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1.
Artigo em Inglês | MEDLINE | ID: mdl-33033142

RESUMO

BACKGROUND: Childhood or adolescent cancer survivors are at increased risks of subsequent primary neoplasms (SPN) of the central nervous system (CNS) after cranial irradiation. In a large multicentric cohort, we investigated clinical and therapeutic factors associated with the long-term risk of CNS SPN, and quantified the dose-response relationships. METHODS: We selected all CNS SPN cases diagnosed up to 2016 among members of the French Childhood Cancer Survivor Study at least 5 years after first cancer diagnosis in 1946-2000. Four controls per case were randomly selected within the cohort and matched by sex, year of/age at first cancer diagnosis, and follow-up time. On the basis of medical and radiological reports, cumulative radiation doses received to the SPN or matched location were retrospectively estimated using mathematical phantoms. We computed conditional logistic regression models. RESULTS: Meningioma risk significantly increased with higher radiation doses [excess OR per Gy (EOR/Gy) = 1.377; P < 0.001; 86 cases; median latency time = 30 years], after adjustment for reported genetic syndromes and first CNS tumor. It was higher among youngest individuals at first cancer diagnosis, but did not vary with follow-up time. On the opposite, radiation-related glioma risk (EOR/Gy = 0.049; P = 0.11; 47 cases; median latency time = 17 years) decreased over time (P for time effect = 0.05). There was a significant association between meningioma risk and cumulative doses of alkylating agents, but no association with growth hormone therapy. CONCLUSIONS: The surveillance of patients with cranial irradiation should continue beyond 30 years after treatment. IMPACT: The identified risk factors may inform long-term surveillance strategies.

2.
Cancer Epidemiol ; 68: 101797, 2020 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-32882568

RESUMO

BACKGROUND: Few studies have assessed the relation between maternal prenatal pesticides use and childhood lymphoma risk, some reporting a positive association with non-Hodgkin lymphoma (NHL). We investigated the association between maternal exposure to pesticides during pregnancy and childhood Hodgkin (HL) and non-Hodgkin lymphoma. METHODS: We pooled data from the two French national population-based case-control studies ESCALE (2003-2004) and ESTELLE (2010-2011). Data on domestic and occupational exposures to pesticides during pregnancy were obtained through standardised maternal interviews. Logistic regression models were used to compute odds ratios (OR) and 95% confidence intervals (CI) for HL and NHL, by pesticide category adjusted for potential confounders. Analyses by histological subtypes were also performed. RESULTS: We included 328 H L, 305 non-Hodgkin NHL and 2,415 controls. Around 40% of control mothers reported having used pesticides during index pregnancy, of whom 95% reported insecticides use. Maternal use of herbicides and fungicides occurred mostly in combination with insecticides. Insecticides use was more frequently reported in cases than controls (ORNHL = 1.6 [95%CI 1.3-2.1], p = 0.0001; ORHL = 1.3 [95%CI 1.0-1.7], p = 0.03). This association appeared more marked for Burkitt lymphoma and mixed cellularity classical HL. No obvious association was observed with occupational pesticides exposure during pregnancy. CONCLUSION: These results suggest that maternal domestic use of insecticides during pregnancy might be related to both childhood NHL and HL. Further larger studies are urgently needed.

3.
Eur J Endocrinol ; 183(4): 471-480, 2020 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-32738133

RESUMO

Context: Growth hormone (GH) deficiency is a common late effect of cranial irradiation. However, concerns have been raised that GH treatment might lead to an increased risk of a second neoplasm (SN). Objective: To study the impact of GH treatment on the risk of SN in a French cohort of survivors of childhood cancer (CCS) treated before 1986. Design and setting: Cohort study and nested case-control study. Participants: Of the 2852 survivors, with a median follow-up of 26 years, 196 had received GH therapy (median delay from cancer diagnosis: 5.5 years). Main outcome measures: Occurrence of SN. Results: In total, 374 survivors developed a SN, including 40 who had received GH therapy. In a multivariate analysis, GH treatment did not increase the risk of secondary non-meningioma brain tumors (RR: 0.6, 95% CI: 0.2-1.5, P = 0.3), secondary non-brain cancer (RR: 0.7, 95% CI: 0.4-1.2, P = 0.2), or meningioma (RR: 1.9, 95% CI: 0.9-4, P = 0.09). Nevertheless, we observed a slight non-significant increase in the risk of meningioma with GH duration: 1.6-fold (95% CI: 1.2-3.0) after an exposure of less than 4 years vs 2.3-fold (95% CI: 0.9-5.6) after a longer exposure (P for trend = 0.07) confirmed by the results of a case-control study. Conclusion: This study confirms the overall safety of GH use in survivors of childhood cancer, which does not increase the risk of a SN. The slight excess in the risk of meningioma in patients with long-term GH treatment is non-significant and could be due to difficulties in adjustment on cranial radiation volume/dose and/or undiagnosed meningioma predisposing conditions.


