primary outcome:
Chemotherapy alone versus chemotherapy plus radiotherapy for adults with early stage Hodgkin lymphoma
We evaluated overall survival (OS) as the primary endpoint. The preferred definition of OS was "time from entry onto the clinical trial until death as a result of any cause" (Cheson 2007).PatientsFive trials with 1388 patients reported OS (CALGB 7751; EORTC‐GELA H9‐F; Mexico B2H031; MSKCC trial #90‐44; UK NCRI Rapid). In the UK NCRI Rapid trial, 12% of the patients in the chemotherapy plus radiotherapy arm did not receive treatment as randomised: 26 did not receive radiotherapy. Five of the eight patients who died in the chemotherapy plus radiotherapy arm received no radiotherapy. These patients were included in the published analysis. In the MSKCC trial #90‐44 trial, 11 patients randomised to radiotherapy never received radiotherapy. Because this affects the results and no per‐protocol results were available for both trials, we excluded the trials from the meta‐analysis for a sensitivity analysis and performed subgroup analyses without these trials as well (three trials with 816 patients).ResultsThe addition of radiotherapy to chemotherapy has probably little or no difference on OS (hazard ratio (HR) = 0.48; 95% confidence interval (CI) 0.22 to 1.06; P = 0.07, see Analysis 1.1), with a moderate grade of heterogeneity between trials (I2 = 52%). One reason for the heterogeneity could be the results of the UK NCRI Rapid and MSKCC trial #90‐44 trials. In the UK NCRI Rapid trial 28 of 420 patients did not receive treatment as randomised: two received radiotherapy in the chemotherapy alone arm and 26 did not receive radiotherapy in the chemotherapy plus radiotherapy arm. Five of the eight patients who died in the chemotherapy plus radiotherapy arm received no radiotherapy. These patients were included in the published analysis of the trial. In the MSKCC trial #90‐44 trial, 11 patients randomised to the chemotherapy plus radiotherapy arm never received radiotherapy (six refused, fo ur progressed on chemotherapy prior to receiving radiotherapy, one never received radiotherapy because of bleomycin‐ induced toxicity to radiotherapy).In a sensitivity analysis without UK NCRI Rapid and MSKCC trial #90‐44, the addition of radiotherapy to chemotherapy significantly improved OS (HR 0.31; 95% CI 0.19 to 0.52; P < 0.00001). We found no evidence of heterogeneity across the trials in the meta‐analysis (P value of the homogeneity test = 0.72; I² = 0%), see Figure 3.Subgroup analysesThe subgroup analyses showed no statistically significant differences between the subgroups examined (early favourable or unfavourable disease, bulky or non‐bulky disease, timing and type of radiation therapy, type of chemotherapy). See Analysis 1.2; Analysis 1.3; Analysis 1.4; Analysis 1.5; Analysis 1.6.The P value for the intention‐to‐teat (ITT)‐analysis is P = 0.78, so there are no statistically significant differences between the subgroups in the performed sensitivity analysis, see Analysis 1.7.Subgroup analyses withoutUK NCRI RapidandMSKCC trial #90‐44The subgroup analyses without UK NCRI Rapid and MSKCC trial #90‐44 showed no statistically significant differences between the subgroups examined (early favourable or unfavourable disease, bulky or non‐bulky disease, timing of radiotherapy, type of radiotherapy and type of chemotherapy. See Analysis 2.2; Analysis 2.3; Analysis 2.4; Analysis 2.5; Analysis 2.6.There are no statistically significant subgroup differences in the ITT‐analysis as well (P = 0.42), see Analysis 2.7.PatientsOnly one trial with 276 patients reported OS (HD6), therefore we did not perform subgroup analyses. In this trial, 41 of 399 patients did not receive therapy as randomised, therefore a sensitivity analysis without the HD6 trial could no be performed for the same reasons.ResultsThe use of chemotherapy alone significantly improved OS (HR 2.12; 95% CI 1.03 to 4.37; P = 0.04), see Analysis 11.1.