RESUMO
BACKGROUND: Intensified systemic chemotherapy has the highest primary cure rate for advanced-stage, classical Hodgkin lymphoma but this comes with a cost of severe and potentially life long, persisting toxicities. With the new regimen of brentuximab vedotin, etoposide, cyclophosphamide, doxorubicin, dacarbazine, and dexamethasone (BrECADD), we aimed to improve the risk-to-benefit ratio of treatment of advanced-stage, classical Hodgkin lymphoma guided by PET after two cycles. METHODS: This randomised, multicentre, parallel, open-label, phase 3 trial was done in 233 trial sites across nine countries. Eligible patients were adults (aged ≤60 years) with newly diagnosed, advanced-stage, classical Hodgkin lymphoma (ie, Ann Arbor stage III/IV, stage II with B symptoms, and either one or both risk factors of large mediastinal mass and extranodal lesions). Patients were randomly assigned (1:1) to four or six cycles (21-day intervals) of escalated doses of etoposide (200 mg/m2 intravenously on days 1-3), doxorubicin (35 mg/m2 intravenously on day 1), and cyclophosphamide (1250 mg/m2 intravenously on day 1), and standard doses of bleomycin (10 mg/m2 intravenously on day 8), vincristine (1·4 mg/m2 intravenously on day 8), procarbazine (100 mg/m2 orally on days 1-7), and prednisone (40 mg/m2 orally on days 1-14; eBEACOPP) or BrECADD, guided by PET after two cycles. Patients and investigators were not masked to treatment assignment. Hierarchical coprimary objectives were to show (1) improved tolerability defined by treatment-related morbidity and (2) non-inferior efficacy defined by progression-free survival with an absolute non-inferiority margin of 6 percentage points of BrECADD compared with eBEACOPP. An additional test of superiority of progression-free survival was to be done if non-inferiority had been established. Analyses were done by intention to treat; the treatment-related morbidity assessment required documentation of at least one chemotherapy cycle. This trial was registered at ClinicalTrials.gov (NCT02661503). FINDINGS: Between July 22, 2016, and Aug 27, 2020, 1500 patients were enrolled, of whom 749 were randomly assigned to BrECADD and 751 to eBEACOPP. 1482 patients were included in the intention-to-treat analysis. The median age of patients was 31 years (IQR 24-42). 838 (56%) of 1482 patients were male and 644 (44%) were female. Most patients were White (1352 [91%] of 1482). Treatment-related morbidity was significantly lower with BrECADD (312 [42%] of 738 patients) than with eBEACOPP (430 [59%] of 732 patients; relative risk 0·72 [95% CI 0·65-0·80]; p<0·0001). At a median follow-up of 48 months, BrECADD improved progression-free survival with a hazard ratio of 0·66 (0·45-0·97; p=0·035); 4-year progression-free survival estimates were 94·3% (95% CI 92·6-96·1) for BrECADD and 90·9% (88·7-93·1) for eBEACOPP. 4-year overall survival rates were 98·6% (97·7-99·5) and 98·2% (97·2-99·3), respectively. INTERPRETATION: BrECADD guided by PET after two cycles is better tolerated and more effective than eBEACOPP in first-line treatment of adult patients with advanced-stage, classical Hodgkin lymphoma. FUNDING: Takeda Oncology.
Assuntos
Protocolos de Quimioterapia Combinada Antineoplásica , Doença de Hodgkin , Adulto , Feminino , Humanos , Masculino , Adulto Jovem , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Protocolos de Quimioterapia Combinada Antineoplásica/efeitos adversos , Brentuximab Vedotin/administração & dosagem , Brentuximab Vedotin/efeitos adversos , Brentuximab Vedotin/uso terapêutico , Ciclofosfamida/uso terapêutico , Ciclofosfamida/efeitos adversos , Ciclofosfamida/administração & dosagem , Dacarbazina/uso terapêutico , Dacarbazina/administração & dosagem , Dacarbazina/efeitos adversos , Dexametasona/administração & dosagem , Dexametasona/uso terapêutico , Dexametasona/efeitos adversos , Doxorrubicina/administração & dosagem , Doxorrubicina/efeitos adversos , Doxorrubicina/uso terapêutico , Etoposídeo/administração & dosagem , Etoposídeo/efeitos adversos , Etoposídeo/uso terapêutico , Doença de Hodgkin/tratamento farmacológico , Doença de Hodgkin/diagnóstico por imagem , Doença de Hodgkin/patologia , Doença de Hodgkin/mortalidade , Estadiamento de Neoplasias , Tomografia por Emissão de Pósitrons , Resultado do TratamentoRESUMO
BACKGROUND AND PURPOSE: There are few studies of personality traits in long-term Hodgkin lymphoma survivors (HLSs) treated according to contemporary stage-and risk-adapted approaches. The Distressed Personality (DP) Scale covers negative affectivity and social inhibition. We examined differences in self-reported late adverse effects (LAEs) between HLSs with and without DP and other explanatory variables. MATERIAL AND METHODS: This cross-sectional questionnaire-based study included a population-based cohort of HLSs treated from 1997 to 2006, aged 8-49 years at diagnosis, and alive in 2016. Among 518 eligible HLSs, 303 responded (58%), and 294 completed the DP scale. DP was defined by scores above cut-off on both the negative affectivity and social inhibition subscales. LAEs studied were major depression, posttraumatic stress disorder, sleep problems, obesity, neuropathy, fatigue, memory problems, and general health. DP and 10 other explanatory variables were tested against LAEs as dependent variables in multivariable regression analyses. RESULTS: The mean age at survey was 45.9 years (standard deviation [SD] 4.6), mean follow-up time 16.7 years (SD 3.0), and 48% were females. Eighty-two HLSs had DP (28%, 95% confidence interval 23% - 33%). All LAEs except obesity were significantly more common/had higher mean score in HLSs with DP. In multivariable analyses, presence of DP was significantly associated with all LAEs except obesity. INTERPRETATION: The presence of DP is common among HLSs. The presence of DP was associated with most self-report LAEs examined. Including assessment of personality traits in the survivorship care plans of HLSs should be considered. Prospective studies assessing the influence of pretreatment DP on LAEs are warranted.