Assuntos
Sobreviventes de Câncer/estatística & dados numéricos , Hormônio do Crescimento Humano/uso terapêutico , Segunda Neoplasia Primária/epidemiologia , Adolescente , Adulto , Idoso , Neoplasias Encefálicas/induzido quimicamente , Neoplasias Encefálicas/epidemiologia , Estudos de Casos e Controles , Criança , Pré-Escolar , Estudos de Coortes , Irradiação Craniana/efeitos adversos , Feminino , Seguimentos , França/epidemiologia , Terapia de Reposição Hormonal/efeitos adversos , Terapia de Reposição Hormonal/estatística & dados numéricos , Humanos , Lactente , Recém-Nascido , Masculino , Neoplasias Meníngeas/induzido quimicamente , Neoplasias Meníngeas/epidemiologia , Meningioma/induzido quimicamente , Meningioma/epidemiologia , Pessoa de Meia-Idade , Segunda Neoplasia Primária/induzido quimicamente , Estudos Retrospectivos , Adulto Jovem
4.
Br J Haematol ; 2020 Jul 22.
Artigo em Inglês | MEDLINE | ID: mdl-32700439

RESUMO

The nucleoside analogue, 2-chlorodeoxyadenosine (2CDA), was reported to be an active treatment for childhood Langerhans cell histiocytosis (LCH) without risk organ (RO-) involvement. However, we lack data on long-term effects of 2CDA treatment, including the disease reactivation rate, permanent sequelae and long-term tolerance. This study included 44 children from the French LCH registry, treated for a RO- LCH with 2CDA monotherapy (median number of six courses). The median age at the beginning of 2CDA was 3·6 years (range, 0·3-19·7 years) and the median follow-up after was 5·4 years (range, 0·6-15·1 years). Objective response to 2CDA was observed in 25 patients (56·8%), while six patients (13·6%) had stable disease and 13 patients (29·5%) exhibited progressive disease. Among patients without progression, only two experienced disease reactivation after 2CDA discontinuation. The five-year cumulative incidence of disease progression or reactivation after 2CDA therapy initiation was 34·3%. The lymphopenia reported in all cases [72% below absolute lymphocyte count (ALC) of 0·5 G/l], was addressed with appropriate prophylactic measures. Other toxicities above grade 2 were uncommon, and no second malignant neoplasm or neuropathy was reported. The five-year overall survival was 97·7%. In conclusion, we could confirm that 2CDA monotherapy was a beneficial long-term therapy for treating patients with RO- LCH. Appropriate management of induced immune deficiency is mandatory.

5.
Blood ; 136(14): 1657-1669, 2020 Oct 01.
Artigo em Inglês | MEDLINE | ID: mdl-32573700

RESUMO

Anaplastic large cell lymphoma (ALCL) is a T-cell malignancy predominantly driven by a hyperactive anaplastic lymphoma kinase (ALK) fusion protein. ALK inhibitors, such as crizotinib, provide alternatives to standard chemotherapy with reduced toxicity and side effects. Children with lymphomas driven by nucleophosmin 1 (NPM1)-ALK fusion proteins achieved an objective response rate to ALK inhibition therapy of 54% to 90% in clinical trials; however, a subset of patients progressed within the first 3 months of treatment. The mechanism for the development of ALK inhibitor resistance is unknown. Through genome-wide clustered regularly interspaced short palindromic repeats (CRISPR) activation and knockout screens in ALCL cell lines, combined with RNA sequencing data derived from ALK inhibitor-relapsed patient tumors, we show that resistance to ALK inhibition by crizotinib in ALCL can be driven by aberrant upregulation of interleukin 10 receptor subunit alpha (IL10RA). Elevated IL10RA expression rewires the STAT3 signaling pathway, bypassing otherwise critical phosphorylation by NPM1-ALK. IL-10RA expression does not correlate with response to standard chemotherapy in pediatric patients, suggesting that a combination of crizotinib and chemotherapy could prevent ALK inhibitor resistance-specific relapse.

6.
J Clin Oncol ; 38(16): 1785-1796, 2020 Jun 01.
Artigo em Inglês | MEDLINE | ID: mdl-32196392

RESUMO

PURPOSE: Between 10% and 20% of childhood cancer survivors (CCS) experience impaired growth, leading to small adult height (SAH). Our study aimed to quantify risk factors for SAH or growth hormone deficiency among CCS. METHODS: The French CCS Study holds data on 7,670 cancer survivors treated before 2001. We analyzed self-administered questionnaire data from 2,965 CCS with clinical, chemo/radiotherapy data from medical records. SAH was defined as an adult height ≤ 2 standard deviation scores of control values obtained from a French population health study. RESULTS: After exclusion of 189 CCS treated with growth hormone, 9.2% (254 of 2,776) had a SAH. Being young at the time of cancer treatment (relative risk [RR], 0.91 [95% CI, 0.88 to 0.95] by year of age), small height at diagnosis (≤ 2 standard deviation scores; RR, 6.74 [95% CI, 4.61 to 9.86]), pituitary irradiation (5-20 Gy: RR, 4.24 [95% CI, 1.98 to 9.06]; 20-40 Gy: RR, 10.16 [95% CI, 5.18 to 19.94]; and ≥ 40 Gy: RR, 19.48 [95% CI, 8.73 to 43.48]), having received busulfan (RR, 4.53 [95% CI, 2.10 to 9.77]), or > 300 mg/m2 of lomustine (300-600 mg/m2: RR, 4.21 [95% CI, 1.61 to 11.01] and ≥ 600 mg/m2: RR, 9.12 [95% CI, 2.75 to 30.24]) were all independent risk factors for SAH. Irradiation of ≥ 7 vertebrae (≥ 15 Gy on ≥ 90% of their volume) without pituitary irradiation increased the RR of SAH by 4.62 (95% CI, 2.77 to 7.72). If patients had also received pituitary irradiation, this increased the RR by an additional factor of 1.3 to 2.4. CONCLUSION: CCS are at a high risk of SAH. CCS treated with radiotherapy, busulfan, or lomustine should be closely monitored for growth, puberty onset, and potential pituitary deficiency.

