141 results on '"Brian H, Kushner"'
Search Results
2. Mandibular metastases in neuroblastoma: Outcomes and dental sequelae
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Joseph M. Huryn, Annu Singh, Cherry L. Estilo, Shakeel Modak, Brian H. Kushner, Armand Karl Solano, and Suzanne L. Wolden
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Adult ,Male ,medicine.medical_specialty ,Adolescent ,medicine.medical_treatment ,Kaplan-Meier Estimate ,Mandible ,Trismus ,Article ,Metastasis ,Neuroblastoma ,Young Adult ,03 medical and health sciences ,0302 clinical medicine ,medicine ,Dentition ,Humans ,Child ,Anodontia ,Retrospective Studies ,business.industry ,Medical record ,Infant ,Retrospective cohort study ,Hematology ,medicine.disease ,Surgery ,Radiation therapy ,Mandibular Neoplasms ,Hypodontia ,Oncology ,Child, Preschool ,030220 oncology & carcinogenesis ,Pediatrics, Perinatology and Child Health ,Female ,medicine.symptom ,business ,Progressive disease ,030215 immunology - Abstract
Background Although metastatic involvement of bony sites including cranial bones is common in neuroblastoma (NB), mandibular metastases (MM) are uncommon, and specific outcomes have not been reported upon in the modern therapeutic era. Methods In this retrospective study, medical records on patients with MM from NB were reviewed. Statistical analysis was performed using the Kaplan-Meier method. Results Of 29 patients, nine (31%) had MM at diagnosis, whereas in 20 (69%) MM were first detected at NB relapse at a median time of 26 (6-89) months from diagnosis. Median maximal diameter of lesions was 3 (range 0.8-4.9) cm. MM were unilateral in 83% of patients, with ascending ramus (55%) and mandibular body (38%) being the two most common sites. All patients received systemic chemotherapy, and 26 (93%) patients received radiotherapy to MM. At a median follow-up of 37.3 (24.2-219.5) months, eight of nine patients with MM at diagnosis did not experience mandibular progressive disease. Eighteen of 20 patients with MM at relapse received therapeutic radiotherapy; objective responses were noted in 78%. Seventy-two percent (5/18) had not experienced relapse within the radiation field at a median of 12 (2-276) months postradiotherapy. Dental findings at follow-up after completion of NB therapy included hypodontia, hypocalcification of enamel, and trismus. Median 3-year overall survival in patients with relapsed MM was 51 ± 12% months from relapse. Conclusion MM when detected at diagnosis is associated with a prognosis similar to that for other skeletal metastases of NB. Radiotherapy is effective for control of MM detected both at diagnosis and relapse. Significant dental abnormalities posttherapy warrant regular dental evaluations and appropriate intervention.
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- 2021
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3. Treatment and revaccination of children with paraneoplastic opsoclonus‐myoclonus‐ataxia syndrome and neuroblastoma: The Memorial Sloan Kettering experience
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Ellen M. Basu, Yasmin Khakoo, Yi‐Chih Lin, Cheryl Fischer, Kevin C. De Braganca, Ami Patel, and Brian H. Kushner
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Male ,Pediatrics ,medicine.medical_specialty ,Exacerbation ,Cyclophosphamide ,medicine.medical_treatment ,Disease-Free Survival ,Article ,Neuroblastoma ,03 medical and health sciences ,0302 clinical medicine ,Adrenocorticotropic Hormone ,Antineoplastic Combined Chemotherapy Protocols ,Opsoclonus myoclonus syndrome ,medicine ,Humans ,Stage (cooking) ,Neoplasm Staging ,Retrospective Studies ,Chemotherapy ,Opsoclonus-Myoclonus Syndrome ,business.industry ,Immunoglobulins, Intravenous ,Infant ,Retrospective cohort study ,Hematology ,medicine.disease ,Survival Rate ,Oncology ,030220 oncology & carcinogenesis ,Pediatrics, Perinatology and Child Health ,Cohort ,Female ,Rituximab ,business ,030215 immunology ,medicine.drug - Abstract
Objective To review the treatment and revaccination of neuroblastoma-associated opsoclonus-myoclonus-ataxia syndrome (OMAS) patients at Memorial Sloan Kettering Cancer Center (MSK). Procedure Institutional Review Board approval was obtained for this retrospective study of patients with neuroblastoma-associated OMAS followed at MSK from 2000 to 2016. Results Fourteen patients (nine female) were 9-21 (median 17) months old at diagnosis of neuroblastoma and OMAS syndrome. They had stage 1 (n = 12), stage 2B, or intermediate-risk stage 4. Tumor histology was favorable in 11 patients, unfavorable in two, and unknown in one patient. No patient had amplified MYCN. All patients underwent tumor resection at diagnosis. Anti-neuroblastoma treatment was limited to chemotherapy in one patient. Overall survival is 100% at 3-16 (median 10) years. For OMAS, 13 patients received intravenous immune globulin (IVIg), adrenocorticotropic hormone (ACTH), and rituximab, and one received ACTH and IVIg. Seven patients experienced OMAS relapse. For these relapses, five patients received low-dose cyclophosphamide and two received rituximab. The mean total OMAS treatment was 20-96 (median 48) months. Seven patients started rituximab ≤3 months from diagnosis and did not relapse. The other six experienced OMAS relapse. To date, six patients have been revaccinated at a minimum of 2 years after completion of OMAS therapy without OMAS recurrence. Conclusions Patients with neuroblastoma-associated OMAS had excellent overall survival. Early initiation of rituximab, IVIg, and ACTH may reduce risks of OMAS relapse. Revaccination can be resumed without exacerbation of OMAS. Further investigation with a larger cohort of patients is needed.
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- 2020
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4. Short Hypofractionated Radiation Therapy in Palliation of Pediatric Malignancies: Outcomes and Toxicities
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Stanislav Lazarev, Brian H. Kushner, and Suzanne L. Wolden
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Male ,Cancer Research ,medicine.medical_specialty ,Time Factors ,Hypofractionated Radiation Therapy ,Palliative care ,Adolescent ,Effective dose (radiation) ,Gastroenterology ,Article ,03 medical and health sciences ,0302 clinical medicine ,Recurrence ,Neoplasms ,Internal medicine ,Clinical endpoint ,Humans ,Medicine ,Radiology, Nuclear Medicine and imaging ,Neoplasm Metastasis ,Child ,Radiation Injuries ,Survival analysis ,Radiation ,business.industry ,Palliative Care ,Common Terminology Criteria for Adverse Events ,medicine.disease ,Survival Analysis ,Pediatric cancer ,Treatment Outcome ,Oncology ,Child, Preschool ,030220 oncology & carcinogenesis ,Female ,Radiation Dose Hypofractionation ,Sarcoma ,Safety ,business ,030217 neurology & neurosurgery - Abstract
Purpose Treatment strategies in palliation of pediatric cancer remain a significant challenge. In this study, we aimed to assess the efficacy and safety of a short course of hypofractionated radiation therapy (RT) for metastatic or recurrent childhood tumors. Methods and Materials A total of 104 lesions in 62 pediatric patients with metastatic or recurrent cancer were treated with a short hypofractionation schedule (>1 but ≤5 fractions; ≥3 Gy per fraction) between 2007 and 2017 in our institution. The primary endpoint was local control (LC). Other endpoints included treatment response, overall survival, progression-free survival, and toxicity. Toxicities were assessed using the Common Terminology Criteria for Adverse Events v.4.0. Results The most common histologies were neuroblastoma, comprising 50 of the 104 lesions (48.1%); osteosarcoma, 17 lesions (16.4%); and Ewing sarcoma, 13 lesions (12.5%). A median total dose of 24 Gy was delivered in a median of 5 fractions. Of 104 lesions, 26 (25.0%) were treated with stereotactic body radiation therapy, 24 (23.1%) with intensity modulated RT, and 48 (46.2%) with 2-dimensional RT or 3-dimensional conformal RT. A complete or partial response was observed in 63 (60.6%) of lesions, and stable disease was observed in 34 (32.7%). At a median follow-up of 8.7 months, 21 local failures occurred (20.2%). The 1- and 2-year LC rates were 74% and 68%, respectively. LC was better for tumors without previous irradiation (83% vs 57% with previous RT; P = .004). LC rates did not differ between RT techniques or total biologically effective dose with α/β ratio of 10 (BED10) (≤30 vs >30 Gy). At the time of analysis, 38 deaths in the cohort of 62 patients (61.3%) were recorded. The 1-year progression-free survival and overall survival rates were 31% and 44%, respectively. Incidence of any grade ≥3 toxicity was 6.7% (7 of 104). No grade 5 events occurred. Conclusions A short hypofractionation scheme yields effective disease control and treatment response with a favorable side effect profile. Select pediatric patients with symptomatic metastases or recurrent disease can be considered for a short course of palliative RT.
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- 2018
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5. 963MO Naxitamab for the treatment of refractory/relapsed high-risk neuroblastoma (HR NB): Updated efficacy and safety data from the international, multicenter phase II trial 201
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Godfrey Chi-Fung Chan, Jaume Mora, M. Bear, Brian H. Kushner, Daniel Morgenstern, Karsten Nysom, K. Tornøe, and N. Losic
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Oncology ,medicine.medical_specialty ,Refractory ,business.industry ,Internal medicine ,medicine ,High risk neuroblastoma ,Hematology ,business - Published
- 2021
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6. MYCN-amplified stage 2/3 neuroblastoma: excellent survival in the era of anti-GD2 immunotherapy
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Nai-Kong V. Cheung, Ellen M. Basu, Stephen S. Roberts, Michael P. LaQuaglia, Irene Y. Cheung, Suzanne L. Wolden, Karima Yataghene, Kim Kramer, Brian H. Kushner, and Shakeel Modak
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0301 basic medicine ,Oncology ,Gerontology ,medicine.medical_specialty ,MYCN amplification ,medicine.medical_treatment ,anti-GD2 antibody ,autologous transplantation ,03 medical and health sciences ,neuroblastoma ,0302 clinical medicine ,Internal medicine ,Neuroblastoma ,medicine ,cytokine ,Autologous transplantation ,Stage (cooking) ,business.industry ,Induction chemotherapy ,Immunotherapy ,medicine.disease ,3. Good health ,Transplantation ,030104 developmental biology ,030220 oncology & carcinogenesis ,Good prognosis ,business ,Progressive disease ,Research Paper - Abstract
High-risk neuroblastoma (HR-NB) includes MYCN-amplified stage 2/3, but reports covering anti-GD2 immunotherapy, which recently became standard for HR-NB, do not provide details on this subset. We now report on all 20 MYCN-amplified stage 2/3 patients who received induction chemotherapy at our center during the era of consolidation with anti-GD2 antibody 3F8/ granulocyte-macrophage colony-stimulating factor (GM-CSF) (2000-2015). Early in this period, consolidation included autologous stem-cell transplantation (ASCT). Event-free survival (EFS) and overall survival (OS) were estimated using Kaplan-Meier analyses. With induction, 19/20 (95%) patients achieved complete/very good partial remission (CR/VGPR) but one had progressive disease with early death. One responder did not receive consolidation and died of relapse. Five-year post-diagnosis EFS/OS rates for all 20 patients were 72%/84%. The 18 CR/VGPR patients who received consolidation had EFS/OS 81%/94% at five years from starting 3F8/GM-CSF: 4/4 ASCT patients remained relapse-free, while 11/14 non-ASCT patients remained relapse-free and two of the three relapsed patients achieved 2nd CR (consolidated by retreatment with 3F8/GM-CSF) and remained in 2nd CR at 36+ and 95+ months post-relapse. The 14 non-ASCT patients had EFS/OS 73.5%/93% at five years from starting 3F8/GM-CSF. This subset appears to have a good prognosis with contemporary multi-modality therapy, possibly even without ASCT.