Assuntos
Sobreviventes de Câncer , Doença de Hodgkin , Personalidade , Humanos , Doença de Hodgkin/psicologia , Feminino , Masculino , Pessoa de Meia-Idade , Adulto , Estudos Transversais , Adolescente , Sobreviventes de Câncer/psicologia , Sobreviventes de Câncer/estatística & dados numéricos , Adulto Jovem , Criança , Inquéritos e Questionários , Fadiga/epidemiologia , Fadiga/etiologia , Fadiga/psicologia , Transtornos de Estresse Pós-Traumáticos/epidemiologia , Transtornos de Estresse Pós-Traumáticos/etiologia , Transtornos de Estresse Pós-Traumáticos/psicologia , Transtornos do Sono-Vigília/etiologia , Transtornos do Sono-Vigília/epidemiologia , Transtornos do Sono-Vigília/psicologia , Efeitos Adversos de Longa Duração/psicologia , Efeitos Adversos de Longa Duração/epidemiologia , Efeitos Adversos de Longa Duração/etiologiaRESUMO
BACKGROUND: Disseminated pulmonary involvement in pediatric Hodgkin lymphoma (pHL) is indicative of Ann Arbor stage IV disease. During staging, it is necessary to assess for coexistence of non-malignant lung lesions due to infection representing background noise to avoid erroneously upstaging with therapy intensification. OBJECTIVE: This study attempts to describe new lung lesions detected on interim staging computed tomography (CT) scans after two cycles of vincristine, etoposide, prednisolone, doxorubicin in a prospective clinical trial. Based on the hypothesis that these new lung lesions are not part of the underlying malignancy but are epiphenomena, the aim is to analyze their size, number, and pattern to help distinguish true lung metastases from benign lung lesions on initial staging. MATERIALS AND METHODS: A retrospective analysis of the EuroNet-PHL-C1 trial re-evaluated the staging and interim lung CT scans of 1,300 pediatric patients with HL. Newly developed lung lesions during chemotherapy were classified according to the current Fleischner glossary of terms for thoracic imaging. Patients with new lung lesions found at early response assessment (ERA) were additionally assessed and compared to response seen in hilar and mediastinal lymph nodes. RESULTS: Of 1,300 patients at ERA, 119 (9.2%) had new pulmonary lesions not originally detectable at diagnosis. The phenomenon occurred regardless of initial lung involvement or whether a patient relapsed. In the latter group, new lung lesions on ERA regressed by the time of relapse staging. New lung lesions on ERA in patients without relapse were detected in 102 (7.8%) patients. Pulmonary nodules were recorded in 72 (5.5%) patients, the majority (97%) being<10 mm. Consolidations, ground-glass opacities, and parenchymal bands were less common. CONCLUSION: New nodules on interim staging are common, mostly measure less than 10 mm in diameter and usually require no further action because they are most likely non-malignant. Since it must be assumed that benign and malignant lung lesions coexist on initial staging, this benign background noise needs to be distinguished from lung metastases to avoid upstaging to stage IV disease. Raising the cut-off size for lung nodules to ≥ 10 mm might achieve the reduction of overtreatment but needs to be further evaluated with survival data. In contrast to the staging criteria of EuroNet-PHL-C1 and C2, our data suggest that the number of lesions present at initial staging may be less important.
Assuntos
Doença de Hodgkin , Neoplasias Pulmonares , Estadiamento de Neoplasias , Tomografia Computadorizada por Raios X , Humanos , Masculino , Feminino , Doença de Hodgkin/diagnóstico por imagem , Doença de Hodgkin/patologia , Doença de Hodgkin/tratamento farmacológico , Criança , Neoplasias Pulmonares/diagnóstico por imagem , Neoplasias Pulmonares/patologia , Adolescente , Tomografia Computadorizada por Raios X/métodos , Estudos Retrospectivos , Prevalência , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Estudos Prospectivos , Pré-Escolar , Doxorrubicina/uso terapêutico , Etoposídeo/uso terapêutico , Etoposídeo/administração & dosagem , Vincristina/uso terapêuticoRESUMO
BACKGROUND: Children and adolescents with early-stage classical Hodgkin lymphoma have a 5-year event-free survival of 90% or more with vincristine, etoposide, prednisone, and doxorubicin (OEPA) plus radiotherapy, but late complications of treatment affect survival and quality of life. We investigated whether radiotherapy can be omitted in patients with adequate morphological and metabolic responses to OEPA. METHODS: The EuroNet-PHL-C1 trial was designed as a titration study and recruited patients at 186 hospital sites across 16 European countries. Children and adolescents with newly diagnosed stage IA, IB, and IIA classical Hodgkin lymphoma younger than 18 years of age were assigned to treatment group 1 to be treated with two cycles of OEPA (vincristine 1·5 mg/m2 intravenously, capped at 2 mg, on days 1, 8, and 15; etoposide 125 mg/m2 intravenously, on days 1-5; prednisone 60 mg/m2 orally on days 1-15; and doxorubicin 40 mg/m2 intravenously on days 1 and 15). If no adequate response (a partial morphological remission or greater and PET negativity) had been achieved after two cycles of OEPA, involved-field radiotherapy was administered at a total dose of 19·8 Gy (usually in 11 fractions of 1·8 Gy per day). The primary endpoint was event-free survival. The primary objective was maintaining a 5-year event-free survival rate of 90% in patients with an adequate response to OEPA without radiotherapy. We performed intention-to-treat and per-protocol analyses. The trial was registered at