7.
Lancet Oncol ; 21(3): 446-455, 2020 03.
Artigo em Inglês | MEDLINE | ID: mdl-32078813

RESUMO

BACKGROUND: Patients with Ewing sarcoma or osteosarcoma have a median overall survival of less than 12 months after diagnosis, and a standard treatment strategy has not yet been established. Pharmacological inhibition of MET signalling and aberrant angiogenesis has shown promising results in several preclinical models of Ewing sarcoma and osteosarcoma. We aimed to investigate the activity of cabozantinib, an inhibitor of MET and VEGFR2, in patients with advanced Ewing sarcoma and osteosarcoma. METHODS: We did a multicentre, single-arm, two-stage, phase 2 trial in patients with advanced Ewing sarcoma or osteosarcoma recruited from ten centres in the French Sarcoma Group. Key eligibility criteria were aged 12 years or older, Eastern Cooperative Oncology Group performance status of 0-1, and documented disease progression (according to Response Evaluation Criteria in Solid Tumors version 1.1) before study entry. The number of previous lines of treatment was not limited. Patients received cabozantinib (adults 60 mg, children [<16 years] 40 mg/m2) orally once daily in 28-day cycles until disease progression, unacceptable toxicity, the investigator's decision to discontinue, or participant withdrawal. The primary endpoint for Ewing sarcoma was best objective response within 6 months of treatment onset; for osteosarcoma, a dual primary endpoint of 6-month objective response and 6-month non-progression was assessed. All enrolled patients who received at least one dose of cabozantinib were included in the safety analysis, and all participants who received at least one complete or two incomplete treatment cycles were included in the efficacy population. This study was registered with ClinicalTrials.gov, number NCT02243605. FINDINGS: Between April 16, 2015, and July 12, 2018, 90 patients (45 with Ewing sarcoma 45 with osteosarcoma) were recruited to the study. Median follow-up was 31·3 months (95% CI 12·4-35·4) for patients with Ewing sarcoma and 31·1 months (24·4-31·7) for patients with osteosarcoma. 39 (87%) patients with Ewing sarcoma and 42 (93%) patients with osteosarcoma were assessable for efficacy after histological and radiological review. In patients with Ewing sarcoma, ten (26%; 95% CI 13-42) of 39 patients had an objective response (all partial responses) by 6 months; in patients with osteosarcoma, five (12%; 4-26) of 42 patients had an objective response (all partial responses) and 14 (33%; 20-50) had 6-month non-progression. The most common grade 3 or 4 adverse events were hypophosphataemia (five [11%] for Ewing sarcoma, three [7%] for osteosarcoma), aspartate aminotransferase increase (two [4%] for Ewing sarcoma, three [7%] for osteosarcoma), palmar-plantar syndrome (three [7%] for Ewing sarcoma, two [4%] for osteosarcoma), pneumothorax (one [2%] for Ewing sarcoma, four [9%] for osteosarcoma), and neutropenia (two [4%] for Ewing sarcoma, four [9%] for osteosarcoma). At least one serious adverse event was reported in 61 (68%) of 90 patients. No patients died from drug-related toxic effects. INTERPRETATION: Cabozantinib has antitumor activity in patients with advanced Ewing sarcoma and osteosarcoma and was generally well tolerated. Cabozantinib could represent a new therapeutic option in this setting, and deserves further investigation. FUNDING: Institut Bergonié; French National Cancer Institute; Association pour la Recherche contre le Cancer.


Assuntos
Anilidas/uso terapêutico , Neoplasias Ósseas/tratamento farmacológico , Osteossarcoma/tratamento farmacológico , Inibidores de Proteínas Quinases/uso terapêutico , Piridinas/uso terapêutico , Sarcoma de Ewing/tratamento farmacológico , Adulto , Neoplasias Ósseas/patologia , Estudos de Casos e Controles , Feminino , Seguimentos , Humanos , Masculino , Pessoa de Meia-Idade , Metástase Neoplásica , Osteossarcoma/patologia , Prognóstico , Critérios de Avaliação de Resposta em Tumores Sólidos , Estudos Retrospectivos , Sarcoma de Ewing/patologia , Taxa de Sobrevida , Adulto Jovem
8.
Eur J Cancer ; 125: 58-68, 2020 01.
Artigo em Inglês | MEDLINE | ID: mdl-31838406

RESUMO

BACKGROUND: The role of high-dose chemotherapy in relapsing osteosarcomas has not been established. We evaluated the efficacy and tolerance of high-dose thiotepa (HDTp) after standard chemotherapy (SCT) in patients with relapsed osteosarcoma. PATIENTS AND METHODS: This randomised open-label phase II study enrolled patients 1-50 years, with local or metastatic relapse of a high-grade osteosarcoma, not progressive after two cycles of SCT, for whom a complete surgery can be achievable following treatment. The trial assigned enrolled patients in a 1:1 ratio to receive two additional courses of SCT + HDTp and autologous transplantation (Arm A), or SCT alone (Arm B). Surgery for complete resection was scheduled as soon as feasible. Primary endpoint was overall survival (OS). Secondary objectives included progression-free survival (PFS) and safety. RESULTS: From September 2009 to November 2016, 44 patients were randomised (A:22; B:22). In total, 54.5% were males, and the median age was 16 years (9-32years). The two-year OS rate was 66.7% (95% CI 42.5-82.5) (SCT + HDTp, Arm A) versus 50.0% (95% CI 28.2-68.4) for SCT alone (Arm B). Median OS was 27.4 and 24.8 months, respectively (hazard ratio [HR] 0.826, 95% CI 0.393-1.734; p = 0.6123). Median PFS was 15.6 (8.9-24.9) months in Arm A versus 7.2 (4.8-33.3) months in Arm B, p = 0.3845. Among the 22 patients treated with SCT + HDTp, 16 (72.7%) experienced at least one grade ≥3 adverse events versus 18/22 (81.8%) patients treated with SCT. No toxic death occurred. CONCLUSION: Adjuvant HDTp failed to significantly improve OS and PFS in resectable relapsed osteosarcomas. Despite a trend of prolonged survival and an acceptable toxicity, thiotepa cannot be recommended. KEY MESSAGE: HDTp and autologous transplantation added to SCT did not improve OS and PFS in patients with resectable relapsed osteosarcomas. Despite a trend of prolonged survival, thiotepa cannot be recommended.


