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Ototoxicity is a devastating direct, irreversible side effect of platinum use in children with cancer, with its consequent effect on speech, language and social development, quality of life and adult productivity. Cisplatin, an essential chemotherapeutic agent for the treatment of solid tumors in children, is a DNA cross-linking agent. Which causes hearing loss in 50-70% of cisplatin treated children. Fortunately, to prevent hearing loss, sodium thiosulfate (STS), which binds to cisplatin, and reduces the superoxides in both tumor and outer hair cells of the cochlea has now been discovered to be an effective and safe otoprotectant if administered correctly. The aim of this perspective paper is to explore the key safety issues and challenges important for pediatric oncologists and pharmacists when considering the clinical use of STS as an otoprotectant for children and adolescents receiving cisplatin. These include: the choice of the formulation; the timing, both that of the STS in relation to cisplatin as well as the timing of the cisplatin infusion itself; the dosing; the challenge left by the definition of localized versus disseminated disease and the difference in indication for STS, between cisplatin treated patients and those receiving another platinum chemotherapeutic agent, carboplatin.
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PURPOSE: Hearing loss occurs in 50%-70% of children treated with cisplatin. Scientific efforts have led to the recent approval of a pediatric formula of intravenous sodium thiosulfate (STS) for otoprotection by the US Food and Drug Administration, the European Medicines Agency, and the Medicines and Health Regulatory Authority in the United Kingdom. To inform stakeholders regarding the clinical utility of STS, the current review summarizes available literature on the efficacy, pharmacokinetics (PK), and safety of systemic STS to minimize cisplatin-induced hearing loss (CIHL). DESIGN: A comprehensive narrative review is presented. RESULTS: Thirty-one articles were summarized. Overall, systemic STS effectively reduces CIHL in the preclinical and controlled clinical study settings, in both adults and children with cancer. The extent of CIHL reduction depends on the timing and dosing of STS in relation to cisplatin. Both preclinical and clinical data suggest that systemic STS may affect plasma platinum levels, but studies are inconclusive. Delayed systemic administration of STS, at 6 hours after the cisplatin infusion, does not affect cisplatin-induced inhibition of tumor growth or cellular cytotoxicity in the preclinical setting, nor affect cisplatin efficacy and survival in children with localized disease in the clinical setting. CONCLUSION: Systemic administration of STS effectively reduces the development and degree of CIHL in both the preclinical and clinical settings. More studies are needed on the PK of STS and cisplatin drug combinations, the efficacy and safety of STS in patients with disseminated disease, and the ability of STS to prevent further deterioration of pre-established hearing loss.
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Antineoplásicos , Cisplatino , Perda Auditiva , Neoplasias , Tiossulfatos , Humanos , Tiossulfatos/uso terapêutico , Tiossulfatos/farmacocinética , Tiossulfatos/administração & dosagem , Neoplasias/tratamento farmacológico , Cisplatino/uso terapêutico , Cisplatino/efeitos adversos , Cisplatino/administração & dosagem , Cisplatino/farmacocinética , Antineoplásicos/farmacocinética , Antineoplásicos/efeitos adversos , Antineoplásicos/uso terapêutico , Antineoplásicos/administração & dosagem , Perda Auditiva/induzido quimicamente , Perda Auditiva/prevenção & controle , CriançaRESUMO
Methotrexate is a major component of pediatric leukemia treatment. While toxicities are common after high-dose methotrexate, escalating dose methotrexate (Capizzi methotrexate) is typically well-tolerated. We report an adolescent Hispanic female with pre-B acute lymphoblastic leukemia, preexisting obesity and hepatic steatosis who developed severe multiorgan failure following an escalating dose of methotrexate with delayed methotrexate excretion of 11 days. We identified one similar report in an obese adult; however, this case is the first to our knowledge involving a pediatric patient. With the rising incidence of obesity and associated comorbidities among children and adolescents with leukemia, attention to potential risks for this population is warranted.
