Impact of Social Disparities on 5-Year Survival Rates in Pediatric Hematologic Malignancies.

BACKGROUND: Socioeconomic disparities exist in pediatric patients with hematologic malignancies, leading to suboptimal survival rates. Social determinants of health impact health outcomes, and in children, they may not only lead to worse survival outcomes but carry over into late effects in adult life. The social deprivation index (SDI) is a composite score using geographic county data to measure social determinants of health. Using the SDI, the purpose of the present study is to stratify survival outcomes in pediatric patients with hematologic malignancies based on area deprivation. METHODS: A retrospective cohort study was performed using the national Surveillance, Epidemiology, and End Results oncology registry in the USA from 1975 to 2016 based on county-level data. Pediatric patients (≤18 y old) with a diagnosis of leukemia or lymphoma based on the International Classification for Oncology, third edition (ICD-O-3) were used for inclusion criteria. Patients were grouped by cancer subtype for leukemia into acute lymphoblastic leukemia (ALL) and acute myeloid leukemia while for lymphoma into non-Hodgkin's lymphoma and Hodgkin's lymphoma. SDI scores were calculated for each patient and divided into quartiles, with Q1 being the lowest area of deprivation and Q4 being the highest, respectively. RESULTS: A total of 38,318 leukemia and lymphoma patients were included. Quartile data demonstrated stratification in survival based on area deprivation for ALL, with no survival differences in the other cancer subtypes. Patients with ALL from the most deprived area had a roughly 3% difference in both overall and cancer-specific morality at 5 years compared with the least deprived area. CONCLUSION: Disparities in pediatric patients with ALL represent a significant area for quality improvement. Social programs may have value in improving survival outcomes and could rely on metrics such as SDI.

Symptom management care pathway adaptation process and specific adaptation decisions.

BACKGROUND: There is substantial heterogeneity in symptom management provided to pediatric patients with cancer. The primary objective was to describe the adaptation process and specific adaptation decisions related to symptom management care pathways based on clinical practice guidelines. The secondary objective evaluated if institutional factors were associated with adaptation decisions. METHODS: Fourteen previously developed symptom management care pathway templates were reviewed by an institutional adaptation team composed of two clinicians at each of 10 institutions. They worked through each statement for all care pathway templates sequentially. The institutional adaptation team made the decision to adopt, adapt or reject each statement, resulting in institution-specific symptom management care pathway drafts. Institutional adaption teams distributed the 14 care pathway drafts to their respective teams; their feedback led to care pathway modifications. RESULTS: Initial care pathway adaptation decision making was completed over a median of 4.2 (interquartile range 2.0-5.3) weeks per institution. Across all institutions and among 1350 statements, 551 (40.8%) were adopted, 657 (48.7%) were adapted, 86 (6.4%) were rejected and 56 (4.1%) were no longer applicable because of a previous decision. Most commonly, the reason for rejection was not agreeing with the statement (70/86, 81.4%). Institutional-level factors were not significantly associated with statement rejection. CONCLUSIONS: Acceptability of the 14 care pathways was evident by most statements being adopted or adapted. The adaptation process was accomplished over a relatively short timeframe. Future work should focus on evaluation of care pathway compliance and determination of the impact of care pathway-consistent care on patient outcomes. TRIAL REGISTRATION: clinicaltrials.gov, NCT04614662. Registered 04/11/2020, https://clinicaltrials.gov/ct2/show/NCT04614662?term=NCT04614662&draw=2&rank=1 .

Impact of social disparities on 10 year survival rates in paediatric cancers: a cohort study.

Background: Studies reporting on the impact of social determinants of health on childhood cancer are limited. The current study aimed to examine the relationship between health disparities, as measured by the social deprivation index, and mortality in paediatric oncology patients using a population-based national database. Methods: In this cohort study of children across all paediatric cancers, survival rates were determined using the Surveillance, Epidemiology, and End Results (SEER) database from 1975 to 2016. The social deprivation index was used to measure and assess healthcare disparities and specifically the impact on both overall and cancer-specific survival. Hazard ratios were used to assess the association of area deprivation. Findings: The study cohort was composed of 99,542 patients with paediatric cancer. Patients had a median age of 10 years old (IQR: 3-16) with 46,109 (46.3%) of female sex. Based on race, 79,984 (80.4%) of patients were identified as white while 10,801 (10.9%) were identified as Black. Patients from socially deprived areas had significantly higher hazard of death overall for both non-metastatic [1.27 (95% CI: 1.19-1.36)] and metastatic presentations [1.09 (95% CI: 1.05-1.15)] compared to in more socially affluent areas. Interpretation: Patients from the most socially deprived areas had lower rates of overall and cancer-specific survival compared to patients from socially affluent areas. With an increase in childhood cancer survivors, implementation of social determinant indices, such as the social deprivation index, might aid improvement in healthcare outcomes for the most vulnerable patients. Funding: There was no study sponsor or extramural funding.