Assuntos
Osteossarcoma/tratamento farmacológico , Tiotepa/uso terapêutico , Adolescente , Adulto , Criança , Feminino , Humanos , Masculino , Osteossarcoma/patologia , Tiotepa/farmacologia , Adulto Jovem
9.
J Clin Oncol ; 37(34): 3192-3202, 2019 12 01.
Artigo em Inglês | MEDLINE | ID: mdl-31553693

RESUMO

PURPOSE: The R2Pulm trial was conducted to evaluate the effect of busulfan-melphalan high-dose chemotherapy with autologous stem-cell rescue (BuMel) without whole-lung irradiation (WLI) on event-free survival (main end point) and overall survival, compared with standard chemotherapy with WLI in Ewing sarcoma (ES) presenting with pulmonary and/or pleural metastases. METHODS: From 2000 to 2015, we enrolled patients younger than 50 years of age with newly diagnosed ES and with only pulmonary or pleural metastases. Patients received chemotherapy with six courses of vincristine, ifosfamide, doxorubicin, and etoposide (VIDE) and one course of vincristine, dactinomycin, and ifosfamide (VAI) before either BuMel or seven courses of VAI and WLI (VAI plus WLI) by randomized assignment. The analysis was conducted as intention to treat. The estimates of the hazard ratio (HR), 95% CI, and P value were corrected for the three previous interim analyses by the inverse normal method. RESULTS: Of 543 potentially eligible patients, 287 were randomly assigned to VAI plus WLI (n = 143) or BuMel (n = 144). Selected patients requiring radiotherapy to an axial primary site were excluded from randomization to avoid excess organ toxicity from interaction between radiotherapy and busulfan. Median follow-up was 8.1 years. We did not observe any significant difference in survival outcomes between treatment groups. Event-free survival was 50.6% versus 56.6% at 3 years and 43.1% versus 52.9% at 8 years, for VAI plus WLI and BuMel patients, respectively, resulting in an HR of 0.79 (95% CI, 0.56 to 1.10; P = .16). For overall survival, the HR was 1.00 (95% CI, 0.70 to 1.44; P = .99). Four patients died as a result of BuMel-related toxicity, and none died after VAI plus WLI. Significantly more patients in the BuMel arm experienced severe acute toxicities than in the VAI plus WLI arm. CONCLUSION: In ES with pulmonary or pleural metastases, there is no clear benefit from BuMel compared with conventional VAI plus WLI.


Assuntos
Protocolos de Quimioterapia Combinada Antineoplásica/administração & dosagem , Neoplasias Ósseas/terapia , Transplante de Células-Tronco Hematopoéticas , Neoplasias Pulmonares/terapia , Terapia Neoadjuvante , Sarcoma de Ewing/terapia , Adolescente , Adulto , Protocolos de Quimioterapia Combinada Antineoplásica/efeitos adversos , Neoplasias Ósseas/mortalidade , Neoplasias Ósseas/patologia , Criança , Pré-Escolar , Progressão da Doença , Europa (Continente) , Feminino , Transplante de Células-Tronco Hematopoéticas/efeitos adversos , Transplante de Células-Tronco Hematopoéticas/mortalidade , Humanos , Lactente , Neoplasias Pulmonares/mortalidade , Neoplasias Pulmonares/secundário , Masculino , Pessoa de Meia-Idade , Terapia Neoadjuvante/efeitos adversos , Terapia Neoadjuvante/mortalidade , Recidiva Local de Neoplasia , Pneumonectomia , Intervalo Livre de Progressão , Radioterapia Adjuvante , Medição de Risco , Fatores de Risco , Sarcoma de Ewing/mortalidade , Sarcoma de Ewing/secundário , Fatores de Tempo , Transplante Autólogo , Adulto Jovem
11.
Acta Obstet Gynecol Scand ; 98(5): 630-637, 2019 05.
Artigo em Inglês | MEDLINE | ID: mdl-30919447