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- 2017
7. Reduced-dose craniospinal irradiation for central nervous system relapsed neuroblastoma
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Kim Kramer, Shakeel Modak, Brian H. Kushner, Ellen M. Basu, Nai-Kong V. Cheung, L. Luo, Suzanne L. Wolden, and Stephen S. Roberts
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Male ,medicine.medical_specialty ,Adolescent ,medicine.medical_treatment ,Central nervous system ,Urology ,Antineoplastic Agents ,Craniospinal Irradiation ,Article ,03 medical and health sciences ,Neuroblastoma ,0302 clinical medicine ,Median follow-up ,medicine ,Proton Therapy ,Humans ,Child ,Relapsed Neuroblastoma ,Retrospective Studies ,Chemotherapy ,business.industry ,Brain Neoplasms ,Infant ,Radiotherapy Dosage ,Hematology ,Radioimmunotherapy ,medicine.disease ,Reduced dose ,Combined Modality Therapy ,Survival Rate ,medicine.anatomical_structure ,Treatment Outcome ,Oncology ,030220 oncology & carcinogenesis ,Child, Preschool ,Pediatrics, Perinatology and Child Health ,Female ,business ,030215 immunology - Abstract
Purpose In patients with high-risk neuroblastoma, there is an increased recognition of relapse in the central nervous system (CNS). Craniospinal irradiation (CSI) has been an effective treatment but carries significant long-term complications. It is unclear whether reducing the CSI dose from 21 to 18 Gy can achieve similar CNS tumor control. Patients and methods A retrospective review of pediatric patients with CNS-relapsed neuroblastoma treated with CSI and boost to parenchymal lesions between 2003 and 2019 was performed. The goal was to assess CNS control comparing 18 Gy and 21 Gy regimens. Results Ninety-four patients with CNS-relapsed neuroblastoma were treated with CSI followed by intraventricular compartmental radioimmunotherapy. Median age at the time of CNS disease was 4 years (range 1-13 years). Forty-one patients (44%) received 21 Gy CSI prior to an institutional decision to lower the dose; 53 patients (56%) received 18 Gy CSI. Seventy-nine patients (84%) received additional boosts. With a median follow up of 4.1 years for surviving patients, 2-year CNS relapse-free survival was 74% for 18 Gy group versus 77% for 21 Gy group, and 5-year CNS relapse-free survival was 66% for 18 Gy versus 72% for 21 Gy group, respectively (P = .40). Five-year overall survival rate was 43% in 18 Gy group versus 47% in 21 Gy group (P = .72). Conclusion For patients with CNS-relapsed neuroblastoma, CNS disease control is comparable between 18 Gy and 21 Gy CSI dose regimens, in conjunction with radioimmunotherapy and CNS penetrating chemotherapy. More than 65% of the patients remain CNS disease free after 5 years. The findings support 18 Gy as the new standard CSI dose for CNS-relapsed neuroblastoma.
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- 2020
8. Assessment of pulmonary outcomes, exercise capacity, and longitudinal changes in lung function in pediatric survivors of high-risk neuroblastoma
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Anne Stone, Xian Wu, Charles A. Sklar, Shakeel Modak, Danielle Novetsky Friedman, Michael P. LaQuaglia, Jessica Costello, Nai-Kong V. Cheung, Suzanne L. Wolden, and Brian H. Kushner
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Spirometry ,Male ,Risk ,medicine.medical_specialty ,Adolescent ,Population ,Article ,Pulmonary function testing ,03 medical and health sciences ,Neuroblastoma ,Young Adult ,0302 clinical medicine ,Cancer Survivors ,Internal medicine ,Surveys and Questionnaires ,medicine ,Humans ,education ,Child ,Lung ,education.field_of_study ,Exercise Tolerance ,medicine.diagnostic_test ,business.industry ,Smoking ,Percent Predicted Forced Vital Capacity ,VO2 max ,Hematology ,Respiration Disorders ,Combined Modality Therapy ,Respiratory Function Tests ,medicine.anatomical_structure ,Treatment Outcome ,Oncology ,Cardiothoracic surgery ,030220 oncology & carcinogenesis ,Pediatrics, Perinatology and Child Health ,Cohort ,Disease Progression ,Female ,business ,030215 immunology ,Follow-Up Studies - Abstract
BACKGROUND/OBJECTIVES: Survivors of high-risk neuroblastoma (NB) are exposed to multimodality therapies early in life and confront late therapy-related toxicities. This study assessed respiratory symptoms, exercise capacity, and longitudinal changes in pulmonary function tests (PFTs) among survivors. DESIGN/METHODS: Survivors of high-risk NB followed in the Long-term Follow-up clinic at Memorial Sloan Kettering Cancer Center were enrolled. Symptom and physical activity questionnaires were completed. Medical records were reviewed for treatments and co-morbidities. Participants completed spirometry, plethysmography, diffusion capacity of the lung for carbon monoxide, 6 Minute Walk Tests (6MWTs), and cardiopulmonary exercise testing. Questionnaires and PFTs were repeated at least one year after enrollment. RESULTS: Sixty-two survivors participated (median age at study: 10.92years; median age at diagnosis: 2.75years; median time since completion of therapy: 5.29years). Thirty-two percent had chronic respiratory symptoms. Seventy-seven percent had PFT abnormalities, mostly mild to moderate severity. Thirty-three completed 6MWTs (median 634.3meters); eight completed cardiopulmonary exercise tests (mean VO(2) max: 63 percent predicted); twenty-three completed a second PFT revealing declines over a median 2.97years (mean percent predicted forced vital capacity: 79.9 to 70.0; mean forced expiratory volume in 1 second: 81.6 to 69.9). Risks for abnormalities included thoracic surgery, chest radiation therapy (RT), thoracic surgery plus chest RT, and hematopoietic stem cell transplant. CONCLUSIONS: In this cohort of survivors of high-risk NB, PFT abnormalities were common but mostly mild or moderate. Maximal exercise capacity may be affected by respiratory limitations and declines in lung function may occur over time. Continued pulmonary surveillance of this at-risk population is warranted.
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- 2019
9. Efficacy of naxitamab in patients with refractory/relapse (R/R) high-risk neuroblastoma (HR-NB) by bone/bone marrow (BM) evaluation, potential sites of residual disease
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Karsten Nysom, Karen Tornøe, Nedjad Losic, Brian H. Kushner, Daniel A. Morgenstern, Melissa K. Bear, and Jaume Mora
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Oncology ,Cancer Research ,medicine.medical_specialty ,business.industry ,Disease ,medicine.anatomical_structure ,Refractory ,Internal medicine ,medicine ,High risk neuroblastoma ,In patient ,Bone marrow ,Solid tumor ,business - Abstract
10022 Background: NB is the most common extracranial solid tumor in children and half of patients present with high-risk disease. Bone and BM are frequent sites of metastatic disease and can serve as a reservoir for residual disease driving relapse. Naxitamab, a GD2-binding monoclonal antibody, was recently approved in the United States in combination with GM-CSF for the treatment of pediatric patients ≥1 year of age and adult patients with R/R HR-NB in the bone/BM who have demonstrated a partial response (PR), minor response (MR), or stable disease (SD) to prior therapy. Here we describe outcomes from the registrational Trial 201 (NCT03363373) detailed by bone/BM involvement. Methods: HR-NB patients with primary refractory disease or incomplete response to salvage treatment following relapse or progressive disease (PD) (in both cases including SD, MR and PR) with disease limited to bone and/or BM were eligible. Naxitamab was administered over ≥30 min in the outpatient setting on Days 1, 3 and 5 at 3 mg/kg/infusion (9 mg/kg/cycle) in combination with GM-CSF at 250 µg/m2/day on Days -4 to 0 and at 500 µg/m2/day on days 1 to 5. Treatment cycles were repeated every 4 weeks. Response was assessed after Cycle 2 and then every 2-3 months by revised International Neuroblastoma Response Criteria (INRC) using BM biopsies/aspirates and 123I-MIBG scintigraphy or FDG-PET. Effectiveness was concluded if the lower limit of the Clopper-Pearson exact 95% confidence interval (CI) of overall response rate (ORR) was >20%. We report efficacy data on 22 patients and safety data on the first 25 patients enrolled. Results: 13 (59%) patients had NB in bone, 2 (9%) had NB in BM, and 7 (32%) had NB in both bone and BM. Summary of overall response and response by compartment. Conclusions: Naxitamab provided clinically meaningful activity in both bone and BM with ORR of 68% and had a manageable AE profile. Clinical trial information: NCT03363373. [Table: see text]
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- 2021
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10. Local Control With 21-Gy Radiation Therapy for High-Risk Neuroblastoma
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Brian H. Kushner, Dana L. Casey, Nai-Kong V. Cheung, Suzanne L. Wolden, Shakeel Modak, and Michael P. LaQuaglia
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Male ,Cancer Research ,medicine.medical_specialty ,Adolescent ,medicine.medical_treatment ,New York ,Urology ,Comorbidity ,Article ,Disease-Free Survival ,Cohort Studies ,Neuroblastoma ,03 medical and health sciences ,0302 clinical medicine ,Risk Factors ,medicine ,Humans ,Radiology, Nuclear Medicine and imaging ,Cumulative incidence ,030212 general & internal medicine ,Child ,Radiation Injuries ,Survival rate ,Retrospective Studies ,Chemotherapy ,Radiation ,business.industry ,Incidence ,Incidence (epidemiology) ,Dose fractionation ,Infant ,Chemoradiotherapy ,medicine.disease ,Debulking ,Surgery ,Causality ,Survival Rate ,Radiation therapy ,Oncology ,Child, Preschool ,030220 oncology & carcinogenesis ,Female ,Dose Fractionation, Radiation ,Neoplasm Recurrence, Local ,business - Abstract
Purpose To evaluate local control after 21-Gy radiation therapy (RT) to the primary site in patients with high-risk neuroblastoma. Methods and Materials After receiving dose-intensive chemotherapy and gross total resection (GTR), 246 patients (aged 1.2-17.9 years, median 4.0 years) with high-risk neuroblastoma underwent RT to the primary site at Memorial Sloan Kettering from 2000 to 2014. Radiation therapy consisted of 21 Gy in twice-daily fractions of 1.5 Gy each. Local failure (LF) was correlated with biologic prognostic factors and clinical findings at the time of diagnosis and start of RT. Results Median follow-up of surviving patients was 6.4 years. Cumulative incidence of LF was 7.1% at 2 years after RT and 9.8% at 5 years after RT. The isolated LF rate was 3.0%. Eighty-six percent of all local failures were within the RT field. Local control was worse in patients who required more than 1 surgical resection to achieve GTR (22.4% vs 8.3%, P =.01). There was also a trend toward inferior local control with MYCN- amplified tumors or serum lactate dehydrogenase ≥1500 U/L ( P =.09 and P =.06, respectively). Conclusion After intensive chemotherapy and maximal surgical debulking, hyperfractionated RT with 21 Gy in high-risk neuroblastoma results in excellent local control. Given the young patient age, concern for late effects, and local control >90%, dose reduction may be appropriate for patients without MYCN amplification who achieve GTR.
