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Risk-adapted therapeutic strategies effective for early-stage Hodgkin lymphoma
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A risk-adapted strategy that intensifies combined-modality treatment in early-unfavorable Hodgkin lymphoma and reduces dosage for early-favorable Hodgkin lymphoma has demonstrated long-term safety and efficacy, according to extended follow-up from four German Hodgkin Study Group trials.
Combined-modality treatment is widely considered the standard of care in patients with early-stage Hodgkin lymphoma; however, treatment-related toxicities remain a concern.
“These potentially treatment-related morbidities might have an effect on long-term treatment outcome and significantly contribute to late mortality,” Peter Borchmann, MD, assistant medical director in the department of hematology and oncology at University Hospital of Cologne in Germany, and colleagues wrote. “Therefore, subsequent trials evaluated a reduction of the radiotherapy field size and dose, as well as chemotherapy intensity, aiming at achieving sufficient tumor control while potentially reducing treatment-associated toxicity.”
Despite these concerns, long-term follow-up in treatment of Hodgkin lymphoma has been limited.
Borchmann and colleagues updated data from four German Hodgkin Study Group phase 3 trials — the HD7 and HD10 trials for early-stage favorable Hodgkin lymphoma and HD8 and HD11 trials for early-stage unfavorable Hodgkin lymphoma — with extended follow-up to assess the long-term safety and efficacy of applied risk-adapted, combined-modality treatment strategies.
The analysis included 4,276 patients with early-stage Hodgkin lymphoma treated between 1993 and 2003.
Early-stage favorable Hodgkin lymphoma
In the HD7 trial, researchers randomly assigned patients to receive 30 Gy extended-field radiotherapy plus 10 Gy extended-field radiotherapy with or without preceding chemotherapy. Median follow-up was 120 months (n = 627).
Patients treated with the combined-modality treatment compared with extended-field radiotherapy alone demonstrated superior 15-year PFS (73% vs. 52%; HR = 0.5; 95% CI, 0.3-0.6). OS did not differ significantly between arms (77% vs. 80%; HR = 0.8; 95% CI, 0.6-1.2).
Fifteen-year estimates showed a cumulative incidence of second neoplasia of 16% in the combined-modality treatment arm and 14% in the extended-field radiotherapy arm, with comparable incidence of solid and hematologic malignancies (standardized incidence ratio, 2.7 vs. 3).
Researchers of the HD10 trial randomly assigned patients four or two cycles of ABVD chemotherapy (doxorubicin, bleomycin, vinblastine and dacarbazine) followed by 30 Gy or 20 Gy involved-field radiotherapy. After the original analysis from this trial, two cycles of ABVD followed by 20 Gy involved-field radiotherapy became the standard of care.
Median follow-up was 98 months (n = 1,190).
Comparison of pooled chemotherapy and radiotherapy groups did not reveal any differences in terms of efficacy.
However, researchers confirmed the noninferiority of two cycles of ABVD plus 20 Gy involved-field radiotherapy to more intensive four cycles of ABVD plus 30 Gy involved-field radiotherapy based on a 10-year PFS of 87% in each arm (HR = 1; 95% CI, 0.6-1.5) and 10-year OS of 94% in each arm (HR = 0.9; 95% CI, 0.5-1.6).
Researchers reported no differences in 10-year estimates of standardized incidence ratio and type of second neoplasia.
Early-stage unfavorable Hodgkin lymphoma
In the HD8 trial, researchers randomly assigned patients 30 Gy or extended-field or involved-field radiotherapy after two alternating cycles of COPP (cyclophosphamide, vincristine, procarbazine and prednisone) and ABVD chemotherapy. After a median follow-up of 153 months (n = 1,064), researchers confirmed noninferiority of involved-field radiotherapy to extended-field radiotherapy in terms of PFS (HR = 1; 95% CI, 0.8-1.2) and OS (HR = 0.9; 95% CI, 0.7-1.2).
Researchers observed a nonsignificant trend toward more second neoplasia after extended-field radiotherapy (15-year cumulative incidence estimates, 17% vs. 14%). This trend became more pronounced in solid second neoplasia with longer follow-up but did not meet statistical significance (12% vs. 10.4%).
In the HD11 trial, patients received four cycles of ABVD or BEACOPP (bleomycin, etoposide, doxorubicin, cyclophosphamide, vincristine, procarbazine and prednisone) chemotherapy followed by 30 Gy or 20 Gy involved-field radiation. Original results from the trial showed a moderate increase of chemotherapy intensity using BEACOPP at baseline dosage did not improve outcomes compared with ABVD.
After prolonged follow-up of 106 months (n = 1,395), researchers again did not observe a difference in PFS with BEACOPP at baseline dosage over ABVD when consolidated with 30 Gy (HR = 1.1; 95% CI, 0.7-1.5).
However, compared with 5-year analysis, BEACOPP no longer appeared to be significantly superior when followed by 20 Gy involved-field radiotherapy (HR = 0.8; 95% CI, 0.6-1.1).
After BEACOPP at baseline, 20 Gy radiotherapy appeared noninferior to 30 Gy (10-year PFS, 84% vs. 84%; HR = 1; 95% CI, 0.7-1.5). In contrast, 20 Gy radiotherapy conferred poorer PFS compared with 30 Gy radiotherapy when following ABVD (10-year PFS, 76% vs. 84%; HR = 1.5; 95% CI, 1-2.1).
Researchers observed no differences in OS or second neoplasias.
“Our updated analyses confirm the excellent efficacy of two cycles of ABVD followed by 20 Gy involved-field radiotherapy in early-favorable Hodgkin lymphoma and support the approach to apply an intensified chemotherapy regimen in early-unfavorable Hodgkin lymphoma to improve tumor control and to enable a reduction of radiotherapy intensity,” Borchmann and colleagues wrote. “The documented impact of treatment-related second neoplasia and organ toxicity on long-term survival in all four trials underlines the persistent need to develop less toxic but equally effective approaches for the treatment of Hodgkin lymphoma.” – by Kristie L. Kahl
Disclosure: Borchmann reports no relevant financial disclosures. Please see the full study for a list of all other researchers’ relevant financial disclosures.
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