A phase I study of irinotecan and temozolomide with bevacizumab in children with recurrent/refractory central nervous system tumors.

PURPOSE: Children with relapsed/refractory central nervous system (CNS) tumors require novel combinations of therapies. Irinotecan and temozolomide (IT) is a frequently used therapy with an established toxicity profile. Bevacizumab is an anti-VEGF monoclonal antibody with demonstrated activity in CNS tumors. Therefore, the combination of these agents has therapeutic potential in CNS tumors. The objective of this study was to determine the maximum tolerated dose (MTD) of escalating dose IT combined with a fixed dose of bevacizumab (BIT) in children with relapsed/refractory CNS tumors. METHODS: A phase I trial was performed in a 3 + 3 design. Therapy toxicities and radiologic responses to treatment were described. RESULTS: One hundred eighty cycles of therapy were administered to 26 patients. The MTD of BIT was dose level 1, (bevacizumab 10 mg/kg on days 1 and 15, irinotecan 125 mg/m2 on days 1 and 15, and temozolomide 125 mg/m2 on days 1-5 of 28-day cycles). The regimen was well tolerated with primarily hematologic toxicity, which was not dose limiting. Among 22 response-evaluable patients, there was 1 complete response (CR), 6 partial responses (PR), and 10 stable diseases (SD) with an overall response rate (ORR: CR + PR) of 31.8%. CONCLUSION: At the MTD, BIT therapy was well tolerated, and prolonged treatment courses of up to 24 cycles were feasible, with radiographic responses observed. Further evaluation is needed for efficacy in a phase II trial (NCT00876993, registered April 7, 2009, www. CLINICALTRIALS: gov ).

Modern Therapy for Chest Wall Ewing Sarcoma: An Update of the University of Florida Experience.

PURPOSE: Owing to adjacent critical organs, the aggressive multimodality local therapy necessary for Ewing sarcoma of the chest wall is a challenge. Our previous review of historical outcomes at our institution revealed suboptimal disease control and a high incidence of grade ≥3 toxic effects in patients treated before 2006. The purpose of this study was to evaluate changes during the past decade since the introduction of proton therapy. METHODS AND MATERIALS: Thirty-nine consecutive pediatric patients with a chest wall Ewing sarcoma treated between 2006 and 2020 at the University of Florida were identified. The median maximum tumor diameter was 10 cm (range, 4-28 cm). At diagnosis, 19 patients had local disease and the others had a pleural effusion (11), pleural nodules (5), or pulmonary metastases (4). Patients were treated with chemotherapy regimens according to contemporary North American and European protocols: 7 were treated with preoperative, 18 with postoperative, and 14 with definitive radiation. Preceding primary site treatment, 15 patients required hemithorax radiation and 4 patients underwent whole-lung irradiation using photon techniques. The total median radiation dose to the primary tumor was 52.8 GyRBE [relative biological effectiveness] (range, 44.4-55.8 GyRBE). RESULTS: With a median follow-up of 4 years (range, 0.7-14.7 years), the 5-year local control, progression-free survival, and overall survival rates were 97.2%, 74.4%, and 81.6%, respectively, for the whole cohort. For the 19 patients with nonmetastatic disease, the 5-year local control, progression-free survival, and overall survival rates were 100%, 78.9%, and 78.9%, respectively. No patients developed grade ≥4 toxic effects. Two patients (5%) experienced grade 3 toxic effects related to multimodality treatment; both were patients who required surgery to correct scoliosis. Two patients (5%) developed grade 2 pneumonitis. CONCLUSIONS: Compared with our prior published institutional experience, our data suggest improvements in disease control and multimodality toxic effects since the introduction of proton therapy. This should be confirmed with a larger sample size and longer follow-up.

Modern Therapy for Spinal and Paraspinal Ewing Sarcoma: An Update of the University of Florida Experience.