ClinicalTrials.gov (NCT00433459) and with EUDRACT, (2006-000995-33) and is completed. FINDINGS: Between Jan 31, 2007, and Jan 30, 2013, 2131 patients were registered and 2102 patients were enrolled onto EuroNet-PHL-C1. Of these 2102 patients, 738 with early-stage disease were allocated to treatment group 1. Median follow-up was 63·3 months (IQR 60·1-69·8). We report on 714 patients assigned to and treated on treatment group 1; the intention-to-treat population comprised 713 patients with 323 (45%) male and 390 (55%) female patients. In 440 of 713 patients in the intention-to-treat group who had an adequate response and did not receive radiotherapy, 5-year event-free survival was 86·5% (95% CI 83·3-89·8), which was less than the 90% target rate. In 273 patients with an inadequate response who received radiotherapy, 5-year event-free survival was 88·6% (95% CI 84·8-92·5), for which the 95% CI included the 90% target rate. The most common grade 3-4 adverse events were neutropenia (in 597 [88%] of 680 patients) and leukopenia (437 [61%] of 712). There were no treatment-related deaths. INTERPRETATION: On the basis of all the evidence, radiotherapy could be omitted in patients with early-stage classical Hodgkin lymphoma and an adequate response to OEPA, but patients with risk factors might need more intensive treatment. FUNDING: Deutsche Krebshilfe, Elternverein für Krebs-und leukämiekranke Kinder, Gießen, Kinderkrebsstiftung Mainz of the Journal Oldtimer Markt, Tour der Hoffnung, Menschen für Kinder, Mitteldeutsche Kinderkrebsforschung, Programme Hospitalier de Recherche Clinique, and Cancer Research UK.
Assuntos
Doença de Hodgkin , Adolescente , Criança , Feminino , Humanos , Recém-Nascido , Masculino , Doxorrubicina , Etoposídeo , Prednisona , Qualidade de Vida , VincristinaRESUMO
Childbirth rates in classical Hodgkin lymphoma (cHL) survivors have historically been reduced compared to the general population. Understanding if contemporary treatment protocols are associated with reduced fertility is crucial as treatment guidelines shift toward more liberal use of intensive chemotherapy. We identified 2834 individuals aged 18-40 years with cHL in Swedish and Danish lymphoma registers, and in the clinical database at Oslo University Hospital diagnosed 1995-2018, who were linked to national medical birth registers. Cox regression adjusted for stage, performance status, year, and age at diagnosis was used to estimate hazard ratios (HRs) and 95% confidence intervals (CI) contrasting time to first childbirth by treatment groups (ABVD, 2-4 BEACOPP, 6-8 BEACOPP) up to 10 years after diagnosis. Overall, 74.8% of patients were treated with ABVD, 3.1% with 2-4 BEACOPP and 11.2% with 6-8 BEACOPP. Adjusted HRs comparing childbirth rates in individuals treated with 6-8 BEACOPP, and 2-4 BEACOPP to ABVD were 0.53 (CI: 0.36-0.77) and 0.33 (CI: 0.12-0.91) for males, and 0.91 (CI: 0.61-1.34) and 0.38 (CI: 0.12-1.21) for females. Cumulative incidence of childbirths after 10 years was 19.8% (CI: 14.5%-27.0%) for males and 34.3% (CI: 25.8%-45.6%) for females treated with 6-8 BEACOPP. Proportions of children born after assisted reproductive technique (ART) treatments were 77.4% (CI: 60.2-88.6%) for males following 6-8 BEACOPP, and <11% for females. Among ABVD treated patients the corresponding proportions were 12.2% (CI: 8.5%-17.3%) and 10.6% (CI: 7.4%-14.9%). BEACOPP treatment is associated with decreased childbirth rates compared to ABVD in male, but not female, cHL patients, despite widespread access to ART in the Nordics.
Assuntos
Doença de Hodgkin , Feminino , Criança , Humanos , Masculino , Doença de Hodgkin/tratamento farmacológico , Doença de Hodgkin/epidemiologia , Doxorrubicina/uso terapêutico , Bleomicina/efeitos adversos , Suécia/epidemiologia , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Estudos de Coortes , Vimblastina/uso terapêutico , Dacarbazina , Vincristina/uso terapêutico , Ciclofosfamida/uso terapêutico , Etoposídeo , Reprodução , Prednisona/uso terapêutico , DinamarcaRESUMO
Previous studies concerning reproductive patterns among non-Hodgkin lymphoma (NHL) survivors are scarce and those available have reported conflicting results. Treatment regimens vary considerably between aggressive and indolent NHL and studies of reproductive patterns by subtypes are warranted. In this matched cohort study, we identified all NHL patients aged 18-40 years and diagnosed between 2000 and 2018 from the Swedish and Danish lymphoma registers, and the clinical database at Oslo University Hospital (n = 2090). Population comparators were matched on sex, birth year and country (n = 19 427). Hazard ratios (HRs) were estimated using Cox regression. Males and females diagnosed with aggressive lymphoma subtypes had lower childbirth rates (HRfemale : 0.43, 95% CI: 0.31-0.59, HRmale : 0.61, 95% CI: 0.47-0.78) than comparators during the first 3 years after diagnosis. For indolent lymphomas, childbirth rates were not significantly different from comparators (HRfemale : 0.71, 95% CI: 0.48-1.04, HRmale : 0.94, 95% CI: 0.70-1.27) during the same period. Childbirth rates reached those of comparators for all subtypes after 3 years but the cumulative incidence of childbirths was decreased throughout the 10-year follow-up for aggressive NHL. Children of NHL patients were more likely to be born following assisted reproductive technology than those of comparators, except for male indolent lymphoma patients. In conclusion, fertility counselling is particularly important for patients with aggressive NHL.