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Obesidade Infantil , Leucemia-Linfoma Linfoblástico de Células Precursoras B , Leucemia-Linfoma Linfoblástico de Células Precursoras , Adulto , Criança , Humanos , Adolescente , Feminino , Metotrexato/efeitos adversos , Obesidade Infantil/complicações , Leucemia-Linfoma Linfoblástico de Células Precursoras/complicações , Leucemia-Linfoma Linfoblástico de Células Precursoras/tratamento farmacológico , Leucemia-Linfoma Linfoblástico de Células Precursoras B/tratamento farmacológico , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêuticoRESUMO
Purpose: This study aimed to identify cancer incidence trends in the United States and globally in adolescents and young adults (AYAs) 15-39 years of age, by sex, and to speculate on causes for trend changes. Methods: For the United States, SEER*Stat was used to obtain average annual percent change (AAPC) trends in cancer incidence during the period 2000-2019 among 395,163 AYAs. For global data, the source was the Institute of Health Metrics and Evaluation and its sociodemographic index (SDI) classification system. Results: In the United States, the invasive cancer incidence increased during the period 2000-2019 in both females (AAPC: 1.05, 95% CI: 0.90-1.20, p << 0.001) and males (AAPC: 0.56, 95% CI: 0.43-0.69, p << 0.001). A total of 25 and 20 types of cancers increased statistically significantly in female and male AYAs, respectively. Among potential causes for the increases, the obesity epidemic in the United States strongly correlates with the overall cancer increase in both its female (Pearson correlation coefficient R2 = 0.88, p = 0.0007) and male (R2 = 0.83, p = 0.003) AYAs, as does the most common malignancy in American AYAs, breast cancer (R2 = 0.83, p = 0.003). Worldwide, cancer incidence in the age group increased steadily during the period 2000-2019 among high-middle, middle, and low-middle SDI countries, but not in low SDI countries and with slowing of increase in high SDI countries. Conclusions: The increases and their age-dependent profiles implicate several causations that are preventable, including obesity, overdiagnosis, unnecessary diagnostic radiation, human papilloma virus infection, and cannabis avoidance. The United States is beginning to reverse the increasing incidence, and prevention efforts should be augmented accordingly.
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Neoplasias da Mama , Humanos , Masculino , Feminino , Adolescente , Adulto Jovem , Estados Unidos/epidemiologia , Neoplasias da Mama/epidemiologia , IncidênciaRESUMO
BACKGROUND: Compared with their ensured counterparts, uninsured adolescents and young adults (AYAs) with cancer are more likely to present with advanced disease and have poor prognoses. The Patient Protection and Affordable Care Act (ACA), enacted in 2010, provided health care coverage to millions of uninsured young adults by allowing them to remain on their parents' insurance until age 26 years (the Dependent Care Expansion, DCE). The impact of the expansion of insurance coverage on survival outcomes for young adults with cancer has not been assessed. PARTICIPANTS: Utilizing the Surveillance, Epidemiology, and End Results database, we identified all patients aged 12-16 (younger-AYAs), 19-23 (middle-AYAs), and 26-30 (older-AYAs) who were diagnosed with cancer between 2006-2008 (pre-ACA) and 2011-2013 (post-ACA). METHODS: In this population-based cohort study, we used an accelerated failure time model to assess changes in survival rates before and after the enactment of the ACA DCE. RESULTS: Middle-AYAs ages 19-23 (thus eligible to remain on their parents' insurance) experienced significantly increased 2-year survival after the enactment of the ACA DCE (survival time ratio 1.25, 95% confidence interval: 0.75-2.43, P = .029) and that did not occur in younger-AYAs (ages 12-16). Patients with sarcoma and acute myeloid leukemia accounted for the majority of improvement in survival. Middle-AYAs of hispanic ethnicity and those with low socioeconomic status experienced trends of improved survival after the ACA DCE was enacted. CONCLUSION: Survival outcomes improved for young adults with cancer following the expansion of health insurance coverage. Efforts are needed to expand coverage for the millions of young adults who do not have health insurance.
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Neoplasias , Patient Protection and Affordable Care Act , Adolescente , Estudos de Coortes , Humanos , Cobertura do Seguro , Seguro Saúde , Neoplasias/epidemiologia , Neoplasias/terapia , Estados Unidos/epidemiologia , Adulto JovemRESUMO
Bone tumors are a group of histologically diverse diseases that occur across all ages. Two of the commonest, osteosarcoma (OS) and Ewing sarcoma (ES), are regarded as characteristic adolescent and young adult (AYA) cancers with an incidence peak in AYAs. They are curable for some but associated with unacceptably high rates of treatment failure and morbidity. The introduction of effective new therapeutics for bone sarcomas is slow, and to date, complex biology has been insufficiently characterized to allow more rapid therapeutic exploitation. This review focuses on current standards of care, recent advances that have or may soon change that standard of care and challenges to the expert clinical research community that we suggest must be met.