PURPOSE: In 2010, we published a comprehensive review of our institutional outcomes about treating children with spinal and paraspinal Ewing sarcoma using photon therapy. Multimodality therapy was associated with fair disease control but also with serious toxicity, including a 37% rate of grade 3 or greater toxicity. We therefore sought to assess our more recent experience about treating children with more modern technology and treatment regimens. METHODS AND MATERIALS: Between 2010 and 2021, 32 pediatric patients with nonmetastatic spinal and paraspinal Ewing sarcoma were treated at University of Florida and enrolled in a retrospective outcome study. Median age at diagnosis was 9.8 years (range, 2.1-21.8 years). Within the cervical, thoracic, and lumbar spine regions, 3, 22, and 7 tumors arose, respectively. Median maximum tumor diameter was 5 cm (range, 3-19 cm). At diagnosis, 28 of 32 patients had motor, bowel, or bladder deficits. Chemotherapy was delivered according to contemporary North American and European interval-compressed regimens. Before radiation therapy, 14 patients underwent gross total resection, whereas 18 underwent a biopsy or subtotal resection with cord decompression. All patients were treated with proton therapy; 6 with hardware stabilization also received a component of intensity modulated photon therapy. Median prescription dose was 50.4 gray relative biological effectiveness (GyRBE; range, 45-55.8 GyRBE). Median maximum dose to the spinal cord was 50.2 GyRBE (range, 0-54.9 GyRBE). RESULTS: With a median follow-up of 4.1 years (range, 0.7-9.4 years), the 5-year local control, progression-free survival, and overall survival rates were 92%, 79%, and 85%, respectively. Ten of 30 living patients have residual motor, bowel, or bladder deficits. Overall, 22% of patients experienced Common Terminology Criteria for Adverse Events grade 3 late toxicity related to multimodality treatment: kyphosis (n = 4), esophagitis (n = 2), and chronic kidney disease (n = 1). No patients developed grade 4 or greater toxicity, new neurologic deficits, or second malignancy. CONCLUSIONS: Modern treatment advances may offer an improved therapeutic ratio for pediatric patients with spinal and paraspinal Ewing sarcoma. With appropriate management, most patients can be cured with recovery of long-term neurologic function and modest side effects.

Treatment Outcomes After Proton Therapy for Ewing Sarcoma of the Pelvis.

PURPOSE: Ewing sarcoma of the pelvis is associated with inferior local control compared with those arising from other primary sites. Despite its increased use, outcome data for treatment with proton therapy remain limited. We report 3-year disease control and toxicity in pediatric patients treated with proton therapy. METHODS AND MATERIALS: Thirty-five patients aged ≤21 years (median, 14 years) with nonmetastatic pelvic Ewing sarcoma received proton therapy and chemotherapy between 2010 and 2018. Overall survival and tumor control rates were calculated using the Kaplan-Meier method. A log-rank test assessed significance between strata of prognostic factors. Significant toxicity was reported per the Common Terminology Criteria for Adverse Events, version 4.0. RESULTS: Most patients received definitive radiation (n = 26; median dose 55.8 Gy relative biological effectiveness [RBE]; range, 54.0-64.8), 7 received preoperative radiation (50.4 Gy RBE), and 2 received postoperative radiation (45 Gy RBE and 54 Gy RBE). The median primary tumor size was 10.5 cm. With a median follow-up of 3 years (range, 0.3-9.0 years), the 3-year overall survival, progression-free survival, and local control rates were 83% (95% confidence interval [CI], 65%-93%), 64% (95% CI, 45%-79%), and 92% (95% CI, 74%-98%), respectively. There was no association between local control, progression-free survival, or overall survival and tumor size, patient age, radiation dose, or definitive versus pre-/postoperative radiation therapy. Median time to progression was 1 year (range, 0.1-1.9 years). All patients with large tumors (≥8 cm) who underwent definitive proton therapy with a higher dose (≥59.4 Gy RBE) remained free from tumor recurrence (n = 5). Five patients experienced grade ≥2 subacute/late toxicity, all of whom were treated with combined surgery and radiation. CONCLUSIONS: Definitive proton therapy offers local control comparable to photon therapy in pediatric patients with pelvic Ewing sarcoma. These data lend preliminary support to radiation dose escalation without significant toxicity, which may contribute to the favorable outcomes. Combined surgery and radiation therapy, particularly preoperative radiation, is associated with postoperative complications, but not survival, compared with radiation alone.

Intravenous and Oral Posaconazole Pharmacokinetics in a Five-Year-Old With Mucor: A Case Report and Review of the Literature.