Assuntos
Linfoma não Hodgkin , Criança , Humanos , Masculino , Feminino , Suécia/epidemiologia , Estudos de Coortes , Linfoma não Hodgkin/tratamento farmacológico , Sobreviventes , Reprodução , Dinamarca/epidemiologiaRESUMO
Elderly Hodgkin Lymphoma (HL) patients are poorly characterized and underrepresented in studies. In this national population-based study, we investigated cause-specific survival using competing-risk analysis in elderly HL patients compared to the normal population. Patients ≥ 60 years diagnosed between 2000-2015 were identified by Cancer Registry of Norway, records reviewed in detail and compared to data from Norwegian Cause of Death Registry for patients and cancer-free controls. Of 492 patients, 81 (17%) were ineligible for treatment directed specifically towards HL, mostly because of an underlying other lymphoma entity, whereas 74 (15%) and 337 (69%) were treated with palliative or curative intent, respectively. Median overall survival in patients ineligible for assessment of HLdirected therapies was 0.5 years (95% confidence interval [CI] 0.4-0.6), and for palliatively and curatively treated patients 0.8 (0.4-1.2) and 9.1 (7.5-10.7) years, respectively. After correction of discrepancies in registry data, with 359 deaths, 108 (30%) died of HL, the most common cause of death. In curatively treated patients, treatment-related mortality was 6.5% and the risk-difference of dying from HL compared to controls was 28% (95% CI 23-33%) after 10 years. These numbers indicate disease control in a majority of elderly patients eligible for curative treatment, compared to risk-differences for death from HL of 59% (48-71%) and 42% (31-53%) after 10 years in the palliative and ineligible groups, respectively. There was an increased risk of dying from hematological malignancies other than HL in all groups, but not from other competing causes of death, showing no excess mortality from long-term treatment complications.
RESUMO
BACKGROUND: Rebound thymic hyperplasia (RTH) is a common phenomenon caused by stress factors such as chemotherapy (CTX) or radiotherapy, with an incidence between 44% and 67.7% in pediatric lymphoma. Misinterpretation of RTH and thymic lymphoma relapse (LR) may lead to unnecessary diagnostic procedures including invasive biopsies or treatment intensification. The aim of this study was to identify parameters that differentiate between RTH and thymic LR in the anterior mediastinum. METHODS: After completion of CTX, we analyzed computed tomographies (CTs) and magnetic resonance images (MRIs) of 291 patients with classical Hodgkin lymphoma (CHL) and adequate imaging available from the European Network for Pediatric Hodgkin lymphoma C1 trial. In all patients with biopsy-proven LR, an additional fluorodeoxyglucose (FDG)-positron emission tomography (PET)-CT was assessed. Structure and morphologic configuration in addition to calcifications and presence of multiple masses in the thymic region and signs of extrathymic LR were evaluated. RESULTS: After CTX, a significant volume increase of new or growing masses in the thymic space occurred in 133 of 291 patients. Without biopsy, only 98 patients could be identified as RTH or LR. No single finding related to thymic regrowth allowed differentiation between RTH and LR. However, the vast majority of cases with thymic LR presented with additional increasing tumor masses (33/34). All RTH patients (64/64) presented with isolated thymic growth. CONCLUSION: Isolated thymic LR is very uncommon. CHL relapse should be suspected when increasing tumor masses are present in distant sites outside of the thymic area. Conversely, if regrowth of lymphoma in other sites can be excluded, isolated thymic mass after CTX likely represents RTH.
Assuntos
Doença de Hodgkin , Linfoma , Hiperplasia do Timo , Neoplasias do Timo , Humanos , Criança , Doença de Hodgkin/diagnóstico por imagem , Doença de Hodgkin/tratamento farmacológico , Doença de Hodgkin/complicações , Hiperplasia do Timo/diagnóstico por imagem , Hiperplasia do Timo/etiologia , Recidiva Local de Neoplasia/diagnóstico por imagem , Recidiva Local de Neoplasia/tratamento farmacológico , Linfoma/tratamento farmacológico , Tomografia Computadorizada por Raios X , Tomografia por Emissão de Pósitrons/métodos , Neoplasias do Timo/diagnóstico por imagem , Neoplasias do Timo/tratamento farmacológico , Neoplasias do Timo/complicações , Fluordesoxiglucose F18/uso terapêutico , Compostos RadiofarmacêuticosRESUMO
BACKGROUND: Chronic fatigue (CF), substantial fatigue for ≥ six months, can manifest as a late effect (LE) after cancer treatment, and may affect several aspects of life. In a Norwegian cohort of Hodgkin's lymphoma survivors (HLS), more than a decade after contemporary risk-adapted treatment regimens with limited use of radiotherapy (RT), we assessed: (1) Prevalence of, (2) factors associated with (3) and implications of CF on socioeconomic status (SES) and work ability (WA). MATERIAL AND METHODS: HLS treated between 1997-2006, aged 8-49 years at diagnosis, were invited to participate in a population-based cross-sectional study on late effects in 2018-2019. In a mailed questionnaire, HLS responded to a fatigue questionnaire (FQ), work ability score (WAS) and short-form health survey (SF-36). Disease- and treatment data were extracted from hospital records. Factors associated with CF were identified by uni- and multivariate analysis. To study the implications of CF on SES and WA, a multinomial regression analysis was performed. RESULTS: Invitations were extended to 518 HLS and 298 (58%) responded to FQ, of whom 42% had CF with mean (standard deviation [SD]) physical- and mental fatigue scores of 10.2 (4.3) and 5.5 (2.1) respectively. Median age at survey was 45 years, 47% were females. In multivariate analysis female sex (p = 0.03), lower education (p = 0.03), body mass index ≥30 kg/m2 (p = 0.04), and an increasing number of comorbidities (p = 0.01) were associated with CF. No association with disease stage, chemotherapy or RT was found. CF was associated with poorer WAS scores at survey (p < 0.001), unemployment (p = 0.03), and receiving disability pension (p = 0.003). CONCLUSION: After risk-adapted treatment, CF is still a frequent LE among long-term HLS, without apparent association with disease or treatment-related parameters. CF is associated with reduced WA and SES. As no apparent risk reduction is seen with contemporary treatment, further studies should emphasize etiological factors of CF and treatment to alleviate this common LE.