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Neoplasias Ósseas , Osteossarcoma , Sarcoma de Ewing , Sarcoma , Adolescente , Neoplasias Ósseas/patologia , Humanos , Osteossarcoma/patologia , Sarcoma/tratamento farmacológico , Sarcoma de Ewing/patologia , Adulto JovemRESUMO
Four categories of important factors improving outcome of young adults and older adolescents with acute lymphoblastic leukemia (ALL) are biologic type, clinical trials, pediatric vs. adult treatment regimen, and psychosocial challenges. Overall, the outcome of ALL in the age group has improved and beginning to catch up with that in children, as exemplified by CALGB 10403, a pediatric treatment regimen. Each is dependent for optimum development, however, on progress in the others. Without adequate psychosocial support and improvement, progress in clinical trials, translational research, and pediatric regimen application is impaired. Without clinical trials, advances in translational research, optimal pediatric regimen application and adequate psychosocial research are restricted. Overall, we have improved the outcome and outlook of ALL in AYAs, as exemplified by CALGB 10403, but we and our current and future patients still have a long way to go.
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Leucemia-Linfoma Linfoblástico de Células Precursoras , Adolescente , Criança , Humanos , Leucemia-Linfoma Linfoblástico de Células Precursoras/terapia , Resultado do Tratamento , Adulto JovemAssuntos
Carcinoma de Células Renais , Neoplasias Renais , Anticorpos Monoclonais Humanizados/uso terapêutico , Carcinoma de Células Renais/tratamento farmacológico , Carcinoma de Células Renais/cirurgia , Humanos , Neoplasias Renais/tratamento farmacológico , Neoplasias Renais/cirurgia , NefrectomiaRESUMO
BACKGROUND: Both adolescent and young adult (AYA) and Black or African American (hereafter referred to as Black) cancer patients are historically under-enrolled in cancer treatment trials (CTT). The purpose of this study was to quantify enrollment of Black AYAs in National Cancer Institute (NCI)-sponsored CTTs overall and by age, sex, and cancer diagnosis during 2000-2015. METHODS: Utilizing data from NCI's Cancer Therapy Evaluation Program and the Surveillance, Epidemiology and End Results (SEER) Program, we assessed CTT enrollment in Black patients with cancer and measured changes in enrollment over time between the study periods 2000-2007 and 2008-2015. Enrollment patterns were compared across age groups (≤14 years [y], 15-19y, 20-29y, 30-39y and 40+ years), sex, and cancer diagnosis. RESULTS: From 2000 through 2015, <3% of Black AYAs (20-39y) enrolled on CTTs. While AYAs had significantly higher cancer incidence than children, 20.5% fewer Black AYAs enrolled on CTTs. Enrollment was lowest among Black males 20-29y, with a mean of 18 enrolling in CTTs annually. The proportion of AYA enrollees who were Black did not change significantly over time periods (2000-2007 vs 2008-2015). CONCLUSIONS: Few Black AYAs enroll in CTTs each year. Given known benefits of clinical trial participation and the well-documented racial and age-related differences in cancer outcomes, addressing barriers to enrollment in these patients may, in turn, reduce disparities. Targeted interventions aimed at increasing the CTT enrollment of Black cancer patients, particularly young Black men, are urgently needed. PRECIS: This study documents that compared with Black children, Black adolescent, and young adult (AYA) patients were less likely to enroll in NCI-sponsored CTTs from 2000 to 2015. Black AYA male enrollment decreased with increasing age, highlighting disparities among this specific population in CTT enrollment.
