Comparison of 30 Gy versus 20 Gy Involved Field Radiotherapy After Two Versus Four Cycles ABVD in Early Stage Hodgkin's Lymphoma: Interim Analysis of the German Hodgkin Study Group Trial HD10

Reviewer: Voika BarAd, MD
Abramson Cancer Center of the University of Pennsylvania
Ultima Vez Modificado: 17 de octubre del 2005

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Presenter: R.P. Muller
Presenter's Affiliation: Medical University of Vienna, Austria
Type of Session: Plenary

Background

  • Combined modality treatment consisting of few cycles of chemotherapy, usually ABVD, followed by involved field radiotherapy is the standard of care in the treatment of early stage Hodgkin's lymphoma in the majority of medical centers. The cure rates are very high, more than 90%.
  • The search continues for finding whether the treatment intensity of chemotherapy, radiotherapy, or both treatment modalities may be reduced in these patients.
  • The optimal choice of chemotherapy and the number of cycles are unclear.
  • Optimal radiotherapy dose is unclear.
  • Lowering the dose of radiation and the number of chemotherapy cycles may lower the risk of the major side effects, including second cancers and accelerated coronary artery disease
  • This trial was performed to evaluate the reduction in both chemotherapy and radiation therapy in the treatment of good prognosis Hodgkin's Disease

Materials and Methods

  • 1131 Hodgkin's lymphoma patients with early disease , clinical stage I, II, without risk factors ( defined as large mediastinal adenopathy, >= 3 sites of disease, extranodal disease, ESR>= 30 without B symptoms, or ESR >= 50) were randomized between May 1998 and May 2000.
  • The randomization was between 4 cycles of ABVD (Doxorubicin, Bleomycin, Vinblastine, and Dacarbazine) followed by involved field radiation ( 30 Gy, arm A), 4 cycles ABVD followed by involved field radiation ( 20 Gy, arm B), 2 cycles ABVD followed by involved field radiation ( 30 Gy, arm C), and 2 cycles ABVD followed by involved field radiation ( 20 Gy, arm D).
  • The second interim analysis done on September 2003, showed that 847 (75%) of patients were balanced between treatment arms with regard to age, gender, clinical stage, histopathology and performance status.
  • The summary of the third interim analysis are presented here.
  • The primary endpoint of the study was freedom from treatment failure.

Results

  • The complete remission rates were high with 98.4% for all patients, while progressive disease or no change was observed in 0.9% of cases.
  • The relapse rate was 2.5%, 13 (1.5%) patients died during the study.
  • More hematological WHO-grade 3-4 toxicity (leucopenia and infection) was reported in chemotherapy groups; the most common WHO grade 3-4 toxicity during chemotherapy was leukopenia : 22% in ABVDx4 group and 15% in ABVDx2 group.
  • The radiotherapy was well tolerated, with only 3% WHO-grade 3-4 toxicity (dysphagia, mucositis).
  • No significant differences were seen in secondary neoplasias; ten secondary neoplasias were reported: 1 AML, 4 NHL, 5 solid tumors.
  • Freedom from treatment failure after a median observation time of 2 years was 96.6% with no statistical differences between the arms.
  • Overall survival was 98.5% with no statistical differences between the arms.

Author's Conclusions

  • Further analysis will show if these promising interim results will allow to reduce further intensity in combined modality of early stage Hodgkin's disease.
  • The aim of ongoing trials is to study further reduction of toxicity without loss of efficacy, with HD-13 trial comparing different chemotherapeutic protocols ( ABVD vs ABV vs ADV vs AV) followed by involved field irradiation, with a total dose of 30 Gy, in early stage favorable Hodgkin's disease.

Clinical/Scientific Implications

The study suggests that lowering the dose of radiation and the number of chemotherapy cycles is safe and will not affect the cure rates in patients with early stage Hodgkin's disease, without risk factors. The strength of the study consists in the large number of patients, with centralized quality control for radiotherapy fields. However, the follow up is short. We will need more than 5 years data to confirm relapse outcome and more than 10 years data to ascertain the late effects.  In the data presented, their appears to be a separtion of the curves at 5 years, and there may be more failures in the lower dose radiation arm.  This will require further follow up. The results of the study and the consequent implications are applicable for only selected, "favorable prognosis" early stage Hodgkin's disease patients.

Most evidence suggests that lower doses of exposure to radiation produce a lower risk of developing second cancers, but the risk never reaches zero.  Factors affecting the development of second cancers, especially breast cancers, are complicated and include age, age at exposure, dose, energy of radiation, duration of exposure, condition being treated, and overall risk of breast cancer in the individual and in the population exposed.  Given the facts about the risk of breast cancer and accelerated coronary artery disease after mantle- field radiation therapy, we need to counsel patients and provide heightened surveillance.

At the present time, the radiation and chemotherapy doses should not be reduced until there is further follow up that shows equivalent results in regards to tumor control.


News
Limited Radiation Acceptable in Pediatric Hodgkin's Lymphoma

Jun 27, 2012 - For patients with favorable-risk Hodgkin's lymphoma who achieve a complete early response to chemotherapy with vinblastine, Adriamycin (doxorubicin), methotrexate, and prednisone, two-year event-free survival rates are high with limited use of radiotherapy, according to a study published in the June 27 issue of the Journal of the American Medical Association.



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