BACKGROUND: Children and adolescents with intermediate-stage and advanced-stage classical Hodgkin lymphoma achieve an event-free survival at 5 years of about 90% after treatment with vincristine, etoposide, prednisone, and doxorubicin (OEPA) followed by cyclophosphamide, vincristine, prednisone, and procarbazine (COPP) and radiotherapy, but long-term treatment effects affect survival and quality of life. We aimed to investigate whether radiotherapy can be omitted in patients with morphological and metabolic adequate response to OEPA and whether modified consolidation chemotherapy reduces gonadotoxicity. METHODS: Our study was designed as a titration study with an open-label, embedded, multinational, non-inferiority, randomised controlled trial, and was carried out at 186 hospital sites across 16 European countries. Children and adolescents with newly diagnosed intermediate-stage (treatment group 2) and advanced-stage (treatment group 3) classical Hodgkin lymphoma who were younger than 18 years and stratified according to risk using Ann Arbor disease stages IIAE, IIB, IIBE, IIIA, IIIAE, IIIB, IIIBE, and all stages IV (A, B, AE, and BE) were included in the study. Patients with early disease (treatment group 1) were excluded from this analysis. All patients were treated with two cycles of OEPA (1·5 mg/m2 vincristine taken intravenously capped at 2 mg, on days 1, 8, and 15; 125 mg/m2 etoposide taken intravenously on days 1-5; 60 mg/m2 prednisone taken orally on days 1-15; and 40 mg/m2 doxorubicin taken intravenously on days 1 and 15). Patients were randomly assigned to two (treatment group 2) or four (treatment group 3) cycles of COPP (500 mg/m2 cyclophosphamide taken intravenously on days 1 and 8; 1·5 mg/m2 vincristine taken intravenously capped at 2 mg, on days 1 and 8; 40 mg/m2 prednisone taken orally on days 1 to 15; and 100 mg/m2 procarbazine taken orally on days 1 to 15) or COPDAC, which was identical to COPP except that 250 mg/m2 dacarbazine administered intravenously on days 1 to 3 replaced procarbazine. The method of randomisation (1:1) was minimisation with stochastic component and was centrally stratified by treatment group, country, trial sites, and sex. The primary endpoint was event-free survival, defined as time from treatment start until the first of the following events: death from any cause, progression or relapse of classical Hodgkin lymphoma, or occurrence of secondary malignancy. The primary objectives were maintaining 90% event-free survival at 5 years in patients with adequate response to OEPA treated without radiotherapy and to exclude a decrease of 8% in event-free survival at 5 years in the embedded COPDAC versus COPP randomisation to show non-inferiority of COPDAC. Efficacy analyses are reported per protocol and safety in the intention-to-treat population. The trial is registered with ClinicalTrials.gov (trial number NCT00433459) and EUDRACT (trial number 2006-000995-33), and is closed to recruitment. FINDINGS: Between Jan 31, 2007, and Jan 30, 2013, 2102 patients were recruited. 737 (35%) of the 2102 recruited patients were in treatment group 1 (early-stage disease) and were not included in our analysis. 1365 (65%) of the 2102 patients were in treatment group 2 (intermediate-stage disease; n=455) and treatment group 3 (advanced-stage disease; n=910). Of these 1365, 1287 (94%) patients (435 [34%] of 1287 in treatment group 2 and 852 [66%] of 1287 in treatment group 3) were included in the titration trial per-protocol analysis. 937 (69%) of 1365 patients were randomly assigned to COPP (n=471) or COPDAC (n=466) in the embedded trial. Median follow-up was 66·5 months (IQR 62·7-71·7). Of 1287 patients in the per-protocol group, 514 (40%) had an adequate response to treatment and were not treated with radiotherapy (215 [49%] of 435 in treatment group 2 and 299 [35%] of 852 in treatment group 3). 773 (60%) of 1287 patients with inadequate response were scheduled for radiotherapy (220 [51%] of 435 in the treatment group 2 and 553 [65%] of 852 in treatment group 3. In patients who responded adequately, event-free survival rates at 5 years were 90·1% (95% CI 87·5-92·7). event-free survival rates at 5 years in 892 patients who were randomly assigned to treatment and analysed per protocol were 89·9% (95% CI 87·1-92·8) for COPP (n=444) versus 86·1% (82·9-89·4) for COPDAC (n=448). The COPDAC minus COPP difference in event-free survival at 5 years was -3·7% (-8·0 to 0·6). The most common grade 3-4 adverse events (intention-to-treat population) were decreased haemoglobin (205 [15%] of 1365 patients during OEPA vs 37 [7%] of 528 treated with COPP vs 20 [2%] of 819 treated with COPDAC), decreased white blood cells (815 [60%] vs 231 [44%] vs 84 [10%]), and decreased neutrophils (1160 [85%] vs 223 [42%] vs 174 [21%]). One patient in treatment group 2 died of sepsis after the first cycle of OEPA; no other treatment-related deaths occurred. INTERPRETATION: Our results show that radiotherapy can be omitted in patients who adequately respond to treatment, when consolidated with COPP or COPDAC. COPDAC might be less effective, but is substantially less gonadotoxic than COPP. A high proportion of patients could therefore be spared radiotherapy, eventually reducing the late effects of treatment. With more refined criteria for response assessment, the number of patients who receive radiotherapy will be further decreased. FUNDING: Deutsche Krebshilfe, Elternverein für Krebs-und leukämiekranke Kinder Gießen, Kinderkrebsstiftung Mainz, Tour der Hoffnung, Menschen für Kinder, Programme Hospitalier de Recherche Clinique, and Cancer Research UK.

