Intensified Chemotherapy and Dose-Reduced Involved Field Radiotherapy in Patients with Early Unfavorable Hodgkin Lymphoma: Final Analysis of the German Hodgkin Study Group (GHSG) Randomized HD11 Trial
Authors: H. T. Eich, R. P. Mueller, V. Diehl, H. Gorgen, H. Mueller-Hermelink, B. Schmidt, Grosu, J. Karstens, N. Willich, A. Engert
Institutions: Department of Radiation Oncology, University of Cologne, Cologne, Germany; Clinic for Internal Medicine, University of Cologne, Cologne, Germany; Institute of Pathology, University of Wurzburg, Wurzburg, Germany; Department of Radiation Oncology, Katharinenhospital, Stuttgart, Germany; Department of Radiation Oncology, University of Freiburg, Freiburg, Germany; Department of Radiation Oncology, University of Hannover, Hannover, Germany; Department of Radiation Oncology, University of Munster, Munster, 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 extended field radiotherapy (EFRT) to involved field radiotherapy (IFRT) due to late effects such as heart disease, pulmonary dysfunction, and the development of secondary malignancies.
- Combined modality treatment consisting of 4-6 cycles of chemotherapy followed by involved field radiotherapy (IFRT) to doses of 30-36 Gy is the standard treatment for early unfavorable HL.
- However, the optimal CT regimen and adequate radiation dose is unclear.
- The previous unfavorable HL trial conducted by this group (HD8), revealed an overall survival (OS) and freedom from treatment failure (FFTF) at 5 years of 91% and 83%, respectively.
- The HD11 trial thus addressed two major questions: (1) improving outcome by intensifying CT (4xABVD vs. 4xBEACOPPbaseline; Bbas) and (2) defining the best radiation dose (30 Gy vs. 20 Gy IF- RT).
Materials and Methods
- Between May 1998 and January 2003, 1,395 eligible patients aged 16-75 years with untreated early unfavorable stage HL (CS I, IIA with at least one of the following risk factors: large mediastinal mass (a), extranodal disease (b), elevated ESR (c) or ?3 nodal areas (d); IIB with risk factors c and/or d) were randomized into one of the following 4 treatment arms:
- 4xABVD + 30 Gy (A)
- 4xABVD + 20 Gy (B)
- 4x Bbas + 30 Gy (C)
- 4x Bbas + 20 Gy (D)
- A 2x2 factorial design was chosen to potentially demonstrate superiority of the Bbas regimen over ABVD and to test non-inferiority of 20 Gy compared with 30 Gy of IFRT.
- Since there are strong indications for an interaction between CT- and RT-doses, a comparison of pooled treatment arms (A+B vs. C+D for comparison of 4xABVD vs. 4x Bbas and A+C vs. B+D for comparison of 30 Gy IFRT vs. 20 Gy IFRT) would be misleading. Therefore, all treatment arms were analyzed separately.
- All patients received either 30 or 20 Gy of IFRT in fractions of 1.8 to 2.0 Gy administered five times weekly.
- Centralized QA was performed and individual radiotherapy plans were provided for each patient, with the expert radiotherapy panel retrospectively evaluating the following items: radiation fields, radiation doses applied, treatment duration, and technical parameters according to the initial radiotherapy plan.
- Between May 1998 and January 2003, 342 participating centers in Germany, Switzerland, Austria, Czech Republic, and the Netherlands recruited a total of 1,570 patients.
- 165 patients were disqualified as a result of wrong initial staging, reference histology not confirming HL, and other inclusion criteria violations.
- 10 patients were excluded from all analyses because they dropped out prior to administration of any treatment.
- The final analysis set for the chemotherapy comparison comprised 1,395 patients (356 patients in arm A, 347 in arm B, 341 in arm C, and 351 in arm D). Forty-four patients dropped out before radiotherapy and were excluded from the radiotherapy comparison, leaving 675 patients treated with 30 Gy of IFRT and 676 patients treated with 20 Gy of IFRT in the respective intent-to-treat analysis set.
- Patient characteristics were well balanced between the 4 arms (median age 33 years; 49% male; 6% stage I; 29% B-symptoms).
- CT- and RT-related acute toxicity occurred significantly more often in the arms with the more intensive therapy (CT: 74.1% vs. 51.8%; RT: 12.3% vs. 5.5%).
- The complete remission (CR) rate 3 months after end of therapy was 94.1% for the whole group and did not differ significantly between the 4 arms. The 5-year estimate of FFTF (primary endpoint) is 85.0% (OS 94.5%, PFS 86.0%).
- Bbas appeared more effective than ABVD only if followed by 20 Gy IFRT (5y-FFTF difference 5.7%, 95%-CI [0.1%; 11.3%]).
- This effect did not exist in combination with 30 Gy IFRT (5y-FFTF difference 1.6% [-3.6%; 6.9%]).
- Similar results are observed for the RT question: After 4xBbas, 20 Gy is not inferior to 30 Gy (5y-FFTF difference -0.1%, 95%-CI [-5.1%; 4.9%]), whereas after 4xABVD, a relevant inferiority of 20 Gy cannot be excluded (-4.0% [-9.5%; 1.4%]).
- In the HD11 study presented here, four cycles of ABVD or Bbas were combined with 20 or 30 Gy of IFRT to define the best treatment for patients with early unfavorable HL.
- The final analysis shows that 4 cycles of AVBD followed by 30 Gy IFRT leads to equivalent outcomes as compared to 4 cycles of Bbas followed by either 20 or 30 Gy IFRT.
- Four cycles of AVBD followed by 20 Gy IFRT was inferior to the other three arms, implying that a reduction of IFRT dose from 30 to 20 Gy is only possible when combined with a more intensive chemotherapy regimen than ABVD.
- Therefore, a reduction of RT dose from 30 Gy to 20 Gy IFRT seems to be justified only in combination with Bbas, but not with a less effective chemotherapy such as 4xABVD.
- Four cycles of ABVD followed by 30 Gy IFRT remains the standard of care for HL patients in early unfavorable stages.
- HD11 demonstrates that a more intensive chemotherapy regimen such as Bbas allows for radiation dose reduction at the expense of greater chemotherapy-related toxicity.
- Strengths of this investigation include: patient numbers, long follow-up and RT quality control with central prospective review by an expert panel.
- This is the only trial performed in adult early, unfavorable HL examining RT dose de-escalation.
- IFRT dose reduction from 30 to 20 Gy:
- Yields inferior results following 4xAVBD
- Is possible following 4xBbas but with increased systemic toxicity.
- Bottom line: 4xABVD followed by IFRT to 30 Gy remains the standard of care for early, unfavorable HL.
- EORTC H9U demonstrated that Bbas is not superior to ABVD (4 yr OS 93% vs. 94%, respectively).
- In HD11, patients treated with Bbas more often developed severe toxicity than patients treated with ABVD (73.8% vs. 51.5%, respectively; p <0.001).
- There are some limitations of the generalizability of this study to everyday practice:
- The results from HD11 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 "unfavorable prognosis" patients, "involved-field" radiation and "involved nodal" radiation, particularly given the differences in the EORTC and GHSD "unfavorable prognosis" criteria.
- Confusion with this terminology may lead to inappropriate treatment of patients not fitting within the parameters of the HD11 study.
- Major questions to be addressed in future early-stage unfavorable HL include: possibility of dose reduction or omission of radiation, the appropriate use of PET in the identification of patients who may not require radiation after an excellent response to chemotherapy, and whether involved nodal irradiation is adequate following response to systemic therapy.