Posaconazole is a lipophilic triazole antifungal that exhibits variable absorption when administered orally. It possesses a broad spectrum of activity against various fungi, such as Aspergillus and traditionally resistant molds such as Rhizopus and Mucor, which carry a poor prognosis. Unfortunately, the tablet and suspension formulations of posaconazole are Food and Drug Administration approved for treatment of fungal diseases only in patients older than 13 years of age. Furthermore, the approval of the IV formulation is exclusively for adult patients. Nevertheless, the extended spectrum of activity and available dosage forms make it an attractive option for pediatric use. The data that exist to guide dosing of posaconazole in young pediatric patients are limited primarily to case series and case reports. Thus, we recommend therapeutic drug monitoring to ensure both safety and efficacy in pediatric patients. Herein we describe our experience with both oral and IV posaconazole in the salvage therapy of a 5-year-old female with extensive cutaneous Mucor. In contrast to previous reports, which show larger doses may be necessary to obtain therapeutic concentrations in pediatric patients as compared with adults, our patient reached targeted concentrations with weight-based dosing.

Esophagitis associated with multimodality management of pediatric Ewing sarcoma of thorax.

BACKGROUND: Ewing sarcoma of the thoracic spine and chest wall is frequently treated with concurrent chemotherapy and radiation therapy (RT). Treatment-related acute esophagitis can lead to hospitalization and treatment delays. The aim of this study was to analyze the incidence, risk factors, and management of esophagitis in pediatric patients with Ewing sarcoma of the thoracic region. METHODS: We conducted a single-institution retrospective review of patients treated over a 10-year period. Medical records were reviewed for patient and treatment characteristics associated with Common Terminology Criteria for Adverse Events grade 2 or higher esophagitis. RT plans were also reviewed and various esophageal dose metrics were analyzed. RESULTS: Twelve of 37 patients (32%) developed acute esophagitis. Neutropenia was associated with an increased risk of esophagitis (60% vs. 14%; P < 0.01). RT significantly contributed to its incidence when maximum esophageal dose was >47 Gy (69% vs. 5%; P < 0.0001) and esophageal D5cm3 was >15 Gy (67% vs. 9%; P < 0.001). All 12 patients with esophagitis were managed with oral opioid analgesics. Nine patients with persistent symptoms received subsequent fluconazole for empiric fungal treatment and each had a decreased need for opioid analgesics within 2-5 days. CONCLUSION: Approximately one-third of patients with Ewing sarcoma of the thoracic region will develop acute esophagitis. An esophageal D5cm3 dose < 15 Gy and maximal esophageal dose < 47 Gy may keep the rate of acute esophagitis under 5%. However, the association with neutropenia and consistent response to antifungal therapy suggest chemotherapy-associated toxicity and an infectious component as part of the process.

Glutamic acid not beneficial for the prevention of vincristine neurotoxicity in children with cancer.

BACKGROUND: Vincristine causes known side effects of peripheral sensory, motor, autonomic and cranial neuropathies. No preventive interventions are known. PROCEDURE: We performed a randomized, placebo-controlled, double-blind trial of oral glutamic acid as a preventive agent in pediatric patients with cancer who would be receiving vincristine therapy for at least 9 consecutive weeks (Stratum 1 = Wilms tumor and rhabdomyosarcoma) or 4 consecutive weeks in conjunction with steroids (Stratum 2 = Acute lymphoblastic leukemia and non-Hodgkin lymphoma). At designated time points, a scored neurologic exam using the Modified Balis Pediatric Scale of Peripheral Neuropathies was performed to document neurologic toxicity. RESULTS: Between 2007 and 2012, 250 patients were enrolled (Stratum 1 = 50, Stratum 2 = 200). The glutamic acid treated group did not have a significantly lower percentage of neurotoxicity compared to placebo treated group either overall or within stratum or age subgroups. The only subgroup which was suggestive of treatment effect was for age. Patients 13 years or older showed a larger benefit in favor of glutamic acid (P = 0.055) compared to patients less than 13 years (P = 1.00). Constipation was the most frequently reported (14%) Grade II or higher neurotoxicity. CONCLUSION: Vincristine-associated neurotoxicity in pediatric oncology remains a frequent complication of chemotherapy for multiple diagnoses with an approximate 30% of patients affected. Glutamic acid is not effective for prevention in pre-adolescents. There is a suggestion of benefit in patients 13 years or older, but the study was not designed to provide adequate power to test the treatment effect within this age group alone.

Comparison of pharmacokinetics and safety of voriconazole intravenous-to-oral switch in immunocompromised children and healthy adults.

