The long-term effect of intensive first-line treatment in advanced-stage HL

In October 2018, Bastian von Tresckow and colleagues, published on behalf of the German Hodgkin Study Group (GHSG) in The Lancet Haematology, a pre-planned follow-up analysis of two GHSG trials (HD9 and HD12 [NCT00265031]), which evaluated the use of intensive first-line chemotherapy in newly-diagnosed Hodgkin lymphoma (HL) patients. The aim of this analysis was to assess whether patient outcomes are impaired after a 10- or 15-year follow-up.

The primary analyzes of the HD9 and HD12 indicated that first-line chemotherapy aids tumor control and improves survival in advanced-stage HL patients. The primary endpoint of this follow-up study was progression-free survival (PFS). Secondary endpoints included, overall survival (OS) and the incidence of second primary malignant neoplasm.

Study design

• HD9
  • From 1993−1998, N = 1282 newly-diagnosed, advanced-stage HL patients received eight alternating cycles of COPP and ABVD (COPP/ABVD), bBEACOPP or eBEACOPP
  • Median observation time in HD9 (range) = 141 (101−204) months
• HD12
  • From 1999−2003, N = 1670 newly-diagnosed, advanced stage HL patients received eight cycles of eBEACOPP or four cycles of eBEACOPP plus four cycles of bBEACOPP (4 + 4), plus consolidation radiotherapy to initial bulk and residual disease or no radiotherapy
  • Median observation time in HD12 (range) = 97 (69−143) months
• In both trials, patients were stratified to regimen according to centre, age, stage, international prognostic score, the presence or absence of a large mediastinal mass, and bulky disease

Key findings 

• HD9 – Patient outcomes
  • For COPP/ABVD, 15-year PFS = 57.0% (95% CI, 50.0−0) and 15-year OS = 72.3% (95% CI, 66.5–78.1)
  • For bBEACOPP, 15-year PFS = 66.8% (95% CI, 61.9–71.8) and 15-year OS = 74.5% (95% CI, 70.1–78.9)
  • For eBEACOPP, 15-year PFS = 74.0% (95% CI, 69.0–79.0) and 15-year OS = 80.9% (95% CI, 76.7–85.0)
  • Both, PFS and OS in patients treated with eBEACOPP remained significantly higher than those seen in the COPP/ABVD group (HR = 0.53, [95% CI, 0.41–0.69]; P < 0·0001, and HR = 0.68 [95% CI, 0.50–0.93]; P = 0·015, respectively)
• HD9 – Toxicity
  • For COPP/ABVD, 15-year cumulative incidence of second primary malignant neoplasm = 7.2% (95% CI, 3.7−7)
  • For bBEACOPP, 15-year cumulative incidence of second primary malignant neoplasm = 13.0% (95% CI, 9.1–16.9)
  • For eBEACOPP, 15-year cumulative incidence of second primary malignant neoplasm = 11.4% (95% CI, 7.6–15.1)
• HD12 – Patient outcomes
  • For the 4 + 4 regimen, 10-year PFS = 80.6% (95% CI, 77.4−7) and 10-year OS = 86.8% (95% CI, 84.2–89.4)
  • For eBEACOPP, 10-year PFS = 82.6% (95% CI, 79.6–85.6) and 10-year OS = 87.3% (95% CI, 84.7–89.9)
  • The 4 + 4 regimen was not inferior to eBEACOPP, both in terms of PFS and OS outcomes with a non-inferiority margin of 1.5 (HR = 1.13 [95% CI, 0·89–1·43] and HR = 1.02 [95% CI, 0.77–1.36], respectively)
• HD12 – Toxicity
  • For the 4 + 4 regimen, 10-year cumulative incidence of second primary malignant neoplasm = 6.4% (95% CI, 3.3−5)
  • For eBEACOPP, 10-year cumulative incidence of second primary malignant neoplasm = 8.8% (95% CI, 5.2–12.4)

The long-term follow-up of the HD9 and HD12 studies showed that intensive first-line treatment for newly-diagnosed advanced stage HL patients maintains its PFS and OS benefits even after 10 or 15 years. The analysis also indicated that eBEACOPP is a superior regimen for advance-stage HL. Nevertheless, the authors stated that the incidence of second primary malignant neoplasms is quite high and that more tolerable treatments need to be developed for HL.