RESUMO

INTRODUCTION: The preservation of fertility is an integral part of care of children requiring gonadotoxic treatments for cancer or non-malignant diseases. In France, the cryopreservation of ovarian tissue has been considered and has been offered as a clinical treatment since its inception. The aim of this study is to review 20 years of activity in fertility preservation by ovarian tissue cryopreservation (OTC) for children and the feasibility of oocyte isolation and cryopreservation from the ovarian tissue at a single center. MATERIAL AND METHODS: Retrospective study including patients aged 15 years or younger who underwent OTC, combined for some with oocyte cryopreservation of isolated oocytes, before a highly gonadotoxic treatment for malignant or non-malignant disease was initiated. We describe the evolution of activities in our program for fertility preservation and patient characteristics at the time of OTC and follow up. RESULTS: From April 1998 to December 2018, 418 girls and adolescents younger than 15 years of age underwent OTC, representing 40.5% of all females who have had ovarian tissue cryopreserved at our center. In all, 313 patients had malignant diseases and 105 had benign conditions. Between November 2009 and July 2013, oocytes were isolated and also cryopreserved in 50 cases. The mean age of patients was 6.9 years (range 0.3-15). The most frequent diagnoses in this cohort included neuroblastoma, acute leukemia and hemoglobinopathies; neuroblastoma being the most common diagnosis in very young patients. During follow up, three patients requested the use of their cryopreserved ovarian tissue. All had undergone ovarian tissue transplantation, one for puberty induction and the two others for restoring fertility. So far, no pregnancies have been achieved. Eighty-four patients who had OTC died. CONCLUSIONS: Ovarian tissue cryopreservation is the only available technique for preserving fertility of girls. To our knowledge this is the largest series of girls and adolescents younger than 15 years so far reported on procedures of OTC before highly gonadotoxic treatment in a single center.


Assuntos
Antineoplásicos , Criopreservação , Preservação da Fertilidade , Neoplasias , Ovário , Adolescente , Antineoplásicos/uso terapêutico , Antineoplásicos/toxicidade , Criança , Pré-Escolar , Criopreservação/métodos , Criopreservação/estatística & dados numéricos , Feminino , Preservação da Fertilidade/métodos , Preservação da Fertilidade/estatística & dados numéricos , França/epidemiologia , Humanos , Lactente , Neoplasias/epidemiologia , Neoplasias/terapia , Recuperação de Oócitos , Avaliação de Processos e Resultados em Cuidados de Saúde , Utilização de Procedimentos e Técnicas/estatística & dados numéricos , Estudos Retrospectivos
12.
Eur J Heart Fail ; 21(4): 509-518, 2019 04.
Artigo em Inglês | MEDLINE | ID: mdl-30592114

RESUMO

BACKGROUND: Paediatric cancer survivors have a high risk of developing cardiac diseases, and the most frequent cardiac disease is heart failure (HF). The radiation dose-volume effects in the heart and cardiac substructures have not been explored in childhood cancer survivors (CCS). Therefore, the role of irradiated heart volume in the occurrence of HF among this population remains unclear. The aims of this study were to determine the doses and irradiated volumes of the heart and left ventricle (LV) related to the risk of HF in CCS and to investigate the impact of anthracycline exposure on this risk. METHODS AND RESULTS: A case-control study nested in the French Childhood Cancer Survivors Study cohort. The mean heart and left ventricular doses and volumes indicators were estimated by reconstruction of individual treatments. A total of 239 HF cases and 1042 matched controls were included. The median age of HF diagnosis was 25.1 years. The median volume of the heart that received ≥ 30 Gy was 61.1% for cases and 16.9% for controls. In patients who did not receive anthracycline, the risk of HF was increased 3.6-fold when less than 10% of the LV received ≥ 30 Gy when compared to patients who were not exposed to any cardiac radiation and anthracycline. CONCLUSIONS: Small irradiated volumes of the heart or LV were significantly associated with HF risk. To the author's knowledge, this is the first study to report a dose-response relationship based on dose-volume indicators in CCS, which can be translated efficiently into current clinical practice.


Assuntos
Volume Cardíaco/efeitos da radiação , Cardiotoxicidade/fisiopatologia , Insuficiência Cardíaca/fisiopatologia , Coração/efeitos da radiação , Neoplasias/radioterapia , Radioterapia/efeitos adversos , Adulto , Antraciclinas/efeitos adversos , Antraciclinas/uso terapêutico , Volume Cardíaco/efeitos dos fármacos , Cardiotoxicidade/etiologia , Estudos de Casos e Controles , Criança , Pré-Escolar , Relação Dose-Resposta à Radiação , Feminino , Coração/efeitos dos fármacos , Insuficiência Cardíaca/induzido quimicamente , Insuficiência Cardíaca/etiologia , Ventrículos do Coração/efeitos dos fármacos , Ventrículos do Coração/efeitos da radiação , Humanos , Masculino , Doses de Radiação
13.
Pediatr Blood Cancer ; 66(2): e27495, 2019 02.
Artigo em Inglês | MEDLINE | ID: mdl-30345604

RESUMO

BACKGROUND: Very few previous studies have addressed the question of colorectal cancer (CRC) after childhood cancer treatment. We aimed to quantify the roles of radiation therapy and chemotherapy agents in the occurrence of subsequent CRC. METHODS: A nested case-control study was conducted using 36 CRC cases and 140 controls selected from 7032 five-year survivors of the French Childhood Cancer Survivor Study (FCCSS) cohort, treated from 1945 to 2000 in France. The radiation dose-distribution metrics at the site of CRC and doses of individual chemotherapeutic agents were calculated. Conditional logistic regressions were performed to calculate odds ratios (ORs). RESULTS: Overall, patients who received radiotherapy with estimated dose to colon had a 4.3-fold (95% CI, 1.3-17.6) increased risk for CRC compared with patients who did not receive radiotherapy, after adjustment for chemotherapy. This risk increased to 8.9-fold and 19.3-fold among patients who received radiation doses ranging from 20 to 29.99 Gy and ≥30 Gy, respectively. Our data reported a significantly elevated OR for anthracyclines, after controlling for radiotherapy and MOPP regimen. But, restricted analyses excluding patients who had received ≥30 Gy showed that only radiation doses ranging from 20 to 29.99 Gy produced a significant increase in subsequent CRC risk (OR = 7.8; 95% CI, 1.3-56.0), after controlling for anthracyclines and MOPP regimen. CONCLUSIONS: The risk of subsequent CRC was significantly increased after radiation dose (even < 30 Gy). This novel finding supports the need to update monitoring guidelines for CRC to optimize the long-term follow-up for subsequent CRC in survivors of childhood cancer.