Assuntos
Síndrome de Fadiga Crônica , Doença de Hodgkin , Humanos , Feminino , Pessoa de Meia-Idade , Masculino , Doença de Hodgkin/radioterapia , Doença de Hodgkin/diagnóstico , Síndrome de Fadiga Crônica/epidemiologia , Estudos Transversais , Sobreviventes , Inquéritos e Questionários , Qualidade de VidaRESUMO
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.
Assuntos
Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Doença de Hodgkin/tratamento farmacológico , Adolescente , Protocolos de Quimioterapia Combinada Antineoplásica/efeitos adversos , Criança , Ciclofosfamida/uso terapêutico , Feminino , Hormônio Foliculoestimulante/sangue , Doença de Hodgkin/mortalidade , Doença de Hodgkin/radioterapia , Humanos , Masculino , Estadiamento de Neoplasias , Prednisona/uso terapêutico , Procarbazina/uso terapêutico , Vincristina/uso terapêuticoRESUMO
BACKGROUND/OBJECTIVES: There is limited long-term data comparing the outcomes of sleeve gastrectomy (SG) and Roux-en-Y gastric bypass (RYGB) for severe obesity, both with respect to body weight, quality of life (QOL) and comorbidities. We aimed to determine 7-year trajectories of body mass index (BMI), QOL, obesity-related comorbidities, biomarkers of glucose and lipid metabolism, and early major complications after SG and RYGB. SUBJECTS/METHODS: Patients scheduled for bariatric surgery at two Norwegian hospitals, preferentially performing either SG or RYGB, were included consecutively from September 2011 to February 2015. Data was collected prospectively before and up to 7 years after surgery. Obesity-specific, generic and overall QOL were measured by the Impact of Weight on Quality of Life-Lite, Short-Form 36 and Cantril's ladder, respectively. Comorbidities were assessed by clinical examination, registration of medication and analysis of glucose and lipid biomarkers. Outcomes were examined with linear mixed effect models and relative risk estimates. RESULTS: Of 580 included patients, 543 (75% women, mean age 42.3 years, mean baseline BMI 43.0 kg/m2) were operated (376 SG and 167 RYGB). With 84.2% of participants evaluable after 5-7 years, model-based percent total weight-loss (%TWL) at 7 years was 23.4 after SG versus 27.3 after RYGB (difference 3.9%, p = 0.001). All levels of QOL improved similarly after the two surgical procedures but remained below reference data from the general population at all timepoints. Remission rates for type 2 diabetes, dyslipidemia, obstructive sleep-apnea and gastroesophageal reflux disease (GERD) as well as the rate of de novo GERD significantly favored RYGB. SG had fewer major early complications, but more minor and major late complications combined over follow-up. CONCLUSION: In routine health care, both SG and RYGB are safe procedures with significant long-term weight-loss, improvement of QOL and amelioration of comorbidities. Long-term weight-loss and remission rates of main obesity-related comorbidities were higher after RYGB.
