-stage favorable Hodgkin lymphoma (HD10), which addressed these questions, the results of which are presented here.
Materials and Methods
- HD10 was an international prospectively randomized multicenter non-inferiority trial comparing 2 and 4 cycles of ABVD as well as 20 Gy or 30 Gy involved field radiotherapy (IFRT) in a 2 x 2 statistical design.
- The non-inferiority margin was defined as 7% in the study protocol.
- Between 5/1998 and 1/2003, a total of 1370 patients from 329 centers were randomized into one of four arms:
- 4 x ABVD + 30 Gy
- 4 x ABVD + 20 Gy
- 2 x ABVD + 30 Gy
- 2 x ABVD + 20 Gy
- Stratification factors included trial center and prognostic factors that might influence the primary end point, such as age (<50 vs. ?50 years), systemic symptoms, supradiaphragmatic or infradiaphragmatic disease, and albumin level (<4 vs. ?4 g/dl).
- 179 patients did not qualify for analysis and there were 27 patients who did not complete treatment.
- The subgroup of patients with lymphocyte predominant HL stage IA without clinical risk factors were excluded from the HD10 trial.
- All patients had their initial histology centrally reviewed by a lymphoma expert panel.
- Documentation was complete in more than 99.1% of cases for this final analysis.
- Patients were equally balanced for age, gender, stage, histology, performance status, and risk factors between arms.
- 91.6% and 96.8% of patients received the prescribed dose in the 20 Gy and 30 Gy arms, respectively.
- 12 and 7 patients switched dose groups in the 20 Gy and 30 Gy arms, respectively.
- Only 22 patients (1.9%) discontinued therapy due to toxicity.
- There were significant differences in major toxicity (WHO grade III/IV) between 4 x ABVD and 2 x ABVD in the overall number of events (52% vs. 33%, p <0.0001) including leukopenia (24% vs. 15%) and hair loss (28% vs. 15%).
- Acute toxicity was low overall: WHO grade III/IV toxicities were observed in 8.7% of patients treated with 30 Gy and 2.9% in patients treated with 20 Gy.
- In terms of radiation dose, there also was a difference in grade III/IV toxicity between 30 Gy and 20 Gy IFRT (all events: 8.7% vs. 2.9%), dysphagia (3% vs. 2%), or mucositis (3.4% vs. 0.7%).
- Complete remission was achieved in 97% of patients treated with 4xABVD, 97% with 2xABVD, 99% after 30 Gy and 97% after 20 Gy.
- With a median follow-up of 79 - 91 months, there was no significant difference between 4xABVD and 2xABVD in terms of overall survival at 5 years (OS: 4xABVD 97.1%; 2xABVD: 96.6%), freedom from treatment failure (FFTF: 93.0% vs. 91.1%) and progression free survival (PFS: 93.5% vs. 91.2%).
- For the radiotherapy question, there were no significant differences between patients receiving 30 Gy IFRT and those with 20 Gy IFRT with respect to OS (97.6% vs. 97.5%).
- There are less acute toxicities with 20 Gy IFRT than with 30 Gy (all events: 8.7% vs. 2.9%).
- At a median follow-up of 79 months, no significant late toxicities of RT have been observed.
- Chemotherapy followed by 20 Gy IFRT is an effective treatment option for early-stage HL (5 yr PFS 93%; 95% CI: 90.6-95.0%)
- 20 Gy IFRT is not inferior to 30 Gy IFRT as consolidation therapy following chemotherapy.
- 2xAVBD followed by 20 Gy IFRT is the new standard treatment for early-stage favorable HL.
- A key objective in the treatment of HL is to reduce the intensity of first-line therapy to the extent possible without sacrificing disease control. This is most relevant for early-stage, favorable HL patients, which account for nearly 1 in 3 HL patients.
- In the HD10 study, two cycles of ABVD as well as 20 Gy resulted in lower rates of acute toxicity compared to 4 cycles of ABVD and/or 30 Gy. Overall, 52% of patients treated with four cycles of ABVD had grade III/IV toxicity, as compared with 33% of those receiving two cycles (p <0.001). The rates of acute toxicity (grade III/IV) were also higher among patients treated with 30 Gy of involved-field radiation therapy than among those receiving 20 Gy (8.7% vs. 2.9%, p <0.001).
- Longer term follow-up will be needed to identify long-term toxicities and differences between groups, particularly with respect to secondary malignancies and end organ damage, which may not occur for many years following completion of first-line therapy.
- There are some limitations of the generalizability of this study to everyday practice:
- The results from HD10 were obtained in a highly selected patient population by prospective centralized evaluation of the histology, initial staging, and IFRT treatment fields.
- Much confusion exists, particularly in the community setting, with respect to standardization of definitions regarding what constitutes "favorable prognosis" patients, "involved-field" radiation and "involved nodal" radiation.
- Confusion with this terminology may lead to inappropriate dose reduction for patients not fitting within the parameters of the HD10 study.
- The results of this study suggest that in patients with early-stage HL and a favorable prognosis, treatment with two cycles of ABVD followed by 20 Gy of IFRT is as effective as, and less toxic than, four cycles of ABVD followed by 30 Gy of involved-field radiation therapy.
- Further trials are ongoing and will test further treatment reduction given the excellent overall survival in HD10.
- HD13 is an ongoing trial looking at 2xABVD vs. 2 cycles of ABV, AVD or AV plus IFRT to 30 Gy in first-line treatment of early-stage HL.
- HD16 is an ongoing trial examining whether RT can be omitted following a CR as determined by FDG-PET, although the arm not receiving RT was closed prematurely after interim analysis demonstrated clear inferiority to RT treatment.