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- 2016
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11. A phase I/Ib trial targeting the Pi3k/Akt pathway using perifosine: Long-term progression-free survival of patients with resistant neuroblastoma
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Stephen S. Roberts, Nai-Kong V. Cheung, Shakeel Modak, Oren J. Becher, Ira J. Dunkel, Ellen M. Basu, Brian H. Kushner, and Kim Kramer
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0301 basic medicine ,Oncology ,Cancer Research ,medicine.medical_specialty ,business.industry ,Standard treatment ,Salvage therapy ,Pharmacology ,Perifosine ,medicine.disease ,03 medical and health sciences ,chemistry.chemical_compound ,030104 developmental biology ,0302 clinical medicine ,chemistry ,030220 oncology & carcinogenesis ,Internal medicine ,Toxicity ,Medicine ,Progression-free survival ,business ,Protein kinase B ,PI3K/AKT/mTOR pathway ,Progressive disease - Abstract
AKT plays a pivotal role in driving the malignant phenotype of many cancers, including high-risk neuroblastoma (HR-NB). AKT signaling, however, is active in normal tissues, raising concern about excessive toxicity from its suppression. The oral AKT inhibitor perifosine showed tolerable toxicity in adults and in our phase I trial in children with solid tumors (clinicaltrials.gov NCT00776867). We now report on the HR-NB experience. HR-NB patients received perifosine 50-75mg/m2/day after a loading dose of 100-200mg/m2 on day 1, and continued on study until progressive disease. The 27 HR-NB patients included three treated for primary refractory disease and 24 with disease resistant to salvage therapy after 1-5 (median 2) relapses; only one had MYCN-amplified HR-NB. Pharmacokinetic studies showed μM concentrations consistent with cytotoxic levels in preclinical models. Nine patients (all MYCN-non-amplified) remained progression-free through 43+ to 74+ (median 54+) months from study entry, including the sole patient to show a complete response and eight patients who had persistence of abnormal 123I-metaiodobenzylguanidine skeletal uptake but never developed progressive disease. Toxicity was negligible in all 27 patients, even with the prolonged treatment (11-to-62 months, median 38) in the nine long-term progression-free survivors. The clinical findings 1) confirm the safety of therapeutic serum levels of an AKT inhibitor in children; 2) support perifosine for MYCN-non-amplified HR-NB as monotherapy after completion of standard treatment or combined with other agents (based on preclinical studies) to maximize antitumor effects; and 3) highlight the welcome possibility that refractory or relapsed MYCN-non-amplified HR-NB is potentially curable. This article is protected by copyright. All rights reserved.
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- 2016
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12. Enigmatic entities: opsoclonus myoclonus ataxia syndrome linked to neuroblastoma
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Yasmin Khakoo and Brian H. Kushner
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Pathology ,medicine.medical_specialty ,Opsoclonus-Myoclonus Syndrome ,business.industry ,Opsoclonus Myoclonus Ataxia ,Immunoglobulins, Intravenous ,medicine.disease ,Neuroblastoma ,03 medical and health sciences ,0302 clinical medicine ,030220 oncology & carcinogenesis ,Pediatrics, Perinatology and Child Health ,Developmental and Educational Psychology ,Humans ,Prednisone ,Medicine ,Ataxia ,Child ,business ,030217 neurology & neurosurgery - Published
- 2018
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13. 74P Pivotal trial 201 data on outpatient administration of naxitamab (Hu3F8), a humanized GD2 targeted immunotherapy for the treatment of refractory/relapsed (R/R) high-risk (HR) neuroblastoma (NB)
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Brian H. Kushner, Daniel Morgenstern, Jaume Mora, L. Worsaae Dalby, Melissa K. Bear, Godfrey Chi-Fung Chan, Steen Lisby, and Karsten Nysom
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Oncology ,medicine.medical_specialty ,Refractory ,business.industry ,Neuroblastoma ,Internal medicine ,Medicine ,Hematology ,business ,medicine.disease ,Targeted immunotherapy - Published
- 2020
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14. 75P Efficacy and updated safety results from pivotal phase II trial 201 of naxitamab (Hu3F8): A humanized GD2-targeted immunotherapy for the treatment of refractory/relapsed (R/R) high-risk (HR) neuroblastoma (NB)
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Jaume Mora, Karsten Nysom, Daniel Morgenstern, Godfrey Chi-Fung Chan, Melissa K. Bear, L. Worsaae Dalby, Steen Lisby, and Brian H. Kushner
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Oncology ,medicine.medical_specialty ,Refractory ,business.industry ,Internal medicine ,Neuroblastoma ,medicine ,Hematology ,business ,medicine.disease ,Targeted immunotherapy - Published
- 2020
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15. Long-term Survivors Receive Multimodality Treatment of Second Central Nervous System Relapse in Pediatric Patients with Neuroblastoma
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Kathryn R. Tringale, Brian H. Kushner, Dana L. Casey, Suzanne L. Wolden, L. Luo, and Kim Kramer
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Oncology ,Cancer Research ,medicine.medical_specialty ,Radiation ,business.industry ,Multimodality Treatment ,Central nervous system ,medicine.disease ,Term (time) ,medicine.anatomical_structure ,Internal medicine ,Neuroblastoma ,medicine ,Radiology, Nuclear Medicine and imaging ,business - Published
- 2020
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16. Abstract LB-092: Survival impact of anti-GD2 antibody response - A phase II ganglioside vaccine trial in relapsed neuroblastoma
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Govind Ragupathi, Ellen M. Basu, Irene Y. Cheung, Audrey Mauguen, Stephen S. Roberts, Brian H. Kushner, Nai-Kong V. Cheung, and Shakeel Modak
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Cancer Research ,medicine.medical_specialty ,Prognostic variable ,business.industry ,medicine.medical_treatment ,Hazard ratio ,Vaccine trial ,Antibody titer ,Dinutuximab ,Salvage therapy ,Gastroenterology ,Oncology ,Internal medicine ,Medicine ,Seroconversion ,business ,Adjuvant - Abstract
Background and Aim: High-risk neuroblastoma (HR-NB) relapse carries a dismal prognosis. Recent experience, however, suggests that cure is possible when remission is achieved with salvage therapy that includes anti-GD2 monoclonal antibody (mAb). The long-term survival and the favorable safety profile of gangliosides GD2 and GD3 vaccine among these patients in a Phase I trial (n=15, Clinical Cancer Res 2014) need to be confirmed. Moreover, the kinetics of seroconversion (mounting anti-vaccine antibody response) and its prognostic impact on survival need to be explored. Patients and Methods: In this Phase II trial (Clinicaltrials.gov NCT00911560), 102 HR-NB patients who achieved complete remission after salvage therapy were enrolled. They received 7 subcutaneous vaccine injections (week 1-2-3-8-20-32-52) plus oral beta-glucan (starting in week 6 at 40 mg/kg/day, 14 days on/14 days off). Each subcutaneous vaccine injection consisted of 30 µg each of GD2 and GD3, lactonized and conjugated to keyhole limpet hemocyanin and mixed with the saponin OPT-821 adjuvant. Serum anti-vaccine antibody titers were quantified by ELISA. Kaplan-Meier statistics and landmark Cox Regression models were used for survival estimates and prognostic impact analyses. Results: Among 102 patients, 63% had one, 21% had 2, and 16% had 3-6 prior disease progressions. 83/101 patients had failed prior anti-GD2 mAb (m3F8, dinutuximab, or naxitamab) therapy before vaccine: one mAb (n=62), two mAbs (n=15), or all three (n=6). Common toxicities were self-limited injection-related local reactions and fever. No pain, neuropathy, or grade 3/4 toxicities occurred during or post treatment. Progression-free survival (PFS) was 44%±5% and overall survival (OS) was 88%±4% at 2 years, and 36%±7% and 70%±8% at 5 years, respectively. Serum anti-GD2 (IgG1 and IgM) and anti-GD3 (IgG1) titers had marked increases following the initiation of beta-glucan at week 6. In univariate analyses, favorable prognostic factors included: one versus ≥2 prior disease progressions (PFS p=0.005, OS p=0.04), none versus any prior anti-GD2 mAb failures (PFS p=0.004, OS p=0.01); and the induction of ≥150 ng/ml anti-GD2-IgG1 titers by week 8 (PFS p=0.02, OS p=0.06). Factors not prognostic included: time to first NB progression, MYCN amplification status, anti-GD2-IgM, anti-GD3-IgG1 or anti-KLH-IgG1 titers, and treatment with anti-GD2 mAb right before vaccine. In multivariate analyses, week 8 anti-GD2-IgG1 titer ≥150 ng/ml yielded a hazard ratio (HR) of 0.41 [0.20, 0.83], p=0.01 for PFS, and HR=0.15 [0.02, 1.12], p=0.06 for OS. The second independent prognostic variable was the number of prior disease progressions (≥2 vs 1), yielding HR of 2.12 [1.26, 3.58], p=0.005 for PFS, and HR=2.77 (1.03, 7.47), p=0.04 for OS. Conclusions: Even with prior disease progressions, anti-GD2 (though not anti-GD3) seroconversion was associated with notable long-term survival among HR-NB patients previously thought to be unsalvageable. A randomized trial to assess the role of beta-glucan in seroconversion is actively accruing patients. Citation Format: Irene Y. Cheung, Nai-Kong V. Cheung, Shakeel Modak, Audrey Mauguen, Ellen Basu, Stephen S. Roberts, Govind Ragupathi, Brian H. Kushner. Survival impact of anti-GD2 antibody response - A phase II ganglioside vaccine trial in relapsed neuroblastoma [abstract]. In: Proceedings of the Annual Meeting of the American Association for Cancer Research 2020; 2020 Apr 27-28 and Jun 22-24. Philadelphia (PA): AACR; Cancer Res 2020;80(16 Suppl):Abstract nr LB-092.