Assuntos
Diabetes Mellitus Tipo 2 , Derivação Gástrica , Refluxo Gastroesofágico , Obesidade Mórbida , Adulto , Diabetes Mellitus Tipo 2/complicações , Diabetes Mellitus Tipo 2/epidemiologia , Diabetes Mellitus Tipo 2/cirurgia , Feminino , Gastrectomia , Derivação Gástrica/métodos , Refluxo Gastroesofágico/complicações , Refluxo Gastroesofágico/cirurgia , Glucose , Humanos , Masculino , Obesidade/complicações , Obesidade/epidemiologia , Obesidade/cirurgia , Obesidade Mórbida/complicações , Obesidade Mórbida/epidemiologia , Obesidade Mórbida/cirurgia , Qualidade de Vida , Estudos Retrospectivos , Resultado do Tratamento , Redução de PesoRESUMO
OBJECTIVE: With increasing cancer incidence and survival rates, follow-up care becomes a major healthcare concern, placing increased demands on general practitioners (GPs). We explored GPs' awareness of late effects (LEs) after cancer treatment. Their degree of involvement and attitudes towards follow-up care was studied separately for solid cancers and Hodgkin's lymphoma (HL). DESIGN AND SETTING: Mailed questionnaire study in Norwegian general practice. SUBJECTS: 185 responding GPs with responsibility for HL survivors, more than 10 years since diagnosis. MAIN OUTCOME MEASURES AND RESULTS: All GPs reported some awareness of LEs. Increasing awareness of LEs was associated with female sex, being a specialist, having experience from hospital-based cancer care and familiarity with official guidelines on LEs after treatment. The majority of GPs were involved in follow-up care, which increased with patients' time since treatment and was associated with higher awareness of LEs. GPs with work experience in hospital-based cancer care were more likely to be engaged in HL follow-up. Most GPs were willing to provide follow-up care at some point after treatment. Older and more experienced GPs, and those satisfied with the collaboration with hospital specialists, were more likely to provide follow-up earlier. CONCLUSION: GPs' awareness of LEs and their willingness to provide follow-up care were related to familiarity with guidelines and experience. GPs more involved in follow-up care also had higher knowledge of LEs. Distribution of guidelines on LEs and follow-up care, and improving collaboration with hospital specialists, might increase GPs' knowledge and willingness to become involved in follow-up care, especially early in their careers. GPs' involvement and attitude towards follow-up of survivors of common solid cancers and HL, a rare malignant disease, were similar.KEY POINTSNorwegian general practitioners (GPs) are involved in survivorship care after cancer treatment. We investigated their awareness of late effects (LEs), their involvement and their attitude towards follow-up care of solid cancers and Hodgkin's lymphoma. ⢠GPs registered as specialists, aware of guidelines and with experience from hospital-based cancer care reported higher awareness of LEs. ⢠GPs with higher awareness of LEs were more frequently involved in follow-up care. ⢠GPs with longer experience in general practice were comfortable with follow-up care at an earlier stage after treatment. ⢠Results were similar for follow-up care of survivors of solid cancers and Hodgkin's lymphoma.
Assuntos
Medicina Geral , Clínicos Gerais , Doença de Hodgkin , Humanos , Feminino , Doença de Hodgkin/terapia , Seguimentos , Medicina de Família e Comunidade , Atitude do Pessoal de SaúdeRESUMO
BACKGROUND: In the EuroNet Pediatric Hodgkin Lymphoma (EuroNet-PHL) trials, decision on Waldeyer's ring (WR) involvement is usually based on clinical assessment, that is, physical examination and/or nasopharyngoscopy. However, clinical assessment only evaluates mucosal surface and is prone to interobserver variability. Modern cross-sectional imaging technology may provide valuable information beyond mucosal surface, which may lead to a more accurate WR staging. PATIENTS, MATERIALS, AND METHODS: The EuroNet-PHL-C1 trial recruited 2102 patients, of which 1752 underwent central review including reference reading of their cross-sectional imaging data. In 14 of 1752 patients, WR was considered involved according to clinical assessment. In these 14 patients, the WR was re-assessed by applying an imaging-based algorithm considering information from 18 F-fluorodeoxyglucose positron emission tomography, contrast-enhanced computed tomography, and/or magnetic resonance imaging. For verification purposes, the imaging-based algorithm was applied to 100 consecutive patients whose WR was inconspicuous on clinical assessment. RESULTS: The imaging-based algorithm confirmed WR involvement only in four of the 14 patients. Of the remaining 10 patients, four had retropharyngeal lymph node involvement and six an inconspicuous WR. Applying the imaging-based algorithm to 100 consecutive patients with physiological appearance of their WR on clinical assessment, absence of WR involvement could be confirmed in 99. However, suspicion of WR involvement was raised in one patient. CONCLUSIONS: The imaging-based algorithm was feasible and easily applicable at initial staging of young patients with Hodgkin lymphoma. It increased the accuracy of WR staging, which may contribute to a more individualized treatment in the future.
Assuntos
Doença de Hodgkin/diagnóstico por imagem , Adolescente , Criança , Pré-Escolar , Feminino , Fluordesoxiglucose F18/análise , Humanos , Imageamento por Ressonância Magnética , Masculino , Imagem Multimodal , Estadiamento de Neoplasias , Tomografia por Emissão de Pósitrons , Tomografia Computadorizada por Raios XRESUMO
BACKGROUND: Chemotherapy-induced peripheral neuropathy (CIPN) is a dose-limiting side effect of Hodgkin's lymphoma (HL) treatment. We aimed to describe the prevalence of CIPN associated symptoms in long-term HL survivors compared to controls, and determine associated factors, including impact on health-related quality of life (HRQoL). MATERIAL AND METHODS: A questionnaire, including EORTC QLQ-CIPN-20 for CIPN related symptoms and SF-36 for HRQoL, was completed by 303 HL survivors at a median of 16 years after diagnosis. CIPN results were compared to a normative population (n = 606). CIPN associated factors were identified by linear regression analysis. RESULTS: Total CIPN score and subscores were significantly higher in HL survivors compared to controls. In multivariate analysis of HL survivors, a number of comorbidities (p < 0.001) and female gender (p = 0.05) were significantly associated with more CIPN. No association with disease or treatment factors was found. In a multivariate analysis including survivors and controls, the number of comorbidities (p < 0.001) and caseness (p < 0.001) were significantly associated with more CIPN. In HL survivors higher CIPN score was associated with reduced HRQoL (p < 0.001). CONCLUSION: HL survivors more than a decade after treatment report higher neuropathy-related symptom burden than controls, with a negative impact on HRQoL. Symptoms may be related to factors other than neurotoxic chemotherapy.