Assuntos
Neoplasias Colorretais/epidemiologia , Neoplasias Colorretais/etiologia , Segunda Neoplasia Primária/epidemiologia , Segunda Neoplasia Primária/etiologia , Radioterapia/efeitos adversos , Adolescente , Antineoplásicos/efeitos adversos , Estudos de Casos e Controles , Criança , Pré-Escolar , Feminino , História Antiga , Humanos , Recém-Nascido , Masculino , Fatores de Risco
14.
Br J Haematol ; 183(4): 608-617, 2018 11.
Artigo em Inglês | MEDLINE | ID: mdl-30421536

RESUMO

Neurodegenerative (ND) complications in Langerhans cell histiocytosis (LCH) are a late-onset but dramatic sequelae for which incidence and risk factors are not well defined. Based on a national prospective registry of paediatric LCH patients, we determined the incidence rate of clinical ND LCH (cND-LCH) and analysed risk factors, taking into account disease extent and molecular characteristics. Among 1897 LCH patients, 36 (1·9%) were diagnosed with a cND-LCH. The 10-year cumulative incidence of cND-LCH was 4·1%. cND-LCH typically affected patients previously treated for a multisystem, risk organ-negative LCH, represented in 69·4% of cND-LCH cases. Pituitary gland, skin and base skull/orbit bone lesions were more frequent (P < 0·001) in cND-LCH patients compared to those without cND-LCH (respectively 86·1% vs. 12·2%, 75·0% vs. 34·2%, and 63·9% vs. 28·4%). The 'cND susceptible patients' (n = 671) i.e., children who had experienced LCH disease with pituitary or skull base or orbit bone involvement, had a 10-year cND risk of 7·8% vs. 0% for patients who did not meet these criteria. Finally, BRAFV 600E status added important information among these cND susceptible patients, with the 10-year cND risk of 33·1% if a BRAFV 600E mutation was present compared to 2·9% if it was absent (P = 0·002).


Assuntos
Histiocitose de Células de Langerhans/epidemiologia , Doenças Neurodegenerativas/epidemiologia , Sistema de Registros , Adolescente , Criança , Pré-Escolar , Feminino , Seguimentos , Histiocitose de Células de Langerhans/metabolismo , Histiocitose de Células de Langerhans/patologia , Humanos , Incidência , Lactente , Recém-Nascido , Estudos Longitudinais , Masculino , Doenças Neurodegenerativas/metabolismo , Doenças Neurodegenerativas/patologia , Fatores de Risco
15.
Int J Radiat Oncol Biol Phys ; 102(3): 578-583, 2018 11 01.
Artigo em Inglês | MEDLINE | ID: mdl-30096470

RESUMO

PURPOSE: Male breast cancer (MBC) is uncommon, accounting for less than 1% of all breast cancers. Secondary breast cancers among childhood cancer survivors have been well described in the literature, but less is known about MBC. METHODS AND MATERIALS: We carried out an analysis in a cohort of 7019 five-year survivors of a solid childhood (aged ≤20 years) cancer treated in France before 2001 and followed for an average of 20 years and compared breast cancers occurring in both men and women. RESULTS: Among the 7019 survivors, 4 out of 3893 male survivors developed breast cancer, compared with 99 out of 3126 female survivors. All of the men had a history of radiation therapy. The 4 men with MBC had estrogen receptors and 3 had progesterone receptors. CONCLUSIONS: MBC is a rare second malignancy among childhood cancer survivors. Receipt of radiation therapy is a recognized risk factor, but more data about eventual genetic mutations are necessary. Regular screening based only on a history of radiation therapy is not recommended; however, attention must be given in the case of suspicious symptoms.


Assuntos
Neoplasias da Mama Masculina/patologia , Neoplasias da Mama Masculina/secundário , Neoplasias da Mama/patologia , Neoplasias da Mama/secundário , Neoplasias Induzidas por Radiação/etiologia , Radioterapia/efeitos adversos , Adolescente , Adulto , Idoso , Criança , Pré-Escolar , Estudos de Coortes , Feminino , Seguimentos , França , Humanos , Lactente , Recém-Nascido , Masculino , Programas de Rastreamento/métodos , Pessoa de Meia-Idade , Segunda Neoplasia Primária/etiologia , Doses de Radiação , Fatores de Risco , Fatores Sexuais , Sobreviventes , Adulto Jovem
16.
J Adolesc Young Adult Oncol ; 7(4): 415-423, 2018 08.
Artigo em Inglês | MEDLINE | ID: mdl-29851372

