Early stage Hodgkin Lymphoma: updated analyses based on long-term follow-up of four German Hodgkin Study Group trials – HD7, HD8, HD10, and HD11

On 18^th April 2017, the Journal of Clinical Oncology published an article by Stephanie Sasse, from the University Hospital of Cologne, Cologne, Germany, and colleagues who reported updated analyses from four German Hodgkin Study Group trials: HD7 and HD10 in early stage favorable Hodgkin Lymphoma, as well as HD8 and HD11 in early stage unfavorable Hodgkin Lymphoma.

Key Highlights:

HD7

• Arm A (Combined-Modality Treatment; CMT): 30Gy Extended Field (EF)-Radiotherapy (RT) plus 10Gy to the Involved Field (IF); Arm B: 2 cycles of ABVD followed by the same RT
• In total, 650 pts enrolled; 627 included in the current analysis
• Updated follow-up data beyond previous analysis (Dec. 2005) available for 56% of pts alive by the time of this last analysis; data acquired from residents’ registries in 26% of pts
• Median follow-up time for OS = 136 months
• Superiority of CMT vs. EF-RT confirmed; 15-year PFS estimates = 52% and 73% (HR, 0.5; 95% CI, 0.3–0.6; P < 0.001)
• No significant difference in OS found between arms (P = 0.3), with 15-year estimates of 77% vs. 80% and a HR of 0.8 (95% CI, 0.6–1.2)
• 15-year estimates for cumulative incidence of any Second Neoplasias (SNs) = 16% and 14%; comparable distribution of solid and hematologic malignancies and Standardized Incidence Ratios (SIRs) of 2.7 (95% CI, 1.9–3.6) and 3.0 (95% CI, 2.2–4.0)
• Only a few deaths were HL-related (2% of analyzed pts in each arm), other causes included SN (5% vs. 6%), cardiovascular disease (3% each), or respiratory disease (2% vs. 1%)

HD10 (NCT00265018)

• Arm A: 4 cycles ABVD followed by 30Gy RT; Arm B: 4 cycles of ABVD followed by 20Gy RT; Arm C: 2 cycles ABVD followed by 30Gy RT; Arm D: 2 cycles ABVD followed by 20Gy RT
• In total, 1,370 pts enrolled; 1,190 included in the current analysis
• Updated follow-up data beyond the previous analysis (June 2009) available for 44% of pts alive by the time of this last analysis; data acquired from residents’ registries in 11% of pts
• Median follow-up time for OS = 113 months
• No differences in terms of efficacy found when comparing pooled chemotherapy and RT groups
• Non-inferiority of 2 cycles of ABVD plus 20Gy (least intensive) to 4 cycles of ABVD plus 30Gy (most intensive) was confirmed; 10-year PFS estimates = 87% each (HR, 1.0; 95% CI, 0.6–1.5 within the calculated margin for non-inferiority of 2.2)
• 10-year OS estimates = 94% each (HR, 0.9; 95% CI, 0.5–1.6)
• No difference in terms of incidence and type of SN was observed between least and most intensive arms
• Most deaths attributed to SN (2% of analyzed pts); HL-related death reported in 1% of pts

HD8

• Arm A: 2 cycles of COPP plus ABVD followed by 30Gy EF-RT plus 10Gy to bulky disease; Arm B: 2 cycles of COPP plus ABVD followed by 30Gy IF-RT plus 10Gy to bulky disease
• In total, 1,204 pts enrolled; 1,064 included in the current analysis
• Updated follow-up data beyond the previous analysis (Jan. 2011) available for 41% of pts alive by the time of this last analysis; data acquired from residents’ registries in 28% of pts
• Median follow-up time for OS = 174 months
• Non-inferiority of IF-RT vs. EF-RT confirmed in terms of PFS and OS with HRs of 1.0 (95% CI, 0.8–1.2 within the calculated non-inferiority margin of 1.6) and 0.9 (95% CI, 0.7–1.2), respectively
• A non-significant trend reported toward increased SN after EF-RT vs. IF-RT; 15-year cumulative incidence estimates = 17% vs. 14% (P = 0.3)
• Trend was more distinct when only studying incidence of AML or MDS (2.4% vs. 0.8%; P = 0.1), but not in NHL (2.6% vs. 2.9%; P = 1.0)
• In solid SN, the trend became more pronounced with longer follow-up but did not meet statistical significance (12% vs. 10.4%; P = 0.7)
• In both arms, SN resulted in the majority of deaths (6% vs. 5% of pts), followed by HL (3% each), then cardiovascular disease (2% vs. 3%)