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- 2020
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17. Reduced-dose Radiation Therapy to the Primary Site is Effective for High-risk Neuroblastoma: Results from a Prospective Trial
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Nai-Kong V. Cheung, Michael P. LaQuaglia, Shakeel Modak, Ellen M. Basu, Suzanne L. Wolden, Dana L. Casey, Stephen S. Roberts, and Brian H. Kushner
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Oncology ,Male ,Cancer Research ,medicine.medical_specialty ,medicine.medical_treatment ,Article ,030218 nuclear medicine & medical imaging ,03 medical and health sciences ,Neuroblastoma ,0302 clinical medicine ,Internal medicine ,medicine ,Proton Therapy ,Humans ,Radiology, Nuclear Medicine and imaging ,Progression-free survival ,Prospective Studies ,Prospective cohort study ,Child ,Survival rate ,Postoperative Care ,Radiation ,business.industry ,Dose fractionation ,Induction chemotherapy ,Infant ,Induction Chemotherapy ,medicine.disease ,Primary tumor ,Progression-Free Survival ,Radiation therapy ,Clinical trial ,Survival Rate ,030220 oncology & carcinogenesis ,Child, Preschool ,Female ,Dose Fractionation, Radiation ,Radiotherapy, Intensity-Modulated ,business - Abstract
Purpose For patients with high-risk neuroblastoma (HR-NB), a dose of 21 Gy to the primary tumor site after gross total resection (GTR) provides excellent local control. However, no clinical trial has specifically evaluated the optimal dose of radiation therapy (RT), and RT-related long-term toxicities are of increasing concern. We sought to assess local control, survival outcomes, and toxicity after a reduction in dose to the primary site from 21 Gy to 18 Gy. Methods and Materials After induction chemotherapy and GTR, patients with HR-NB were enrolled and treated on an RT dose-reduction prospective trial with 18 Gy hyperfractionated RT given in twice-daily fractions of 1.5 Gy each. Results The 25 study subjects were 1.6 to 9.5 (median, 4.3) years old at enrollment and included 23 (92%) with stage IV and II (8%) with MYCN-amplified stage III disease. Eleven (44%) were in complete remission (CR), and 14 (56%) had persistence of osteomedullary disease postinduction. Three patients (12%) received proton therapy, and the rest received intensity modulated photon therapy. After a follow-up of 1.8 to 4.2 (median, 3.5) years from initiation of RT, no failures occurred within the RT field; 3 patients had marginal recurrences. The respective 3-year progression-free and overall survival rates were 54.5% and 90.9% for patients in first CR and 42.9% and 76.2% for patients not in metastatic CR. Acute toxicity was negligible. Conclusions Reduced-dose RT with 18 Gy did not compromise local control or survival outcomes in our cohort of patients with HR-NB after GTR. These findings support assessing further RT dose reduction and validation on a larger, multi-institutional trial.
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- 2019
18. Bevacizumab-Associated Bowel Microperforation in a Patient with Neuroblastoma
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Shakeel Modak, Brian H. Kushner, Michael P. LaQuaglia, Anita P. Price, and Rachel Glincher
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0301 basic medicine ,Male ,medicine.medical_specialty ,Bevacizumab ,medicine.medical_treatment ,Acute abdominal pain ,Bowel perforation ,Article ,03 medical and health sciences ,Neuroblastoma ,0302 clinical medicine ,Laparotomy ,medicine ,Pediatric oncology ,Humans ,business.industry ,Hematology ,Radioimmunotherapy ,medicine.disease ,Surgery ,030104 developmental biology ,Oncology ,Intestinal Perforation ,030220 oncology & carcinogenesis ,Child, Preschool ,Pediatrics, Perinatology and Child Health ,business ,Early phase ,Tomography, X-Ray Computed ,medicine.drug - Abstract
The antivascular endothelial growth factor antibody, bevacizumab, is effective against several malignancies in adults but unproven in pediatric oncology. In early phase pediatric studies toxicities were similar to those in adults. Bowel perforation in adults is a rare but serious toxicity, but has not been hitherto reported in children. A 5-year-old boy with chemoresistant neuroblastoma treated with bevacizumab plus radioimmunotherapy developed acute abdominal pain. Computed tomography scan showed free abdominal air and pneumatosis coli. Emergency laparotomy and bowel diversion were performed leading to complete recovery and timely continuation of antineuroblastoma therapy. Early recognition and rapid intervention can prevent a catastrophic outcome in bevacizumab-related bowel perforation.
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- 2018
19. Arsenic Trioxide as a Radiation Sensitizer for 131I-Metaiodobenzylguanidine Therapy: Results of a Phase II Study
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Neeta Pandit-Taskar, Pat Zanzonico, Kim Kramer, Brian H. Kushner, Nai-Kong V. Cheung, Shakeel Modak, Steven M. Larson, and Jorge A. Carrasquillo
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inorganic chemicals ,Adult ,Male ,Radiation-Sensitizing Agents ,medicine.medical_specialty ,Adolescent ,Dose ,medicine.medical_treatment ,Adrenal Gland Neoplasms ,Phases of clinical research ,Pheochromocytoma ,Gastroenterology ,Article ,Arsenicals ,030218 nuclear medicine & medical imaging ,Paraganglioma ,Neuroblastoma ,03 medical and health sciences ,chemistry.chemical_compound ,0302 clinical medicine ,Arsenic Trioxide ,Internal medicine ,medicine ,Humans ,Radiology, Nuclear Medicine and imaging ,Arsenic trioxide ,Child ,Adverse effect ,Chemotherapy ,integumentary system ,Brain Neoplasms ,business.industry ,Oxides ,medicine.disease ,Survival Analysis ,Surgery ,3-Iodobenzylguanidine ,Treatment Outcome ,chemistry ,Drug Resistance, Neoplasm ,Child, Preschool ,030220 oncology & carcinogenesis ,Toxicity ,Female ,Radiopharmaceuticals ,business ,Progressive disease - Abstract
Arsenic trioxide has in vitro and in vivo radiosensitizing properties. We hypothesized that arsenic trioxide would enhance the efficacy of the targeted radiotherapeutic agent 131I-metaiodobenzylguanidine (131I-MIBG) and tested the combination in a phase II clinical trial. Methods: Patients with recurrent or refractory stage 4 neuroblastoma or metastatic paraganglioma/pheochromocytoma (MP) were treated using an institutional review board–approved protocol (Clinicaltrials.gov identifier NCT00107289). The planned treatment was 131I-MIBG (444 or 666 MBq/kg) intravenously on day 1 plus arsenic trioxide (0.15 or 0.25 mg/m2) intravenously on days 6–10 and 13–17. Toxicity was evaluated using National Cancer Institute Common Toxicity Criteria, version 3.0. Response was assessed by International Neuroblastoma Response Criteria or (for MP) by changes in 123I-MIBG or PET scans. Results: Twenty-one patients were treated: 19 with neuroblastoma and 2 with MP. Fourteen patients received 131I-MIBG and arsenic trioxide, both at maximal dosages; 2 patients received a 444 MBq/kg dose of 131I-MIBG plus a 0.15 mg/kg dose of arsenic trioxide; and 3 patients received a 666 MBq/kg dose of 131I-MIBG plus a 0.15 mg/kg dose of arsenic trioxide. One did not receive arsenic trioxide because of transient central line–induced cardiac arrhythmia, and another received only 6 of 10 planned doses of arsenic trioxide because of grade 3 diarrhea and vomiting with concurrent grade 3 hypokalemia and hyponatremia. Nineteen patients experienced myelosuppression higher than grade 2, most frequently thrombocytopenia (n = 18), though none required autologous stem cell rescue. Twelve of 13 evaluable patients experienced hyperamylasemia higher than grade 2 from transient sialoadenitis. By International Neuroblastoma Response Criteria, 12 neuroblastoma patients had no response and 7 had progressive disease, including 6 of 8 entering the study with progressive disease. Objective improvements in semiquantitative 131I-MIBG scores were observed in 6 patients. No response was seen in MP. Seventeen of 19 neuroblastoma patients continued on further chemotherapy or immunotherapy. Mean 5-year overall survival (±SD) for neuroblastoma was 37% ± 11%. Mean absorbed dose of 131I-MIBG to blood was 0.134 cGy/MBq, well below myeloablative levels in all patients. Conclusion:131I-MIBG plus arsenic trioxide was well tolerated, with an adverse event profile similar to that of 131I-MIBG therapy alone. The addition of arsenic trioxide to 131I-MIBG did not significantly improve response rates when compared with historical data with 131I-MIBG alone.
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- 2016
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20. Desmoplastic small round cell tumor 20 years after its discovery
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Oscar M. Tirado, Shakeel Modak, Heather Magnan, Nai-Kong V. Cheung, Jaume Mora, Michael P. LaQuaglia, Juan Rosai, Paul A. Meyers, Brian H. Kushner, Enrique de Alava, and Marc Ladanyi
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Cancer Research ,Round cells ,Pathology ,medicine.medical_specialty ,Disease entity ,Tumor suppressor gene ,Desmoplastic small-round-cell tumor ,business.industry ,Mesenchymal stem cell ,General Medicine ,Abdominal cavity ,Desmoplastic Small Round Cell Tumor ,History, 20th Century ,medicine.disease ,History, 21st Century ,medicine.anatomical_structure ,Oncology ,Stroma ,Abdominal Neoplasms ,Humans ,Medicine ,Disseminated disease ,business - Abstract
ABSTRACT Desmoplastic small round cell tumor (DSRCT) was proposed as a distinct disease entity by William L Gerald and Juan Rosai in 1991. Over 850 patients have been reported in the medical literature. A specific translocation, t(11;22)(p13;q12), is seen in almost all cases, juxtaposing the EWS gene to the WT1 tumor suppressor gene. DSRCT is composed of nests of small round cells with polyphenotypic differentiation, typically a mixture of epithelial, mesenchymal and neural features, surrounded by a prominent desmoplastic stroma. DSRCT has a predilection for adolescent and young adult males, and primarily involves the abdominal cavity and pelvis. Survival is low despite their initial response to multimodal treatment. Most patients relapse with disseminated disease that is unresponsive to further therapy.
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- 2015
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21. Radiation Therapy to Sites of Metastatic Disease as Part of Consolidation in High-Risk Neuroblastoma: Can Long-term Control Be Achieved?