Assuntos
Antineoplásicos , Doença de Hodgkin , Doenças do Sistema Nervoso Periférico , Antineoplásicos/efeitos adversos , Feminino , Doença de Hodgkin/tratamento farmacológico , Doença de Hodgkin/epidemiologia , Humanos , Doenças do Sistema Nervoso Periférico/induzido quimicamente , Doenças do Sistema Nervoso Periférico/epidemiologia , Qualidade de Vida , Inquéritos e QuestionáriosRESUMO
When treating limited stage classical Hodgkin lymphoma (cHL), balancing treatment efficacy and toxicity is important. Toxicities after extended-field radiotherapy are well documented. Investigators have aimed at reducing toxicity without compromising efficacy, mainly by using combined modality treatment (CMT), i.e. chemotherapy and limited-field radiotherapy. In some clinical trials, radiotherapy has been omitted. We evaluated 364 patients with stage I-IIA cHL treated between 1999 and 2005. Patients were treated with two or four cycles of doxorubicin, bleomycin, vinblastine and dacarbazine (ABVD) according to presence of risk factors, followed by 30 Gy limited-field (reduced compared to involved-field) radiotherapy. After a median follow-up of 16 years for survival, freedom from progression at five and ten years was 93% and overall survival at 5 and 10 years was 98% and 96%, respectively. Only two relapses, out of 27, occurred after more than 5 years. There was no excess mortality compared to the general population. Of the analysed subgroups, only patients with progression within five years showed significant excess mortality. The absence of excess mortality questions the concept of omitting radiotherapy after short-term chemotherapy, a strategy that has been associated with an elevated risk of relapse but not yet with a proven reduced long-term excess mortality.
Assuntos
Protocolos de Quimioterapia Combinada Antineoplásica/administração & dosagem , Doença de Hodgkin/mortalidade , Doença de Hodgkin/terapia , Sistema de Registros , Adulto , Idoso , Protocolos de Quimioterapia Combinada Antineoplásica/efeitos adversos , Bleomicina/administração & dosagem , Bleomicina/efeitos adversos , Criança , Terapia Combinada , Dacarbazina/administração & dosagem , Dacarbazina/efeitos adversos , Intervalo Livre de Doença , Doxorrubicina/administração & dosagem , Doxorrubicina/efeitos adversos , Feminino , Seguimentos , Humanos , Masculino , Pessoa de Meia-Idade , Estadiamento de Neoplasias , Taxa de Sobrevida , Vimblastina/administração & dosagem , Vimblastina/efeitos adversosRESUMO
Castleman disease (CD) describes a group of heterogeneous hematologic disorders with characteristic histopathological features. CD can present with unicentric or multicentric (MCD) regions of lymph node enlargement. Some cases of MCD are caused by human herpesvirus-8 (HHV-8), whereas others are HHV-8-negative/idiopathic (iMCD). Treatment of iMCD is challenging, and outcomes can be poor because no uniform treatment guidelines exist, few systematic studies have been conducted, and no agreed upon response criteria have been described. The purpose of this paper is to establish consensus, evidence-based treatment guidelines based on the severity of iMCD to improve outcomes. An international Working Group of 42 experts from 10 countries was convened by the Castleman Disease Collaborative Network to establish consensus guidelines for the management of iMCD based on published literature, review of treatment effectiveness for 344 cases, and expert opinion. The anti-interleukin-6 monoclonal antibody siltuximab (or tocilizumab, if siltuximab is not available) with or without corticosteroids is the preferred first-line therapy for iMCD. In the most severe cases, adjuvant combination chemotherapy is recommended. Additional agents are recommended, tailored by disease severity, as second- and third-line therapies for treatment failures. Response criteria were formulated to facilitate the evaluation of treatment failure or success. These guidelines should help treating physicians to stratify patients based on disease severity in order to select the best available therapeutic option. An international registry for patients with CD (ACCELERATE, #NCT02817997) was established in October 2016 to collect patient outcomes to increase the evidence base for selection of therapies in the future.
Assuntos
Corticosteroides/uso terapêutico , Anticorpos Monoclonais/uso terapêutico , Antineoplásicos/uso terapêutico , Hiperplasia do Linfonodo Gigante/tratamento farmacológico , Anticorpos Monoclonais Humanizados/uso terapêutico , Hiperplasia do Linfonodo Gigante/patologia , Hiperplasia do Linfonodo Gigante/terapia , Ensaios Clínicos como Assunto , Estado Terminal/terapia , Gerenciamento Clínico , Medicina Baseada em Evidências , Humanos , Guias de Prática Clínica como AssuntoRESUMO
Idiopathic multicentric Castleman disease (iMCD) is a rare immunologic disorder characterized by systemic inflammation, multicentric lymphadenopathy, and organ dysfunction. Enlarged lymph nodes demonstrate a spectrum of characteristic but variable histopathologic features historically categorized into hyaline vascular (HV) (or hypervascular [HyperV] more recently), plasmacytic, or "mixed." Though the etiology is unknown, a pro-inflammatory cytokine storm, often involving interleukin-6 (IL-6), contributes to pathogenesis. Anti-IL-6 therapy with siltuximab is the only FDA- or EMA-approved treatment based on efficacy and safety in multiple studies. Importantly, no patients considered to have HV histopathology achieved the primary endpoint in the Phase II study. NCCN currently recommends siltuximab first-line for iMCD, except for patients considered to have HV histopathology. We investigated whether histopathologic subtype should guide siltuximab treatment decisions. Secondary analyses of clinical trial and real-world data revealed similar clinical benefit across histopathologic subtypes. Notably, only 18 of 79 patients in the Phase II study were consistently classified into histopathologic subtype by three independent review panels, demonstrating limited reliability to guide treatment decisions. Real-world data further demonstrate siltuximab's effectiveness in patients considered to have HV (or HyperV). Though histopathology is a critical component for diagnosis, there is insufficient evidence to guide treatment based solely on lymph node histopathologic subtype.