RESUMO

PURPOSE: To describe fecundity in female survivors of childhood cancer and consider the correlation with quality of life (QOL). MATERIALS AND METHODS: Of 1744 women treated for childhood cancer before the age of 15 years at one of eight French cancer treatment centers between 1948 and 1992, 1187 who were alive in 2005 were sent a self-administered questionnaire, including questions about health status, QOL (MOS SF-36), and fecundity. A standardized fecundity ratio (SFR) was calculated (SFR: observed/expected number of children) for each individual based on a national reference. RESULTS: Of the 972 individuals (82%) who responded, 53% had at least 1 child. The overall SFR, 0.65, was dependent upon the initial diagnosis, more decreased in Central Nervous System tumors (0.24; p < 10-3) than in Germ cell (0.46; p = 0.03) or Sympathetic Nervous System tumors (0.79; p = 0.02). The average QOL motor score was 72.5 ± 19.5, and the average mental score was 61.4 ± 16.7. After adjusting for age, pathology, and self-reported sequelae in the questionnaires, it was determined that SF-36 mental (p = 0.002) and motor (p < 0.0002) scores correlated positively with fecundity, and SF-36 scores correlated negatively with locomotor late effects (p < 0.0001), growth insufficiency (p = 0.002), and psychological disorders (p < 0.001). Gonadal insufficiency was correlated with neither motor nor mental scores. CONCLUSION: Women treated for childhood cancer demonstrated impaired fecundity that correlated with poor QOL, as registered by the SF-36. Patients should be warned of the risk of impaired fecundity early during the follow-up. If possible, preservation of fertility should be prioritized at initiation of therapy.


Assuntos
Fertilidade/fisiologia , Neoplasias/complicações , Qualidade de Vida/psicologia , Adolescente , Criança , Pré-Escolar , Feminino , Seguimentos , França , História do Século XX , Humanos , Lactente , Recém-Nascido , Neoplasias/patologia , Sobreviventes/psicologia
17.
J Clin Pharmacol ; 58(12): 1541-1549, 2018 12.
Artigo em Inglês | MEDLINE | ID: mdl-29791011

RESUMO

Growing evidence suggests that polymorphisms of genes coding for transporters or enzymes may partially explain the large between subject variability reported for methotrexate (MTX) pharmacokinetics (PK). This prospective study aimed to develop a population PK-pharmacogenetic model to evaluate the part of between-subject variability due to single-nucleotide polymorphisms (SNPs) in transporters and enzyme genes implicated in MTX distribution and elimination. MTX concentrations and 54 SNPs (located in ABCB1, ABCC1, ABCC2, ABCC3, ABCC4, ABCG2, SLC19A1, SLCO1B1, and UGT1A1 genes) were analyzed in patients treated with MTX included in the OS2006/sarcoma-09 trial (a multicenter, open-label, phase III trial, ClinicalTrials.gov. Identifier: NCT00470223). PK data were analyzed using the nonlinear mixed-effect modeling software program Monolix. The influence of each SNP was evaluated using a stepwise procedure under additive, recessive, or dominant genetic model. The likelihood ratio test was used to test the effect of each SNP on PK parameters. Overall, 187 patients with 7898 MTX blood concentrations were included in the PK-pharmacogenetic analysis. A 2-compartment model adequately described the data. Although high-dose MTX dosing recommendations in pediatric patients are currently based on body surface area, body weight was more predictive of clearance between-subject variability than body surface area. The most significant polymorphism associated with MTX clearance was rs13120400 (on the ABCG2 gene) under the recessive genetic model (P < .0001). GG genotype carriers for rs13120400 appeared to have a moderate decrease in MTX exposure compared to AA or GA carriers.


Assuntos
Antimetabólitos Antineoplásicos/farmacocinética , Neoplasias Ósseas/tratamento farmacológico , Proteínas de Transporte/metabolismo , Metotrexato/farmacocinética , Osteossarcoma/tratamento farmacológico , Adolescente , Antimetabólitos Antineoplásicos/sangue , Antimetabólitos Antineoplásicos/metabolismo , Proteínas de Transporte/genética , Criança , Feminino , Regulação da Expressão Gênica , Humanos , Masculino , Metotrexato/sangue , Metotrexato/metabolismo , Polimorfismo de Nucleotídeo Único , Estudos Prospectivos
18.
Pediatr Blood Cancer ; 65(5): e26916, 2018 05.
Artigo em Inglês | MEDLINE | ID: mdl-29334194

RESUMO

BACKGROUND: The European Paediatric Regulation was introduced in 2007 to facilitate access to new medicines for children. Our study explored accessibility of early-phase trials in pediatric oncology, in line with the European Paediatric Regulation, to identify the reasons for not inviting patients to participate, parents' refusal, or inclusion failure. PROCEDURE: We conducted a retrospective chart review at Institut Curie, Paris, for all pediatric patients whose cancer progressed despite known effective treatments between July 2010 and December 2013. RESULTS: Out of 100 patients in the palliative phase, 52 received one or more invitations to participate in early-phase trials. Twenty parents declined the invitation, mainly prioritizing quality of life or fearing constraints. Fourteen inclusions failed despite parental approval, mostly due to rapid clinical deterioration. Five patients received no invitations because no early-phase trials were available. Major reasons for noninclusion in the 43 remaining patients were presence of exclusion criteria or other physical factors, preference for conventional treatment, constraints, psychological factors, and follow-up in another hospital after moving. CONCLUSIONS: The Paediatric Regulation has led to increased availability of early-phase trials. Better timing of the proposal, designing less constraining early-phase trials, reducing waiting lists, and improving information for parents and children would facilitate pediatric access to new medicines.