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Michael P. LaQuaglia, Kenneth L. Pitter, Nai-Kong V. Cheung, Shakeel Modak, Dana L. Casey, Suzanne L. Wolden, and Brian H. Kushner
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0301 basic medicine ,Oncology ,Male ,Cancer Research ,medicine.medical_specialty ,Time Factors ,Adolescent ,medicine.medical_treatment ,Adrenal Gland Neoplasms ,Bone Neoplasms ,Soft Tissue Neoplasms ,Disease ,Bone and Bones ,Article ,03 medical and health sciences ,Neuroblastoma ,0302 clinical medicine ,Internal medicine ,medicine ,Humans ,Radiology, Nuclear Medicine and imaging ,High risk neuroblastoma ,Child ,Retrospective Studies ,Chemotherapy ,Radiation ,business.industry ,Induction chemotherapy ,Infant ,Retrospective cohort study ,Consolidation Chemotherapy ,Induction Chemotherapy ,Thoracic Neoplasms ,medicine.disease ,Radiation therapy ,030104 developmental biology ,030220 oncology & carcinogenesis ,Abdominal Neoplasms ,Child, Preschool ,Multivariate Analysis ,Feasibility Studies ,Female ,Neoplasm Recurrence, Local ,business ,Follow-Up Studies - Abstract
PURPOSE: As part of consolidative therapy in high-risk neuroblastoma, modern protocols recommend radiation therapy (RT) both to the primary site and to sites of metastatic disease that persist after induction chemotherapy. Although there are abundant data showing excellent local control (LC) with 21 Gy directed at the primary site, there are few data describing the feasibility and efficacy of RT directed at metastatic sites of disease as part of consolidation. METHODS AND MATERIALS: All patients with neuroblastoma who received RT to metastatic sites of disease as a part of consolidative therapy at a single institution between 2000 and 2015 were reviewed. Among 159 patients, 244 metastases were irradiated. RESULTS: The median follow-up period among surviving patients was 7.4 years. Over 85% of the irradiated metastases were treated with 21 Gy (range, 10.5-36 Gy). Tumor recurrence occurred in 43 of 244 irradiated metastases (18%). The 5-year LC rate of treated metastatic sites was 81%. Metastatic sites that cleared with induction chemotherapy had improved LC compared with sites with persistent uptake on metaiodobenzylguanidine scans (LC rate, 92% vs 67%; P
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- 2017
22. Key role for myeloid cells: Phase II results of anti-GD2antibody 3F8 plus granulocyte-macrophage colony-stimulating factor for chemoresistant osteomedullary neuroblastoma
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Irina Ostrovnaya, Irene Y. Cheung, Shakeel Modak, Deborah Kuk, Nai-Kong V. Cheung, Neeta Pandit-Taskar, Brian H. Kushner, Elizabeth Chamberlain, and Kim Kramer
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Oncology ,Cancer Research ,medicine.medical_specialty ,Myeloid ,business.industry ,medicine.medical_treatment ,Immunotherapy ,medicine.disease ,Minimal residual disease ,medicine.anatomical_structure ,Granulocyte macrophage colony-stimulating factor ,Internal medicine ,Neuroblastoma ,Immunology ,medicine ,Bone marrow ,business ,Survival rate ,Progressive disease ,medicine.drug - Abstract
Anti-G(D2) murine antibody 3F8 plus subcutaneously (sc) administered granulocyte-macrophage colony-stimulating factor (GM-CSF) was used against primary refractory neuroblastoma in metastatic osteomedullary sites. Large study size and long follow-up allowed assessment of prognostic factors in a multivariate analysis not reported with other anti-G(D2) antibodies. In a phase II trial, 79 patients without prior progressive disease were treated for persistent osteomedullary neuroblastoma documented by histology and/or metaiodobenzyl-guanidine (MIBG) scan. In the absence of human antimouse antibody, 3F8 + scGM-CSF cycles were repeated up to 24 months. Minimal residual disease (MRD) in bone marrow was measured by quantitative reverse transcription-polymerase chain reaction pre-enrollment and post-cycle #2, before initiation of 13-cis-retinoic acid. Study endpoints were: (i) progression-free survival (PFS) compared with the predecessor trial of 3F8 plus intravenously administered (iv) GM-CSF (26 patients) and (ii) impact of MRD on PFS. Using all 105 patients from the two consecutive 3F8 + GM-CSF trials, prognostic factors were analyzed by multivariate Cox regression model. Complete response rates to 3F8 + scGM-CSF were 87% by histology and 38% by MIBG. Five-year PFS was 24 ± 6%, which was significantly superior to 11 ± 7% with 3F8 + ivGM-CSF (p = 0.002). In the multivariate analysis, significantly better PFS was associated with R/R or H/R FCGR2A polymorphism, sc route of GM-CSF and early MRD response. MYCN amplification was not prognostic. Complement consumption was similar with either route of GM-CSF. Toxicities were manageable, allowing outpatient treatment. 3F8 + scGM-CSF is highly active against chemoresistant osteomedullary neuroblastoma. MRD response may be an indicator of tumor sensitivity to anti-G(D2) immunotherapy. Correlative studies highlight the antineoplastic potency of myeloid effectors.
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- 2014
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23. Striking dichotomy in outcome ofMYCN-amplified neuroblastoma in the contemporary era
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Kim Kramer, Shakeel Modak, Michael P. LaQuaglia, Stephen S. Roberts, Karima Yataghene, Nai-Kong V. Cheung, Brian H. Kushner, and Ellen M. Basu
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Very Good Partial Response ,Oncology ,Cancer Research ,medicine.medical_specialty ,Pathology ,business.industry ,Induction chemotherapy ,Cancer ,Retrospective cohort study ,medicine.disease ,Internal medicine ,Neuroblastoma ,Cohort ,medicine ,Stage (cooking) ,business ,neoplasms ,Progressive disease - Abstract
BACKGROUND The authors exploited a large database to investigate the outcomes of patients with high-risk neuroblastoma in the contemporary era. METHODS All patients with high-risk neuroblastoma aged 18 months with MYCN-nonamplified [MYCN(−)] stage 4 disease. RESULTS A complete response/very good partial response (CR/VGPR) to induction was correlated with significantly superior event-free survival (EFS) (P
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- 2014
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24. Phase I Trial of a Bivalent Gangliosides Vaccine in Combination with β-Glucan for High-Risk Neuroblastoma in Second or Later Remission
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Kim Kramer, Shakeel Modak, Irene Y. Cheung, Nai-Kong V. Cheung, Brian H. Kushner, and Govind Ragupathi
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Male ,Cancer Research ,medicine.medical_specialty ,Neoplasm, Residual ,beta-Glucans ,Adolescent ,medicine.drug_class ,medicine.medical_treatment ,Cancer Vaccines ,Immunostimulant ,Gastroenterology ,Article ,Neuroblastoma ,Antigens, Neoplasm ,Gangliosides ,Internal medicine ,medicine ,Humans ,Outpatient clinic ,Dosing ,Child ,Neoplasm Staging ,Radiotherapy ,biology ,business.industry ,Remission Induction ,Immunotherapy ,Minimal residual disease ,Surgery ,Treatment Outcome ,Oncology ,Child, Preschool ,Immunologic adjuvant ,Toxicity ,biology.protein ,Female ,Neoplasm Recurrence, Local ,business ,Keyhole limpet hemocyanin - Abstract
Purpose: To report on a phase I trial designed to find the maximally tolerated dose in children of the immunologic adjuvant OPT-821 in a vaccine containing neuroblastoma-associated antigens (GD2 and GD3; Clinicaltrials.gov NCT00911560). Secondary objectives were to obtain preliminary data on immune response and activity against minimal residual disease (MRD). Treatment also included the immunostimulant β-glucan. Experimental Design: Patients with neuroblastoma in ≥2nd complete/very good partial remission received vaccine subcutaneously (weeks 1–2–3–8–20–32–52). Vaccine contained 30 μg each of GD2 and GD3 stabilized as lactones and conjugated to the immunologic carrier protein keyhole limpet hemocyanin; and OPT-821, which was dose escalated as 50, 75, 100, and 150 μg/m2 per injection. Oral β-glucan (40 mg/kg/day, 14 days on/14 days off) started week 6. Results: The study was completed with 15 patients because there was no dose-limiting toxicity at 150 μg/m2 of OPT-821 (the dosing used in adults). Thirteen of fifteen patients received the entire protocol treatment, including 12 who remain relapse-free at 24+ to 39+ (median 32+) months and 1 who relapsed (single node) at 21 months. Relapse-free survival was 80% ± 10% at 24 months. Vaccine and β-glucan were well tolerated. Twelve of fifteen patients had antibody responses against GD2 and/or GD3. Disappearance of MRD was documented in 6 of 10 patients assessable for response. Conclusions: This immunotherapy program lacks major toxicity and is transportable to any outpatient clinic. Patient outcome is encouraging but the efficacy is uncertain because of the complexity and heterogeneity of prior therapies. A larger phase II trial is underway. Clin Cancer Res; 20(5); 1375–82. ©2014 AACR.
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- 2014
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25. Naxitamab-based chemoimmunotherapy for resistant high-risk neuroblastoma: Preliminary results of HITS pilot/phase II study
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Shakeel Modak, Vicente Santa-Maria, Ellen M. Basu, Moira Garraus, Brian H. Kushner, Nai-Kong V. Cheung, Miguel Angel Flores, Alicia Castañeda, Maite Gorostegui, Stephen S. Roberts, and Jaume Mora
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Oncology ,Pilot phase ,Cancer Research ,medicine.medical_specialty ,business.industry ,medicine.drug_class ,RELAPSED DISEASE ,medicine.disease ,Monoclonal antibody ,03 medical and health sciences ,0302 clinical medicine ,Chemoimmunotherapy ,030220 oncology & carcinogenesis ,Neuroblastoma ,Internal medicine ,medicine ,Remi ,High risk neuroblastoma ,business ,030215 immunology - Abstract
10025 Background: Chemoresistant and relapsed disease are major obstacles to curing high-risk neuroblastoma (HR-NB). Anti-GD2 monoclonal antibody (MoAb) is effective in preventing relapse after remission but responses in relapsed or progressive disease (PD) are rare. We investigated the combination of humanized anti-GD2 MoAb naxitamab, (previously termed Hu3F8), irinotecan, temozolomide and sargramostim (GM-CSF): a pilot HITS protocol against resistant HR-NB now expanded to a phase II study (NCT03189706). Methods: Salient eligibility criteria included evaluable or measurable chemoresistant disease. Prior anti-GD2 MoAb and/or irinotecan/temozolomide (I/T) therapy was permitted. Each cycle comprised of irinotecan 50 mg/m2/day intravenously (IV) plus temozolomide 150 mg/m2/day IV or orally (days 1-5); naxitamab 2.25 mg/kg/day IV over 30 minutes, days 2, 4, 8 and 10 (total 9 mg/kg or 270 mg/m2 per cycle), and GM-CSF 250 mg/m2/day subcutaneously, days 6-10. Toxicity was measured by CTCAE v4.0 and responses by modified International Neuroblastoma Response Criteria. Results: Forty-six (23 enrolled on protocol and 23 on compassionate-use basis) heavily prior-treated patients (median age at enrollment: 6.6 years; median number of prior relapses: 2) have received 175 (median 2; range 1-12) cycles to date. At enrollment, 7 patients had HR-NB refractory to induction chemotherapy while 39 had prior relapse. Toxicities included myelosuppression and diarrhea expected with I/T, and pain and hypertension expected with naxitamab. No other > grade 2 related toxicities occurred; treatment was outpatient. Early responses, assessed after 2 cycles, were documented in 18 (39%) patients and were complete (n = 9), partial (n = 8), and mixed (n = 1); 13 patients had stable disease. Responses were achieved in refractory (3/7;43%) and PD (15/39;38%) subgroups, in patients who had previously received I/T (12/34;35%) and/or anti-GD2 MoAb (14/36;39%), and in soft tissue (6/22; 27%) MIBG-avid skeletal sites (20/36;56%) and on bone marrow histology (9/12; 75%). Conclusions: High-dose naxitamab-based chemoimmunotherapy is safe and effective against chemoresistant HR-NB. This ongoing phase II study may define a broader role for naxitamab which was recently granted breakthrough designation by the FDA. Clinical trial information: NCT03189706.