Voriconazole pharmacokinetics are not well characterized in children despite prior studies. To assess the appropriate pediatric dosing, a study was conducted in 40 immunocompromised children aged 2 to <12 years to evaluate the pharmacokinetics and safety of voriconazole following intravenous (IV)-to-oral (PO) switch regimens based on a previous population pharmacokinetic modeling: 7 mg/kg IV every 12 h (q12h) and 200 mg PO q12h. Area under the curve over the 12-h dosing interval (AUC(0-12)) was calculated using the noncompartmental method and compared to that for adults receiving approved dosing regimens (6 → 4 mg/kg IV q12h, 200 mg PO q12h). On average, the AUC(0-12) in children receiving 7 mg/kg IV q12h on day 1 and at IV steady state were 7.85 and 21.4 µg · h/ml, respectively, and approximately 44% and 40% lower, respectively, than those for adults at 6 → 4 mg/kg IV q12h. Large intersubject variability was observed. At steady state during oral treatment (200 mg q12h), children had higher average exposure than adults, with much larger intersubject variability. The exposure achieved with oral dosing in children tended to decrease as weight and age increased. The most common treatment-related adverse events were transient elevated liver function tests. No clear threshold of voriconazole exposure was identified that would predict the occurrence of treatment-related hepatic events. Overall, voriconazole IV doses higher than 7 mg/kg are needed in children to closely match adult exposures, and a weight-based oral dose may be more appropriate for children than a fixed dose. Safety of voriconazole in children was consistent with the known safety profile of voriconazole.

Fractionated low-dose radiotherapy after myeloablative stem cell transplantation for local control in patients with high-risk neuroblastoma.

BACKGROUND: The optimal administration of radiotherapy for patients with high-risk neuroblastoma (NB) currently is undefined in the context of modern therapy using myeloablative chemotherapy with autologous stem cell rescue (hematopoietic stem cell transplantation [HSCT]). METHODS: The authors conducted a retrospective review of the records of 21 consecutive patients with high-risk NB to assess local control and toxicity of external beam radiotherapy (XRT). Therapy included multiagent induction chemotherapy and delayed surgical resection, consolidation of HSCT and local XRT, and 13-cis-retinoic acid maintenance therapy. XRT was delivered to the primary site, using postchemotherapy volumes, and to initial metastatic sites with 1-2 cm margins to 2100 centigrays (cGy) using 14 fractions administered once daily. RESULTS: Four of 21 patients did not receive XRT due to toxic death (n = 2), disease progression before XRT (n = 1), or parental refusal (n = 1). The median time to XRT post-HSCT was 54 days. Thirteen patients received a second peripheral blood stem cell infusion after completing XRT. Twelve of the 14 patients who received XRT post-HSCT and for whom toxicity data were available had Grade 3-4 acute toxicities, including gastrointestinal toxicity (n = 8), hematologic toxicity (n = 9), and infection (n = 1). Nonrecurrent long-term toxicities included prolonged nutritional deficiency (n = 9) and leg-length discrepancy (n = 1). Tumors recurred in 7 of 21 patients (5 of 17 patients who received radiotherapy), either within a radiation field (n = 1) or at distant nonirradiated sites (n = 6). The estimated local failure rate was 7% (95% confidence interval [95% CI], 0-14%), with a 2-year event-free survival rate of 48% (95% CI, 26-70%). CONCLUSIONS: Post-HSCT, fractionated XRT to 2100 cGy was a tolerable and effective treatment for patients with high-risk NB, and minimal recurrences were observed at designated XRT sites.

Prolonged survival after invasive aspergillosis: a single-institution review of 11 cases.

PURPOSE: To perform a retrospective review of the authors' experience with invasive aspergillosis (IA) in a pediatric population treated with conventional chemotherapy. Case series of IA in the pediatric oncology population are limited but generally report poor overall survival. METHODS: Medical records were reviewed of all patients receiving conventional chemotherapy for malignant disease who developed IA at Children's Hospital and Regional Medical Center, Seattle, Washington, between January 1, 1995, and January 1, 2002. RESULTS: During the study period there were 11 cases of IA in pediatric cancer patients treated with conventional chemotherapy. All patients had pulmonary IA; two also had evidence of disseminated disease. All patients underwent diagnostic tissue biopsy. Sixty-four percent required further surgery to excise bulky disease. Medical therapy varied with disease presentation and the overall clinical picture, although prolonged treatment with amphotericin B and itraconazole was the mainstay of therapy. Resolution of clinical disease was seen in 91% of patients. Seventy-three percent received further chemotherapy. The 3-year estimated survival was 82%, with a median follow-up of 32.5 months. CONCLUSIONS: Early diagnosis and aggressive intervention improve long-term survival from IA in immunocompromised pediatric oncology patients. Aggressive surgical resection, prolonged medical therapy after gross resolution of disease, and chemoprophylaxis during subsequent chemotherapy decrease the likelihood of recurrent IA despite subsequent cytotoxic therapy. The ability to proceed with intensive chemotherapy despite a history of IA may improve long-term survival.