• MeSH
• cyklofosfamid terapeutické užití   MeSH
• dítě MeSH
• folikuly stimulující hormon krev   MeSH
• Hodgkinova nemoc farmakoterapie   mortalita   radioterapie   MeSH
• lidé MeSH
• mladiství MeSH
• prednison terapeutické užití   MeSH
• prokarbazin terapeutické užití   MeSH
• protokoly antitumorózní kombinované chemoterapie škodlivé účinky   terapeutické užití   MeSH
• staging nádorů MeSH
• vinkristin terapeutické užití   MeSH
• Check Tag
• dítě MeSH
• lidé MeSH
• mladiství MeSH
• mužské pohlaví MeSH
• ženské pohlaví MeSH
• Publikační typ
• časopisecké články MeSH
• multicentrická studie MeSH
• práce podpořená grantem MeSH
• randomizované kontrolované studie MeSH
• srovnávací studie MeSH

To determine whether the current 18F-FDG PET response criterion for skeletal involvement in Hodgkin lymphoma (HL) is suitable, we performed a systematic evaluation of the different types of skeletal involvement and their response on PET after 2 cycles of chemotherapy (PET-2). A secondary objective was to observe the influence of the initial uptake intensity (measured as qPET) and initial metabolic tumor volume (MTV) of skeletal lesions on the PET-2 response. Methods: The initial PET scans of 1,068 pediatric HL patients from the EuroNet-PHL-C1 trial were evaluated for skeletal involvement by central review. Three types of skeletal lesions were distinguished: PET-only lesions (those detected on PET only), bone marrow (BM) lesions (as confirmed by MRI or BM biopsy), and bone lesions. qPET and MTV were calculated for each skeletal lesion. All PET-2 scans were assessed for residual tumor activity. The rates of complete metabolic response for skeletal and nodal involvement on PET-2 were compared. Results: Of the 1,068 patients, 139 (13%) showed skeletal involvement (44 PET-only, 32 BM, and 63 bone). Of the 139 patients with skeletal involvement, 101 (73%) became PET-2-negative in the skeleton and 94 (68%) became PET-2-negative in the lymph nodes. The highest number of PET-2-negative scans in the skeleton was 42 (95%) in the 44 PET-only patients, followed by 22 skeletal lesions (69%) in the 32 BM patients and 37 (59%) in the 63 bone patients. Lesions that became PET-2-negative showed a lower initial median qPET (2.74) and MTV (2 cm3) than lesions that remained PET-2-positive (3.84 and 7 cm3, respectively). Conclusion: In this study with pediatric HL patients, the complete response rate for skeletal involvement on PET-2 was similar to that for nodal involvement. Bone flare seemed to be irrelevant. Overall, the current skeletal PET response criterion-comparison with the local skeletal background-is well suited. The initial qPET and MTV of skeletal lesions were predictive of the PET-2 result. Higher values for both parameters were associated with a worse PET-2 response.

• MeSH
• dítě MeSH
• fluorodeoxyglukosa F18 * MeSH
• Hodgkinova nemoc farmakoterapie   patologie   MeSH
• indukční chemoterapie * MeSH
• lidé MeSH
• mladiství MeSH
• nádory kostí diagnostické zobrazování   sekundární   MeSH
• nádory kostní dřeně diagnostické zobrazování   sekundární   MeSH
• pozitronová emisní tomografie * MeSH
• retrospektivní studie MeSH
• výsledek terapie MeSH
• Check Tag
• dítě MeSH
• lidé MeSH
• mladiství MeSH
• mužské pohlaví MeSH
• ženské pohlaví MeSH
• Publikační typ
• časopisecké články MeSH
• práce podpořená grantem MeSH