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- 2019
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26. Short-Interval Retreatment With Stereotactic Body Radiotherapy (SBRT) for Pediatric Neuroblastoma Resulting in Severe Myositis
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Katarzyna Ibanez, Neil K. Taunk, Brian H. Kushner, and Suzanne L. Wolden
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medicine.medical_specialty ,business.industry ,medicine.medical_treatment ,Hematology ,medicine.disease ,Short interval ,Pediatric cancer ,Radiosurgery ,030218 nuclear medicine & medical imaging ,Radiation therapy ,03 medical and health sciences ,0302 clinical medicine ,Oncology ,030220 oncology & carcinogenesis ,Neuroblastoma ,Pediatrics, Perinatology and Child Health ,medicine ,Combined Modality Therapy ,Medical physics ,Radiology ,business ,Stereotactic body radiotherapy ,Myositis - Abstract
We report a severe and not previously reported toxicity after short-interval retreatment with stereotactic body radiotherapy (SBRT) in a pediatric patient with neuroblastoma. This patient experienced Grade III radiation myositis after treatment with conventional radiation therapy followed by high-dose SBRT for persistent disease a short interval after the initial radiotherapy course. While SBRT shows outstanding rates of local control in adult disease, data in pediatric cancers are extremely limited. In this report, we discuss the rationale of SBRT in this patient's multimodality neuroblastoma treatment, management of the toxicity, and future perspectives on the use of SBRT in pediatric cancer.
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- 2016
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27. Posterior reversible encephalopathy syndrome in neuroblastoma patients receiving anti-GD23F8 monoclonal antibody
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Ellen M. Basu, Stephen S. Roberts, Shakeel Modak, Kim Kramer, Nai-Kong V. Cheung, and Brian H. Kushner
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Cancer Research ,medicine.medical_specialty ,medicine.diagnostic_test ,business.industry ,medicine.medical_treatment ,Cancer ,Posterior reversible encephalopathy syndrome ,Magnetic resonance imaging ,Total body irradiation ,medicine.disease ,Gastroenterology ,Surgery ,Radiation therapy ,Oncology ,Posterior Leukoencephalopathy Syndrome ,Neuroblastoma ,Internal medicine ,medicine ,Headaches ,medicine.symptom ,business - Abstract
BACKGROUND Posterior reversible encephalopathy syndrome (PRES) comprises clinical and radiologic findings with rapid onset and potentially dire consequences. Patients experience hypertension, seizures, headache, visual disturbance, and/or altered mentation. Magnetic resonance imaging reveals edematous changes in the brain (especially in the parietal and occipital lobes). In this report, the authors describe PRES associated with antidisialoganglioside (anti-GD2) monoclonal antibody (MoAb) immunotherapy, which is now standard for high-risk neuroblastoma but has not previously been implicated in PRES. METHODS Successive clinical trials using the anti-GD2 MoAb 3F8 (a murine immunoglobulin 3 MoAb specific for GD2) for patients with neuroblastoma involved multiple cycles of standard-dose 3F8 (SD-3F8) (20 mg/m2 daily for 5 days per cycle) or 2 cycles of high-dose 3F8 (HD-3F8) (80 mg/m2 daily for 5 days per cycle) followed by cycles of SD-3F8. RESULTS PRES was diagnosed in 5 of 215 patients (2.3%), including 3 of 160 (1.9%) who received SD-3F8 and 2 of 55 (3.6%) who received HD-3F8 (P = .6). All 5 patients had a rapid return to clinical-radiologic baseline. PRES occurred in 3 of 26 patients (11.5%) whose prior treatment included external-beam radiotherapy to the brain (2 of 6 patients status-post total body irradiation and 1 of 20 patients status-post craniospinal irradiation) compared with 2 of 189 patients (1.1%) who had not received prior brain irradiation (P = .01). Hypertension, which is strongly linked to PRES, reached grade 3 toxicity in 12 of 215 patients (5.6%), including the 5 patients with PRES and 7 patients without PRES. CONCLUSIONS Patients who receive anti-GD2 MoAb immunotherapy should be closely monitored for, and undergo urgent treatment or evaluation of, symptoms that may herald PRES (eg, hypertension or headaches). Prior brain irradiation may be a predisposing factor for PRES with this immunotherapy. Cancer 2013;119:2789–2795. © 2013 American Cancer Society.
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- 2013
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28. Renal Function Outcomes of High-risk Neuroblastoma Patients Undergoing Radiation Therapy
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Thomas H. Beckham, Shakeel Modak, Suzanne L. Wolden, Dana L. Casey, Michael P. LaQuaglia, and Brian H. Kushner
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Male ,Cancer Research ,medicine.medical_specialty ,Adolescent ,medicine.medical_treatment ,Urology ,Renal function ,Kidney ,Nephrectomy ,Article ,Blood Urea Nitrogen ,03 medical and health sciences ,chemistry.chemical_compound ,Neuroblastoma ,Young Adult ,0302 clinical medicine ,medicine ,Humans ,Radiology, Nuclear Medicine and imaging ,Renal Insufficiency, Chronic ,Child ,Blood urea nitrogen ,Retrospective Studies ,Creatinine ,Radiation ,business.industry ,Infant ,Retrospective cohort study ,Surgery ,Radiation therapy ,medicine.anatomical_structure ,Oncology ,chemistry ,030220 oncology & carcinogenesis ,Child, Preschool ,Cohort ,Female ,Radiotherapy, Intensity-Modulated ,business ,030217 neurology & neurosurgery ,Follow-Up Studies - Abstract
Purpose To analyze the renal function outcomes in patients undergoing radiation therapy for neuroblastoma. Methods and Materials The clinical metrics of renal function were analyzed in patients undergoing radiation therapy for high-risk neuroblastoma from 2000 to 2015. The blood urea nitrogen (BUN) and creatinine values before radiation therapy were compared with last available follow-up values and analyzed with the clinical circumstances, including follow-up length, age at primary irradiation, nephrectomy, and radiation technique. The creatinine clearance was estimated using the Shull method. Results With a median follow-up period of 3.5 years, none of the 266 patients studied developed a chronic renal insufficiency. For all patients, the creatinine level increased from 0.44 to 0.51 mg/dL and the BUN increased from 10.53 to 15.52 mg/dL. Three patients required antihypertensive medication. The patients who underwent intensity modulated radiation therapy did not experience increased creatinine levels during the follow-up period; however, they had a reduced median follow-up length compared with patients treated with anteroposterior/posteroanterior beams (4.7 vs 3.3 years). A longer follow-up length was associated with an increased creatinine level. The preradiation therapy creatinine level increased with patient age, similar to that of the last follow-up creatinine level, suggesting that the changes in creatinine could likely be explained by physiologic increases associated with aging rather than radiation-induced renal damage. The creatinine clearance did not decrease in any circumstance. Conclusions The present cohort had excellent renal outcomes after radiation therapy for neuroblastoma. No patient developed chronic renal insufficiency, and the small increases in BUN and creatinine we observed correlated, as expected, with increases in patient age. The results of the present study revealed a possible advantage for intensity modulated radiation therapy in preserving renal function; however, the follow-up length is a recognized confounding variable. The kidneys are vital structures to consider when planning radiation therapy for neuroblastoma patients, and we have found encouraging evidence that modern techniques to spare them in the setting of multiple treatment-related insults have been successful.
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- 2017
29. Reduced Toxicity With Intensity Modulated Radiation Therapy (IMRT) for Desmoplastic Small Round Cell Tumor (DSRCT): An Update on the Whole Abdominopelvic Radiation Therapy (WAP-RT) Experience
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Shakeel Modak, Heather Magnan, Neil Desai, Michael P. LaQuaglia, Brian H. Kushner, Kaled M. Alektiar, Nicholas F. Stein, Karyn A. Goodman, and Suzanne L. Wolden
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Adult ,Male ,Cancer Research ,medicine.medical_specialty ,Adolescent ,Desmoplastic small-round-cell tumor ,medicine.medical_treatment ,Platelet Transfusion ,Desmoplastic Small Round Cell Tumor ,Young Adult ,Rare Diseases ,Autologous stem-cell transplantation ,Antineoplastic Combined Chemotherapy Protocols ,Granulocyte Colony-Stimulating Factor ,Intestine, Small ,medicine ,Humans ,Radiology, Nuclear Medicine and imaging ,Retroperitoneal Neoplasms ,Child ,Radiation Injuries ,Peritoneal Neoplasms ,Bone Marrow Transplantation ,Retrospective Studies ,Radiation ,business.industry ,Radiotherapy Planning, Computer-Assisted ,Common Terminology Criteria for Adverse Events ,medicine.disease ,Debulking ,Combined Modality Therapy ,Acute toxicity ,Surgery ,Radiation therapy ,Platelet transfusion ,Oncology ,Toxicity ,Female ,Radiotherapy, Intensity-Modulated ,Radiology ,business ,Intestinal Obstruction - Abstract
Purpose Desmoplastic small round cell tumor (DSRCT) is a rare malignancy typically involving the peritoneum in young men. Whole abdominopelvic radiation therapy (WAP-RT) using conventional 2-dimensional (2D) radiation therapy (RT) is used to address local recurrence but has been limited by toxicity. Our objectives were to assess the benefit of intensity modulated radiation therapy (IMRT) on toxicity and to update the largest series on radiation for DSRCT. Methods and Materials The records of 31 patients with DSRCT treated with WAP-RT (22 with 2D-RT and 9 with IMRT) between 1992 and 2011 were retrospectively reviewed. All received multi-agent chemotherapy and maximal surgical debulking followed by 30 Gy of WAP-RT. A further focal boost of 12 to 24 Gy was used in 12 cases. Boost RT and autologous stem cell transplantation were nearly exclusive to patients treated with 2D-RT. Toxicities were assessed with the Common Terminology Criteria for Adverse Events. Dosimetric analysis compared IMRT and simulated 2D-RT dose distributions. Results Of 31 patients, 30 completed WAP-RT, with a median follow-up after RT of 19 months. Acute toxicity was reduced with IMRT versus 2D-RT: P =.04 for gastrointestinal toxicity of grade 2 or higher (33% vs 77%); P =.02 for grade 4 hematologic toxicity (33% vs 86%); P =.01 for rates of granulocyte colony-stimulating factor; and P =.04 for rates of platelet transfusion. Post treatment red blood cell and platelet transfusion rates were also reduced ( P =.01). IMRT improved target homogeneity ([D05-D95]/D05 of 21% vs 46%) and resulted in a 21% mean bone dose reduction. Small bowel obstruction was the most common late toxicity (23% overall). Updated 3-year overall survival and progression-free survival rates were 50% and 24%, respectively. Overall survival was associated with distant metastasis at diagnosis on multivariate analysis. Most failures remained intraperitoneal (88%). Conclusions IMRT for consolidative WAP-RT in DSRCT improves hematologic toxicity in particular. Although the long-term efficacy of current treatment options remains disappointing, the improved therapeutic index of IMRT may aid in generalizing its use and allowing the addition of novel approaches such as intraperitoneal immunotherapy.