HD11 (NCT00264953)

• Arm A: 4 cycles ABVD plus 30Gy IF-RT; Arm B: 4 cycles ABVD plus 20Gy IF-RT; Arm C: 4 cycles BEACOPP_baseline plus 30Gy IF-RT; Arm D: 4 cycles BEACOPP_baseline plus 20Gy IF-RT
• In total, 1,570 pts enrolled; 1,395 included in the current analysis
• Updated follow-up data beyond the previous analysis (July 2009) available for 47% of pts alive by the time of this last analysis; data acquired from residents’ registries in 12% of pts
• Median follow-up time for OS = 117 months
• No difference in PFS found with BEACOPP_baseline standard ABVD when followed by 30Gy (HR, 1.1; 95% CI, 0.7–1.5; P = 0.8)
• Compared to the 5-year analysis, BEACOPP_baseline was no longer significantly superior to ABVD when followed by 20Gy IF-RT (HR, 0.8; 95% CI, 0.6–1.1; P = 0.1)
• A difference of -8.3% (-15.2% to -1.3%) in 10-year PFS for ABVD-treated pts receiving 20Gy rather than 30Gy IF-RT (HR, 1.5; 95% CI, 1.0–2.1 exceeding the calculated non-inferiority margin of 1.6)
• For PFS, 20Gy IF-RT was found to be non-inferior to 30Gy IF-RT after BEACOPP_baseline (HR, 1.0; 95% CI, 0.7–1.5 within the calculated non-inferiority margin of 1.7)
• For OS or SN, no significant differences or relevant trends could be observed between trial arms
• Most frequent causes of death were HL (3%), SN (2%), and cardiovascular disease (1%)

The authors conclude that their updated analyses “confirm the excellent efficacy of two cycles of ABVD followed by 20Gy IF-RT in early favorable HL”. They also stated that their data support the use of intensified chemotherapy regimens in early unfavorable HL in order to “improve tumor control and to enable a reduction of RT intensity”. Lastly, the group emphasized the need to develop less toxic regimens for the treatment of HL based on the impact of SN and organ toxicity on long-term survival reported in all four trials.

Abstract:

Purpose: Combined-modality treatment is widely considered the standard of care in early-stage Hodgkin lymphoma (HL), and treatment intensity has been reduced over the last years. Long-term follow-up is important to judge both efficacy and safety of the different therapies used.

Patients and Methods: We analyzed updated follow-up data on 4,276 patients treated within the German Hodgkin Study Group trials HD7 and HD10 for early-stage favorable HL and HD8 and HD11 for early-stage unfavorable HL between 1993 and 2003.

Results: In HD7 (N = 627; median follow-up, 120 months), combined-modality treatment was superior to extended-field radiotherapy (RT), with 15-year progression-free survival (PFS) of 73% versus 52% (hazard ratio [HR], 0.5; 95% CI, 0.3 to 0.6; P < .001), without differences in overall survival (OS). In HD10 (N = 1,190; median follow-up, 98 months), noninferiority of two cycles of doxorubicin, bleomycin, vinblastine, dacarbazine (ABVD) plus 20 Gy involved-field (IF)-RT to more intensive four cycles of ABVD plus 30 Gy IF-RT was confirmed with 10-year PFS of 87% each (HR, 1.0; 95%, 0.6 to 1.5) and OS of 94% each (HR, 0.9; 95% CI, 0.5 to 1.6), respectively. In both trials, no differences in second neoplasias were observed. In HD8 (N = 1,064; median follow-up, 153 months), noninferiority of involved-field RT to extended-field RT regarding PFS was confirmed (HR, 1.0; 95% CI, 0.8 to 1.2). In HD11 (N = 1,395; median follow-up, 106 months), superiority of bleomycin, etoposide, doxorubicin, cyclophosphamide, vincristine, procarbazine, and prednisone at baseline over ABVD was not observed. After BEACOPPbaseline, 20 Gy IF-RT was noninferior to 30 Gy (10-year PFS, 84% v 84%; HR, 1.0; 95% CI, 0.7 to 1.5). In contrast, PFS was inferior in ABVD-treated patients receiving 20 Gy instead of 30 Gy IF-RT (10-year PFS, 76% v 84%; HR, 1.5; 95% CI, 1.0 to 2.1). No differences in OS or second neoplasias were observed in in both trials.

Conclusion: Long-term follow-up data of the four randomized trials largely support the current risk-adapted therapeutic strategies in early-stage HL. Nevertheless, continued follow-up is necessary to assess the long-term safety of currently applied therapeutic strategies.