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Negro ou Afro-Americano , Ensaios Clínicos como Assunto , Disparidades em Assistência à Saúde/etnologia , Neoplasias/etnologia , Neoplasias/terapia , Seleção de Pacientes , Adolescente , Adulto , Fatores Etários , Feminino , Humanos , Masculino , National Cancer Institute (U.S.) , Fatores Sexuais , Estados Unidos , Adulto JovemRESUMO
In the United States, one in 196 women is diagnosed with breast cancer under the age of 40 years. Adolescents and young adults (AYAs), of age 15-39 years at diagnosis, experience a number of unique challenges when confronting breast cancer. The incidence of invasive breast cancer has increased among AYA women in the United States since 2004, and most of this change is due to an increase in young women diagnosed with distant disease. AYAs are more likely than older women to present with aggressive subtypes and advanced disease, and they often require systemic staging at diagnosis. Clinical trials should be considered whenever possible, particularly in AYAs with locally advanced or metastatic disease at diagnosis and those with disease progression or recurrence. A significant proportion of AYAs carry germline cancer predisposition mutations, which necessitates prompt genetic testing for all AYAs at diagnosis and may influence choice of local therapy. Suppression of ovarian function, as an adjunct to chemotherapy, may improve breast cancer survival in AYAs. To provide optimal care for AYAs with breast cancer, clinicians should engage multidisciplinary teams that offer fertility preservation, genetic counseling, physical and occupational therapy, nutrition, and psychosocial support, along with medical expertise in tailoring cancer-directed therapy and symptom management toward young women.
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Neoplasias da Mama , Adolescente , Adulto , Neoplasias da Mama/diagnóstico , Neoplasias da Mama/epidemiologia , Neoplasias da Mama/genética , Progressão da Doença , Feminino , Testes Genéticos , Mutação em Linhagem Germinativa , Humanos , Recidiva Local de Neoplasia , Estados Unidos/epidemiologia , Adulto JovemRESUMO
Purpose: Delays in diagnosis can affect the short-term survival outcomes of adolescent and young adult (AYA) cancer patients. We sought to determine the extent to which delayed diagnosis, health insurance type, and income status are associated with the long-term survival of AYA cancer patients. Methods: We reviewed an institutional cohort of 268 patients age 15-29 years who were diagnosed with the most common neoplasms of the AYA population between 2001 and 2003. We grouped patients by the time of onset of cancer symptomatology to verified diagnosis (lagtime to diagnosis; short or long), health insurance type at diagnosis (public or private), zip-code-based median household income (≤U.S. $50,000 or >U.S. $50,000), and demographic variables. Overall survival (OS) and late OS (LOS; the time from the 5-year anniversary of cancer diagnosis to death from any cause) were the outcomes of interest. Results: OS and LOS did not differ between those with short or long lagtimes to diagnosis for all cancer and for specific cancer types. Among patients with long lagtimes, those with private insurance had significantly better LOS than those with public insurance (p = 0.03). Compared with those who had public insurance, patients who had private insurance at diagnosis had significantly better LOS (p = 0.008). Patients with household incomes >U.S. $50,000 had better LOS than those with household incomes ≤U.S. $50,000 (p = 0.02). Patients with public insurance and household incomes ≤U.S. $50,000 had the poorest LOS. Conclusions: AYA cancer patients with either public health insurance or a low household income at diagnosis are at risk of an inferior LOS.
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Seguro Saúde , Neoplasias , Adolescente , Adulto , Humanos , Renda , Neoplasias/diagnóstico , Adulto JovemRESUMO
Importance: Previous studies have demonstrated that adolescents and young adults (AYAs) with cancer are a distinct cancer population; however, research on long-term epidemiological trends and characteristics of cancers in AYAs is lacking. Objective: To characterize the epidemiology of cancer in AYAs aged 15 to 39 years with respect to (1) patient demographic characteristics, (2) frequencies of cancer types, and (3) cancer incidence trends over time. Design, Setting, and Participants: This retrospective, serial cross-sectional, population-based study used registry data from the Surveillance, Epidemiology, and End Results (SEER) database from January 1, 1973, to December 31, 2015 (SEER 9 and SEER 18). The study population was from geographically distinct US regions, chosen to represent the racial and ethnic heterogeneity of the country. Initial analyses were performed from January 1 to August 31, 2019. Main Outcomes and Measures: Incidence rates and descriptive epidemiological statistics for patients aged 15 to 39 years with invasive cancer. Results: A total of 497â¯452 AYAs diagnosed from 1973 to 2015 were included in this study, with 293â¯848 (59.1%) female and 397â¯295 (79.9%) White participants. As AYAs aged, an increase in the relative incidence of carcinomas and decrease in the relative incidence of leukemias, lymphomas, germ cell and trophoblastic neoplasms, and neoplasms of the central nervous system occurred. Among the female AYAs, 72â¯564 (24.7%) were diagnosed with breast carcinoma; 48â¯865 (16.6%), thyroid carcinoma; and 33â¯828 (11.5%), cervix and uterus carcinoma. Among the male AYAs, 37â¯597 (18.5%) were diagnosed with testicular cancer; 20â¯850 (10.2%), melanoma; and 19â¯532 (9.6%), non-Hodgkin lymphoma. The rate of cancer in AYAs increased by 29.6% from 1973 to 2015, with a mean annual percentage change (APC) per 100â¯000 persons of 0.537 (95% CI, 0.426-0.648; P < .001). Kidney carcinoma increased at the greatest rate for both male (APC, 3.572; 95% CI, 3.049-4.097; P < .001) and female (APC, 3.632; 95% CI, 3.105-4.162; P < .001) AYAs. Conclusions and Relevance: In this cross-sectional, US population-based study, cancer in AYAs was shown to have a unique epidemiological pattern and is a growing health concern, with many cancer subtypes having increased in incidence from 1973 to 2015. Continued research on AYA cancers is important to understanding and addressing the distinct health concerns of this population.