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- 2013
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30. Combination of bevacizumab, irinotecan, and temozolomide for refractory or relapsed neuroblastoma: Results of a phase II study
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Nai-Kong V. Cheung, Brian H. Kushner, Shakeel Modak, Ellen M. Basu, and Stephen S. Roberts
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0301 basic medicine ,Adult ,Male ,medicine.medical_specialty ,Bevacizumab ,Adolescent ,Phases of clinical research ,Kaplan-Meier Estimate ,Neutropenia ,Irinotecan ,Gastroenterology ,Disease-Free Survival ,Article ,03 medical and health sciences ,Neuroblastoma ,Young Adult ,0302 clinical medicine ,Refractory ,Internal medicine ,Antineoplastic Combined Chemotherapy Protocols ,medicine ,Temozolomide ,Humans ,Child ,business.industry ,Hematology ,medicine.disease ,Surgery ,Dacarbazine ,030104 developmental biology ,Treatment Outcome ,Oncology ,030220 oncology & carcinogenesis ,Child, Preschool ,Pediatrics, Perinatology and Child Health ,Camptothecin ,Female ,Neoplasm Recurrence, Local ,business ,Progressive disease ,medicine.drug - Abstract
Background The rationale for studying the combination of bevacizumab, irinotecan, and temozolomide (BIT) in neuroblastoma (NB) is based on the following: (i) vascular endothelial growth factor (VEGF) expression is associated with an aggressive phenotype, (ii) anti-VEGF antibody bevacizumab enhances irinotecan-mediated suppression of NB xenografts, (iii) bevacizumab safety has been established in pediatric phase I studies, and (iv) irinotecan + temozolomide (IT) is a standard salvage chemotherapy. Procedure We conducted a phase II study of BIT in patients with measurable/evaluable refractory or relapsed high-risk NB (www.clinicaltrials.gov, NCT01114555). Each cycle consisted of bevacizumab (15 mg/kg intravenously [IV]) on days 1 and 15 plus irinotecan (50 mg/m2/day IV) and temozolomide (150 mg/m2/day orally) on days 4–8. Patients could have previously received, but not relapsed on, IT. An early stopping rule mandated continuing therapy only if more than five patients of 27 evaluable patients achieved partial response (PR) or complete response (CR) after four cycles. Results Thirty-three heavily pretreated patients (nine primary refractory; 24 relapsed) received one to eight cycles of BIT. Toxicities were expected and transient. Grade 4 toxicities were neutropenia (30%) and thrombocytopenia (24%). Grade 3 toxicities included hepatic transaminitis (15%), proteinuria (9%), and diarrhea (3%). Overall responses were as follows: three CR (all in prior IT-treated patients), 18 no response, and 12 progressive disease. Only one of 23 patients assessable for the early stopping rule regarding efficacy achieved PR/CR, so patient accrual was discontinued. Median progression-free survival and overall survival was 7.7 ± 1.7 and 31.5 ± 5.6 months, respectively; all patients continued anti-NB therapy post-BIT. Conclusions BIT was well tolerated, but the addition of bevacizumab did not improve response rates in resistant NB compared to historical data for IT.
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- 2016
31. Chemoimmunotherapy for high-risk neuroblastoma
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Brian H. Kushner
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0301 basic medicine ,Oncology ,medicine.medical_specialty ,business.industry ,medicine.medical_treatment ,MEDLINE ,Immunotherapy ,medicine.disease ,03 medical and health sciences ,030104 developmental biology ,0302 clinical medicine ,Chemoimmunotherapy ,030220 oncology & carcinogenesis ,Neuroblastoma ,Internal medicine ,Medicine ,High risk neuroblastoma ,business - Published
- 2017
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32. High-dose cyclophosphamide–irinotecan–vincristine for primary refractory neuroblastoma
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Nai-Kong V. Cheung, Shakeel Modak, Karima Yataghene, Brian H. Kushner, and Kim Kramer
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Male ,Cancer Research ,medicine.medical_specialty ,Vincristine ,Adolescent ,Cyclophosphamide ,medicine.medical_treatment ,Biology ,Irinotecan ,Gastroenterology ,Disease-Free Survival ,Neuroblastoma ,chemistry.chemical_compound ,Internal medicine ,Antineoplastic Combined Chemotherapy Protocols ,medicine ,Humans ,Child ,Retrospective Studies ,Chemotherapy ,Temozolomide ,Infant ,Nitrogen mustard ,Surgery ,Regimen ,Oncology ,chemistry ,Drug Resistance, Neoplasm ,Child, Preschool ,Camptothecin ,Female ,Topotecan ,medicine.drug - Abstract
Background We used a novel regimen for neuroblastoma (NB) that had responded inadequately to standard chemotherapy which now includes topotecan in induction or second-line therapy. Patients and methods We retrospectively studied 38 patients who received one or two courses of high-dose cyclophosphamide (140 mg/kg)-irinotecan (CPT-11) (250 mg/m2)-vincristine (HD-CCV) as treatment for NB that had responded incompletely to induction but had never progressed. Treatment was outpatient and was preceded and followed by extent-of-disease and toxicity evaluations because the patients were being considered for enrolment on formal protocols. Progression-free survival (PFS) was calculated from day 1 of HD-CCV. Results Common toxicities were grade 4 myelosuppression and grade 2 diarrhoea. Responses – 5 complete (CR), 3 partial (PR), 4 mixed (MR) – occurred in 12/28 (43%) patients treated ⩽9 months, and in 1/10 (10%) patients treated >10 months, from diagnosis. HD-CCV was the initial salvage regimen after topotecan-containing induction in 5 patients, achieving 1 CR, 1 MR and 3 stable disease (NR). HD-CCV produced responses (2 PR, 3 MR) in all 5 patients previously treated with CPT-11/ temozolomide. In contrast, all 6 patients treated post-HD-CCV with CPT-11/temozolomide had NR to the latter. Post-HD-CCV treatments included immunotherapy, targeted radiotherapy and/or chemotherapy. PFS was 64% (±8%) at 24 months, with 20 patients progression-free at 2+-to-36+ (median 16+) months and 10 in first CR at 9+-to-36+ (median 16+) months. Conclusions HD-CCV offers a treatment option against topotecan-resistant NB. Results support the concept that combining CPT-11 with very high doses of alkylators can yield greater antitumour effect.