Assuntos
Anticorpos Monoclonais/administração & dosagem , Hiperplasia do Linfonodo Gigante , Anticorpos Monoclonais/efeitos adversos , Hiperplasia do Linfonodo Gigante/classificação , Hiperplasia do Linfonodo Gigante/tratamento farmacológico , Hiperplasia do Linfonodo Gigante/patologia , Feminino , Humanos , Masculino , Pessoa de Meia-IdadeRESUMO
BACKGROUND: We tested interim positron-emission tomography-computed tomography (PET-CT) as a measure of early response to chemotherapy in order to guide treatment for patients with advanced Hodgkin's lymphoma. METHODS: Patients with newly diagnosed advanced classic Hodgkin's lymphoma underwent a baseline PET-CT scan, received two cycles of ABVD (doxorubicin, bleomycin, vinblastine, and dacarbazine) chemotherapy, and then underwent an interim PET-CT scan. Images were centrally reviewed with the use of a 5-point scale for PET findings. Patients with negative PET findings after two cycles were randomly assigned to continue ABVD (ABVD group) or omit bleomycin (AVD group) in cycles 3 through 6. Those with positive PET findings after two cycles received BEACOPP (bleomycin, etoposide, doxorubicin, cyclophosphamide, vincristine, procarbazine, and prednisone). Radiotherapy was not recommended for patients with negative findings on interim scans. The primary outcome was the difference in the 3-year progression-free survival rate between randomized groups, a noninferiority comparison to exclude a difference of 5 or more percentage points. RESULTS: A total of 1214 patients were registered; 937 of the 1119 patients (83.7%) who underwent an interim PET-CT scan according to protocol had negative findings. With a median follow-up of 41 months, the 3-year progression-free survival rate and overall survival rate in the ABVD group were 85.7% (95% confidence interval [CI], 82.1 to 88.6) and 97.2% (95% CI, 95.1 to 98.4), respectively; the corresponding rates in the AVD group were 84.4% (95% CI, 80.7 to 87.5) and 97.6% (95% CI, 95.6 to 98.7). The absolute difference in the 3-year progression-free survival rate (ABVD minus AVD) was 1.6 percentage points (95% CI, -3.2 to 5.3). Respiratory adverse events were more severe in the ABVD group than in the AVD group. BEACOPP was given to the 172 patients with positive findings on the interim scan, and 74.4% had negative findings on a third PET-CT scan; the 3-year progression-free survival rate was 67.5% and the overall survival rate 87.8%. A total of 62 patients died during the trial (24 from Hodgkin's lymphoma), for a 3-year progression-free survival rate of 82.6% and an overall survival rate of 95.8%. CONCLUSIONS: Although the results fall just short of the specified noninferiority margin, the omission of bleomycin from the ABVD regimen after negative findings on interim PET resulted in a lower incidence of pulmonary toxic effects than with continued ABVD but not significantly lower efficacy. (Funded by Cancer Research UK and Others; ClinicalTrials.gov number, NCT00678327.).
Assuntos
Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Bleomicina/administração & dosagem , Doença de Hodgkin/tratamento farmacológico , Tomografia por Emissão de Pósitrons , Tomografia Computadorizada por Raios X , Adolescente , Adulto , Bleomicina/uso terapêutico , Dacarbazina/uso terapêutico , Intervalo Livre de Doença , Doxorrubicina/uso terapêutico , Feminino , Doença de Hodgkin/diagnóstico por imagem , Doença de Hodgkin/mortalidade , Humanos , Masculino , Pessoa de Meia-Idade , Estudos Prospectivos , Taxa de Sobrevida , Resultado do Tratamento , Vimblastina/uso terapêutico , Adulto JovemRESUMO
Human herpesvirus-8 (HHV-8)-negative, idiopathic multicentric Castleman disease (iMCD) is a rare and life-threatening disorder involving systemic inflammatory symptoms, polyclonal lymphoproliferation, cytopenias, and multiple organ system dysfunction caused by a cytokine storm often including interleukin-6. iMCD accounts for one third to one half of all cases of MCD and can occur in individuals of any age. Accurate diagnosis is challenging, because no standard diagnostic criteria or diagnostic biomarkers currently exist, and there is significant overlap with malignant, autoimmune, and infectious disorders. An international working group comprising 34 pediatric and adult pathology and clinical experts in iMCD and related disorders from 8 countries, including 2 physicians that are also iMCD patients, was convened to establish iMCD diagnostic criteria. The working group reviewed data from 244 cases, met twice, and refined criteria over 15 months (June 2015 to September 2016). The proposed consensus criteria require both Major Criteria (characteristic lymph node histopathology and multicentric lymphadenopathy), at least 2 of 11 Minor Criteria with at least 1 laboratory abnormality, and exclusion of infectious, malignant, and autoimmune disorders that can mimic iMCD. Characteristic histopathologic features may include a constellation of regressed or hyperplastic germinal centers, follicular dendritic cell prominence, hypervascularization, and polytypic plasmacytosis. Laboratory and clinical Minor Criteria include elevated C-reactive protein or erythrocyte sedimentation rate, anemia, thrombocytopenia or thrombocytosis, hypoalbuminemia, renal dysfunction or proteinuria, polyclonal hypergammaglobulinemia, constitutional symptoms, hepatosplenomegaly, effusions or edema, eruptive cherry hemangiomatosis or violaceous papules, and lymphocytic interstitial pneumonitis. iMCD consensus diagnostic criteria will facilitate consistent diagnosis, appropriate treatment, and collaborative research.