Randomized Comparison of ABVD Chemotherapy with a Strategy that Includes Radiation Therapy in Patients with Limited-Stage Hodgkin's Lymphoma: National Cancer Institute of Canada Clinical Trials Group and the Eastern Cooperative Oncology Group

Authors: Meyer RE, Gospodarowicz MK, Connors JM, et al.
Source: JCO 23(21):4634-42, 2005.

Background

• 90% of patients with limited-stage Hodgkin's disease achieve a durable disease-free state
• Long-term survival is impacted by treatment-related toxicities such as:
• • Acute leukemia from alkylating agents or epipodophyllotoxins
  • Second cancers
  • Cardiovascular events from radiation

Methods

• A multicenter trial organized by the National Cancer Institute of Canada Clinical Trials Group (NCIC-CTG) and the Eastern Cooperative Oncology Group (ECOG)
• Endpoints
• • The primary endpoint was overall survival at 12 years of follow-up
  • This article presents early data (at 5 years before the study could complete accrual or follow-up), because in the interim, other studies demonstrated that involved field radiation is a better therapeutic strategy compared to the subtotal nodal irradiation used in this trial
• Eligibility Criteria
• • Age > 15 years old
  • Previously untreated, biopsy-confirmed Hodgkin's lymphoma
  • Limited disease stage
  • Clinical stage I to IIA
  • Absence of bulky disease
  • Subdiaphragmatic disease allowed if confined to iliac, inguinal, and/or femoral regions
  • No history of cardiac or lung dysfunction, abnormal hematological, renal or liver labs, HIV, or prior malignancy
• Staging
• • Required to have undergone CBC, ESR, CXR, CT of chest, abdomen, and pelvis
  • Laparotomy not allowed
• Stratification
  • By institution
  • By favorable and unfavorable cohorts
    • Patients were considered to belong to the unfavorable cohort for any of the following:
    • Age over 39
    • ESR = 50 or greater
    • Mixed cellularity or lymphocyte-depleted histology
    • More than 3 sites of disease
• Randomization
  • Favorable cohort
    • Radiation alone vs. ABVD alone
  • Unfavorable cohort
    • Radiation plus 2 cycles of ABVD
  • Treatment techniques
    • Radiation consisted of subtotal nodal irradiation to 3500 cGy over 20 daily fractions via parallel opposed fields
    • ABVD alone was given as 2 cycles of ABVD followed by restaging; patients with complete response at restaging received 2 additional cycles of ABVD; patients without complete response received 4 additional cycles of ABVD
• Power
  • This study was powered to detect a 10% improvement in OS from 80% to 90% between patients receiving or not receiving radiation, respectively
    • This assumed at least 7 years of follow-up in 450 patients, neither of which was achieved
  • 405 patients were evaluated; 6 were excluded

Results

• Median follow up was 4.2 years; all endpoints were assessed at 5 years
• Overall survival was not significantly different between arms; event-free survival was not significantly different between arms
• Freedom from progression was better in the radiation arm (93% vs. 87%, p=0.006), a difference that was maintained in subset analysis of the unfavorable cohort (90% vs. 82%, p = 0.004) but not in the favorable cohort
• Fatal cardiovascular events and second cancers were similar in number
• There were more nonfatal cardiovascular events and second cancers in the arm receiving radiation, but no statistical analysis was applied
  • Cardiovascular events: 10 vs. 4
  • Second cancers: 10 vs. 4

Discussion

• The authors contend that the absence of an overall survival benefit in the setting of an improvement in freedom from progression demonstrates that radiation toxicities are taking a heavy toll on survival. However, with short follow-up, it may be that the improvement in freedom from progression in the radiation arm simply has not had time to make itself apparent in the survival data.
• If the long term toxicities of radiation were to outweigh its disease-control benefits, this effect would likely manifest itself many years after treatment, rather than in the short-term. Therefore, it is not surprising that no overall survival benefit was demonstrated with the omission of radiation in this study given the relatively short follow-up.
• The small number of second cancers and cardiovascular events complicates meaningful analysis. However, the crude numbers do highlight the important toxicities of radiation therapy. The carcinogenic effects of radiation may be reduced with the smaller-volume fields currently in use. The cardiovascular toxicities likely will be reduced with the lower doses currently in use. Clearly, patients in whom the heart is not irradiated will have much less cardiovascular toxicity.
• If this trial compared patients treated with and without involved field radiation (rather than subtotal nodal irradiation) and followed the patients for a longer period of time, the results would likely be of greater clinical relevance.