Assuntos
Antineoplásicos/uso terapêutico , Ensaios Clínicos como Assunto/normas , Tomada de Decisões , Neoplasias/terapia , Seleção de Pacientes , Adolescente , Criança , Pré-Escolar , Feminino , Seguimentos , Humanos , Lactente , Recém-Nascido , Masculino , Prognóstico , Estudos Retrospectivos
19.
Eur J Cancer ; 91: 30-37, 2018 03.
Artigo em Inglês | MEDLINE | ID: mdl-29331749

RESUMO

METHODS: French patients (≤18years) treated for dysgerminoma between 1985 and 2005 in TGM-85, 90, 95 protocols were included. Treatment was based on primary unilateral oophorectomy followed by prophylactic lymph node irradiation (1985-1998) or a wait-and-see strategy (1998-2005) for localised completely resected tumours (pS1) or by platinum-based chemotherapy for advanced diseases. RESULTS: Forty-eight patients (median age 12.8 years) were included. Six patients had gonadal dysgenesis. Two had bilateral dysgerminoma. Twenty-eight patients had loco-regional dissemination, seven with para-aortic lymph nodes. None had distant metastases. Primary surgery was performed in 47/48 patients. Among the 15 patients with pS1 tumour: seven did not receive adjuvant treatment, six had lymph node irradiation and two received chemotherapy. Among the 32 patients with advanced tumour, 31 received cisplatinum-based (n = 25) or carboplatin-based (n = 8) regimen with lymph node irradiation for one of them and one did not receive adjuvant treatment. With a median follow-up of 14 years, all patients are alive in complete remission. Five events occurred: 2 contralateral dysgerminomas, 1 peritoneal relapse and 2 second neoplasms (teratoma and melanoma). Bilateral oophorectomy was necessary for 12 patients. Desire of pregnancy was expressed for 17/36 patients with unilateral oophorectomy, which succeeded in 13 cases (5 medically assisted). 2/17 had ovarian failure. The renal function was normal in 24/25 evaluated patients treated with platinum, ifosfamide or irradiation. The hearing function was evaluated on 17/36 patients treated with platinum: 12 Brock grade-0, 3 brock grade-1 and 2 grade-4. CONCLUSION: Dysgerminoma has an excellent prognosis even in advanced cases with conservative surgery and platinum-based chemotherapy. However the disease and/or treatment resulted in a high rate of bilateral oophorectomies and a significant impact on future fertility.


Assuntos
Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Sobreviventes de Câncer , Carboplatina/administração & dosagem , Cisplatino/administração & dosagem , Disgerminoma/terapia , Neoplasias Ovarianas/terapia , Ovariectomia , Adolescente , Idade de Início , Protocolos de Quimioterapia Combinada Antineoplásica/efeitos adversos , Carboplatina/efeitos adversos , Quimioterapia Adjuvante , Criança , Cisplatino/efeitos adversos , Intervalo Livre de Doença , Disgerminoma/epidemiologia , Disgerminoma/secundário , Feminino , França/epidemiologia , Humanos , Infertilidade Feminina/epidemiologia , Infertilidade Feminina/terapia , Metástase Linfática , Recidiva Local de Neoplasia , Segunda Neoplasia Primária , Neoplasias Ovarianas/epidemiologia , Neoplasias Ovarianas/patologia , Ovariectomia/efeitos adversos , Radioterapia Adjuvante , Técnicas de Reprodução Assistida , Fatores de Tempo , Resultado do Tratamento
20.
Eur J Cancer ; 88: 57-66, 2018 01.
Artigo em Inglês | MEDLINE | ID: mdl-29190507

RESUMO

BACKGROUND: In most countries, reference chemotherapy for osteosarcoma is MAP regimen (M = high-dose methotrexate, AP = doxorubicin-cisplatinum). In France, the standard preoperative chemotherapy for children/adolescents combines M and etoposide-ifosfamide (EI), based on the OS94-trial. We report the safety and efficacy results of patients ≤25 years treated with preoperative M-EI regimen enroled in the French OS2006-study, between 2007 and 2014. METHODS: Treatment comprised preoperative chemotherapy with the 7 M-courses and 2 EI-courses, then surgery and postoperative chemotherapy assigned by risk's groups: standard-risk (good histological response without metastases) received 12 M-courses, 3 EI-courses; high-risk (poor histologic response, initial metastases or unresectable primary) received 5 M-courses alternated with 5 AP-courses. 253 patients were randomised to receive (n = 128) or not (n = 125) zoledronate. RESULTS: 409/522 patients enroled in the OS2006 study who received preoperative M-EI were analysed. Median age was 14.3 years (4.7-24.5), with 55 patients aged 18-25 years. Primary tumour location was limb in 383 patients (94%) and 85 (21%) presented metastases. Median chemotherapy duration was 37.4 weeks. 381 (96%) patients underwent surgery, 258 patients (65%) had a good histologic response. 187/324 patients (58%) with localised disease did not receive doxorubicin nor cisplatinum. Toxicity was evaluated in the randomised study: most patients experienced ≥1 severe toxicity (grade IV haematological or grade III/IV extra-haematological). Median follow-up was 4.8 years, and 168 patients had events. Five-year event-free survival was 56% (95% CI, 51-62%) and overall survival 71% (66-76%). CONCLUSION: M-EI regimen/strategy was feasible for patient aged ≤25 years with survival rates are comparable to those obtained with MAP regimen.


Assuntos
Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Neoplasias Ósseas/tratamento farmacológico , Osteossarcoma/tratamento farmacológico , Adolescente , Adulto , Protocolos de Quimioterapia Combinada Antineoplásica/efeitos adversos , Neoplasias Ósseas/cirurgia , Criança , Pré-Escolar , Cisplatino/administração & dosagem , Terapia Combinada , Difosfonatos/administração & dosagem , Doxorrubicina/administração & dosagem , Etoposídeo/administração & dosagem , Feminino , França , Humanos , Ifosfamida/administração & dosagem , Imidazóis/administração & dosagem , Estimativa de Kaplan-Meier , Masculino , Metotrexato/administração & dosagem , Neutropenia/induzido quimicamente , Osteossarcoma/cirurgia , Adulto Jovem , Ácido Zoledrônico
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