Secondary malignant neoplasms, progression-free survival and overall survival in patients treated for Hodgkin lymphoma: a systematic review and meta-analysis of randomized clinical trials

Abstract

Treatment intensification to maximize disease control and reduced intensity approaches to minimize the risk of late sequelae have been evaluated in newly diagnosed Hodgkin lymphoma. The influence of these interventions on the risk of secondary malignant neoplasms, progression-free survival and overall survival is reported in the meta-analysis herein, based on individual patient data from 9498 patients treated within 16 randomized controlled trials for newly diagnosed Hodgkin lymphoma between 1984 and 2007. Secondary malignant neoplasms were meta-analyzed using Peto's method as time-to-event outcomes. For progression-free and overall survival, hazard ratios derived from each trial using Cox regression were combined by inverse-variance weighting. Five study questions (combined-modality treatment vs. chemotherapy alone; more extended vs. involved-field radiotherapy; radiation at higher doses vs. radiation at 20 Gy; more vs. fewer cycles of the same chemotherapy protocol; standard-dose chemotherapy vs. intensified chemotherapy) were investigated. After a median follow-up of 7.4 years, dose-intensified chemotherapy resulted in better progression-free survival rates (P=0.007) as compared with standard-dose chemotherapy, but was associated with an increased risk of therapy-related acute myeloid leukemia/myelodysplastic syndromes (P=0.0028). No progression-free or overall survival differences were observed between combined-modality treatment and chemotherapy alone, but more secondary malignant neoplasms were seen after combined-modality treatment (P=0.010). For the remaining three study questions, outcomes and secondary malignancy rates did not differ significantly between treatment strategies. The results of this meta-analysis help to weigh up efficacy and secondary malignancy risk for the choice of first-line treatment for Hodgkin lymphoma patients. However, final conclusions regarding secondary solid tumors require longer follow-up.

Figure 1.

Search results (combined for both searches in 2010 and 2015). HL: Hodgkin lymphoma; IPD: individual patient data.

Figure 2.

Additional radiotherapy, cumulative incidence of SMN (Peto meta-analysis). CI: confidence interval; O–E: observed minus expected; V: variance; I² = measure of heterogeneity: EORTC: European Organization for Research and Treatment of Cancer; GHSG: German Hodgkins’ Study Group.

Figure 3.

Additional radiotherapy, cumulative incidence of SMN (Peto meta-analysis). Vertical bars depict approximate 95% confidence intervals (CI) for cumulative incidence rates. CT: chemotherapy; RT: radiotherapy.

Figure 4.

Intensified chemotherapy, secondary malignant neoplasms, forest plot for Peto Odds Ratios. CI: confidence interval; O–E: observed minus expected; V: variance, I²: measure of heterogeneity; ABVD: doxorubicin, bleomycin, vinblastine, dacarbazine.

Figure 5.

Intensified chemotherapy, cumulative incidence of SMN (Peto meta-analysis). Vertical bars depict approximate 95% confidence intervals (CI) for cumulative incidence rates. ABVD: doxorubicin, bleomycin, vinblastine, dacarbazine.