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Saúde do Adolescente/tendências , Neoplasias/epidemiologia , Adolescente , Adulto , Estudos Transversais , Feminino , Humanos , Incidência , Masculino , Sistema de Registros , Estudos Retrospectivos , Programa de SEER , Estados Unidos/epidemiologia , Adulto JovemRESUMO
BACKGROUND: Recent observations suggest that prostate cancer is an increasing disease among older adolescents and young adults. METHODS: Incidence, mortality, and survival data were obtained from the US National Cancer Institute Surveillance, Epidemiology, and End Results program and the Institute for Health Metrics and Evaluation Global Burden of Disease database. RESULTS: Worldwide, the incidence of prostate cancer has increased in all groups between ages 15 and 40 years and increased globally at a steady rate averaging 2% per year since 1990 (P < .01). In the United States, this age group was >6 times more likely than older men to have distant disease at diagnosis. Stage for stage, their survival rate improved less than in older men. Whereas the overall 5-year relative survival rate in the United States for men diagnosed between ages 40 and 80 years was between 95% and 100%, it was 30% in those aged 15 to 24 years, 50% in those aged 20 to 29 years, and 80% in those aged 25 to 34 years. CONCLUSIONS: Prostate cancer in older adolescent and young adult men has increased in most countries. There is some evidence that this may be caused in part by underdiagnosis, prostate-specific antigen screening, and overdiagnosis. It also may be caused by trends in obesity, physical inactivity, HPV infection, substance exposure, environmental carcinogens, and/or referral patterns. How the biology of these cancers differs from that in older men and how the etiologies vary from country to country remain to be determined.
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Detecção Precoce de Câncer , Neoplasias da Próstata/diagnóstico , Neoplasias da Próstata/epidemiologia , Adolescente , Adulto , Distribuição por Idade , Humanos , Masculino , Antígeno Prostático Específico/sangue , Neoplasias da Próstata/sangue , Neoplasias da Próstata/patologia , Programa de SEER , Estados Unidos/epidemiologia , Adulto JovemRESUMO
The efficacy of asparaginase in acute lymphoblastic leukemia (ALL) is dependent on depletion of asparagine, an essential amino acid for ALL cells. The target level of plasma asparaginase activity to achieve asparagine depletion has been between 0.05 and 0.4 IU/mL. COG AALL07P4 examined the asparaginase activity and plasma and CSF asparagine concentration of pegaspargase when given intravenously in the treatment of NCI high risk ALL. Matched plasma asparaginase/asparagine levels of the clearance of 54 doses of pegaspargase given in induction or consolidation demonstrated that all patients who had a plasma asparaginase level >0.02 IU/mL had undetectable plasma asparagine. No difference was observed in CSF asparagine levels associated with matched plasma asparaginase levels of 0.02-0.049 versus 0.05-0.22 IU/mL (p = .25). Our data suggest that a plasma asparaginase activity level of 0.02 IU/mL can effectively deplete plasma asparagine. The data also indicate that the 95% CI for plasma asparagine depletion after a pegaspargase dose is 22-29 days. Clinical trial registration: clinicaltrials.gov identifier NCT00671034.