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- 2011
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33. Humanized 3F8 Anti-GD2Monoclonal Antibody Dosing With Granulocyte-Macrophage Colony-Stimulating Factor in Patients With Resistant Neuroblastoma
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Irene Y. Cheung, Ellen M. Basu, Brian H. Kushner, Shakeel Modak, Nai-Kong V. Cheung, and Stephen S. Roberts
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Adult ,Male ,0301 basic medicine ,Oncology ,Cancer Research ,medicine.medical_specialty ,Adolescent ,Maximum Tolerated Dose ,medicine.medical_treatment ,Phases of clinical research ,Antibodies, Monoclonal, Humanized ,Neuroblastoma ,Young Adult ,03 medical and health sciences ,0302 clinical medicine ,Pharmacokinetics ,Internal medicine ,Antineoplastic Combined Chemotherapy Protocols ,Humans ,Medicine ,Treatment Failure ,Dosing ,Child ,Original Investigation ,Chemotherapy ,Dose-Response Relationship, Drug ,business.industry ,Immunogenicity ,Infant, Newborn ,Antibodies, Monoclonal ,Granulocyte-Macrophage Colony-Stimulating Factor ,Infant ,Dinutuximab ,Clinical trial ,030104 developmental biology ,Drug Resistance, Neoplasm ,Child, Preschool ,030220 oncology & carcinogenesis ,Monoclonal ,Female ,Neoplasm Recurrence, Local ,business - Abstract
Importance Chimeric and murine anti-G D2 antibodies are active against neuroblastoma, but the development of neutralizing antibodies can compromise efficacy. To decrease immunogenicity, hu3F8, a humanized anti-G D2 antibody, was constructed. Objective To find the maximum-tolerated dose of hu3F8 with granulocyte-macrophage colony-stimulating factor. Design, Setting, and Participants This phase 1 clinical trial used a 3 + 3 dose-escalation design in a single referral center (Memorial Sloan Kettering Cancer Center, New York, New York). Participants were enrolled from December 24, 2012, through May 3, 2016, with follow-up and analyses through February 28, 2018. Eligibility criteria included older than 1 year and resistant or recurrent neuroblastoma regardless of the number or kinds of prior treatments. All 57 participants met the eligibility criteria, received treatment according to the protocol, and were included in all analyses. Interventions Treatment cycles were monthly, if human antihuman antibody remained negative. Each cycle comprised hu3F8 infused intravenously for 30 minutes on Monday, Wednesday, and Friday as well as granulocyte-macrophage colony-stimulating factor administered subcutaneously daily from 5 days before infusion through the last day of infusion. After cycle 2, hu3F8 was increased to the highest dose level that had been confirmed as safe. Main Outcomes and Measures Toxicity, pharmacokinetics, immunogenicity, and disease response. Results Of the 57 participants, 34 (60%) were male and 23 (40%) were female (male-to-female ratio of 1.5), with a median (range) age of 6.8 (2.4-31.3) years at enrollment and a median (range) time of 3.1 (0.6-9.0) years since initial chemotherapy. Participants received a median (range) of 4 (1-15) cycles. Treatment was outpatient with reversible neuropathic pain and without unexpected toxic effects. No maximum-tolerated dose was identified. Dose escalation was associated with increased serum levels and proceeded through dosage of 9.6 mg/kg/cycle (approximately 288 mg/m 2 ), which is more than 2.5 times higher than the standard dosage of 75 mg/m 2 /cycle or 100 mg/m 2 /cycle of dinutuximab and m3F8. Human antihuman antibody positivity developed in 5 of 57 patients (9%) after cycle 1, including in 1 of 10 patients (10%) not previously treated with anti-G D2 antibody and in 4 of 47 patients (9%) previously exposed to 1 or 2 anti-G D2 antibodies. Antineuroblastoma activity included major responses associated with higher dosing and prolonged progression-free survival despite a history of relapses. Conclusions and Relevance This phase 1 clinical trial found hu3F8 to be associated with modest toxic effects, low immunogenicity, and substantial antineuroblastoma activity; phase 2 trials are in progress. Trial Registration ClinicalTrials.gov identifier:NCT01757626
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- 2018
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34. Differential impact of high-dose cyclophosphamide, topotecan, and vincristine in clinical subsets of patients with chemoresistant neuroblastoma
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Shakeel Modak, Kim Kramer, Nai-Kong V. Cheung, Li-Xuan Qin, and Brian H. Kushner
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Adult ,Male ,Cancer Research ,Vincristine ,medicine.medical_specialty ,Adolescent ,Cyclophosphamide ,Salvage therapy ,Gastroenterology ,Drug Administration Schedule ,Neuroblastoma ,symbols.namesake ,Refractory ,Internal medicine ,Antineoplastic Combined Chemotherapy Protocols ,medicine ,Humans ,Child ,Fisher's exact test ,Salvage Therapy ,business.industry ,Infant ,medicine.disease ,Pediatric cancer ,Surgery ,Oncology ,Drug Resistance, Neoplasm ,Child, Preschool ,symbols ,Female ,Topotecan ,business ,Progressive disease ,medicine.drug - Abstract
BACKGROUND: In what to the authors' knowledge is the first such study for a pediatric cancer, a large database was retrospectively analyzed to assess statistically the likelihood of response to a given salvage therapy in different clinical subsets of patients. METHODS: Treatment was comprised of high-dose cyclophosphamide (at a dose of 140 mg/kg), topotecan (at a dose of 8 mg/m2), and vincristine (at a dose of 0.067 mg/kg or 2 mg/m2, whichever was lower; maximum dose, 2 mg) (HD-CTV). The Fisher exact test was used for comparisons of response rates among standard subsets of patients (n = 126) with refractory or recurrent neuroblastoma (NB). RESULTS: Among children, major (ie, complete/partial) responses occurred in 11 of 58 (19%) with primary refractory NB, 4 of 14 (29%) with secondary refractory NB, 13 of 25 (52%) with a new (first) disease recurrence, and none of 13 patients with progressive disease (PD) while receiving therapy. Other children had mixed responses (MRs); when combining major responses and MRs, anti-NB activity was noted in 26 of 58 (45%) children with primary refractory NB, 10 of 14 (71%) children with secondary refractory NB, 20 of 25 (80%) children with a new (first) disease recurrence, and 1 of 13 (8%) children with PD while receiving therapy. The response rate was significantly different across the 4 groups of children for both major responses (P = .003) and combined responses (P = .001). All 10 adolescents/adults treated for primary refractory NB had no response, which was a significantly inferior result compared with the response rate of 45% noted in children with primary refractory NB (P = .008). CONCLUSIONS: Response to HD-CTV as salvage therapy is significantly less likely in adolescents/adults and in children with NB that is persistent or progressing on treatment rather than newly recurrent off treatment. These findings are broadly applicable and should be considered when designing, and interpreting the results of, phase 2 studies. Cancer 2010. © 2010 American Cancer Society.
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- 2010
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35. Hypothyroidism after 131 I-monoclonal antibody treatment of neuroblastoma
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Kim Kramer, Nai-Kong V. Cheung, Charles A. Sklar, Shakeel Modak, Glenn Heller, Sonal Bhandari, Samuel Yeh, Brian H. Kushner, and Steven M. Larson
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endocrine system ,Chemotherapy ,medicine.medical_specialty ,endocrine system diseases ,business.industry ,medicine.medical_treatment ,Thyroid ,Primary hypothyroidism ,Hematology ,medicine.disease ,Gastroenterology ,Liothyronine Sodium ,medicine.anatomical_structure ,Endocrinology ,Oncology ,Neuroblastoma ,Internal medicine ,Pediatrics, Perinatology and Child Health ,Monoclonal ,medicine ,Thyroid function ,business ,Survival rate - Abstract
Background To determine the prevalence of and risk factors for primary hypothyroidism following treatment with a radiolabeled monoclonal antibody (131I-3F8) in children with neuroblastoma. Procedure In the current study, we assessed thyroid function in 51 neuroblastoma patients who survived for ≥3 months after treatment with 131I-3F8 (a murine IgG3 monoclonal antibody that reacts with the ganglioside GD2) at 4 mCi/kg/day × 5 days (total 20 mCi/kg). Prior therapy in all subjects included dose-intensive chemotherapy; 13 subjects also received external beam radiation to the neck. Oral iodide and liothyronine sodium (T3) were administered for protection of the thyroid gland. Results Thirty-two of 51 subjects (63%) developed hormonal evidence of primary hypothyroidism. The median time to hypothyroidism after treatment with 131I-3F8 was 6.4 months. The probability of developing hypothyroidism was 56% at 2 years following treatment with 131I-3F8. There was evidence for an association between thyroidal uptake of 131I and development of hypothyroidism (hazard ratio 1.83, 95% confidence interval 0.91–3.30; P = 0.09). Conclusions We conclude that hormonal evidence of primary hypothyroidism developed in a majority of subjects treated with 131I-3F8, despite pretreatment with oral iodide plus liothyronine sodium. Alternative strategies for thyroid gland protection are needed. Pediatr Blood Cancer 2010;55:76–80. © 2010 Wiley-Liss, Inc.
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- 2010
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36. Compartmental intrathecal radioimmunotherapy: results for treatment for metastatic CNS neuroblastoma
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Pat Zanzonico, Neeta Pandit-Taskar, Suzanne L. Wolden, John L. Humm, Shakeel Modak, Kim Kramer, Brian H. Kushner, Mark M. Souweidane, Peter Smith-Jones, Steven M. Larson, Nai-Kong V. Cheung, and Hong Xu
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Adult ,Male ,Oncology ,Cancer Research ,medicine.medical_specialty ,Time Factors ,Adolescent ,medicine.medical_treatment ,Article ,Drug Administration Schedule ,Craniospinal Irradiation ,Central Nervous System Neoplasms ,Neuroblastoma ,Young Adult ,Internal medicine ,medicine ,Humans ,Combined Modality Therapy ,Child ,Injections, Spinal ,Aged ,Retrospective Studies ,Tomography, Emission-Computed, Single-Photon ,Chemotherapy ,Temozolomide ,business.industry ,Antibodies, Monoclonal ,Granulocyte-Macrophage Colony-Stimulating Factor ,Radiotherapy Dosage ,Middle Aged ,Radioimmunotherapy ,medicine.disease ,Surgery ,Regimen ,Treatment Outcome ,medicine.anatomical_structure ,Neurology ,Child, Preschool ,Female ,Neurology (clinical) ,Bone marrow ,business ,medicine.drug - Abstract
Innovation in the management of brain metastases is needed. We evaluated the addition of compartmental intrathecal antibody-based radioimmunotherapy (cRIT) in patients with recurrent metastatic central nervous system (CNS) neuroblastoma following surgery, craniospinal irradiation, and chemotherapy. Twenty one patients treated for recurrent neuroblastoma metastatic to the CNS, received a cRIT-containing salvage regimen incorporating intrathecal (131)I-monoclonal antibodies (MoAbs) targeting GD2 or B7H3 following surgery and radiation. Most patients also received outpatient craniospinal irradiation, 3F8/GMCSF immunotherapy, 13-cis-retinoic acid and oral temozolomide for systemic control. Seventeen of 21 cRIT-salvage patients are alive 7-74 months (median 33 months) since CNS relapse, with all 17 remaining free of CNS neuroblastoma. One patient died of infection at 22 months with no evidence of disease at autopsy, and one of lung and bone marrow metastases at 15 months, and one of progressive bone marrow disease at 30 months. The cRIT-salvage regimen was well tolerated, notable for myelosuppression minimized by stem cell support (n = 5), and biochemical hypothyroidism (n = 5). One patient with a 7-year history of metastatic neuroblastoma is in remission from MLL-associated secondary leukemia. This is significantly improved to published results with non-cRIT based where relapsed CNS NB has a median time to death of approximately 6 months. The cRIT-salvage regimen for CNS metastases was well tolerated by young patients, despite their prior history of intensive cytotoxic therapies. It has the potential to increase survival with better than expected quality of life.
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- 2009
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37. Salvage rates after progression of high-risk neuroblastoma with a soft tissue mass
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Stephen S. Roberts, Irene-Isabel P. Lim, Jennifer M. Murphy, Todd E. Heaton, Benjamin A. Farber, Shakeel Modak, Michael P. LaQuaglia, Brian H. Kushner, and Ellen M. Basu
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Oncology ,Male ,medicine.medical_specialty ,Salvage therapy ,Soft Tissue Neoplasms ,Disease ,Disease-Free Survival ,Article ,03 medical and health sciences ,Neuroblastoma ,0302 clinical medicine ,Internal medicine ,medicine ,Humans ,030212 general & internal medicine ,Stage (cooking) ,Child ,Retrospective Studies ,Salvage Therapy ,business.industry ,Remission Induction ,Soft tissue ,Infant ,Retrospective cohort study ,General Medicine ,medicine.disease ,Prognosis ,Surgery ,medicine.anatomical_structure ,030220 oncology & carcinogenesis ,Concomitant ,Child, Preschool ,Pediatrics, Perinatology and Child Health ,Disease Progression ,Female ,Bone marrow ,business - Abstract
Purpose Treatment of progression in high-risk neuroblastoma remains challenging despite improved survival. We retrospectively evaluated outcomes in children with a first progression that included soft-tissue masses. Methods We reviewed records of 903 consecutive children with high-risk neuroblastoma diagnosed between 2004 and 2014, and identified 42 whose first progression included soft-tissue masses. Data on demographics, disease characteristics, treatment, and survival were collected. Primary outcome was 5-year overall survival (OS) from time of first progression. Secondary outcomes were local disease-free progression (LDFR) and progression-free survival (PFS) postprogression. We evaluated the prognostic significance of concomitant bone/bone marrow involvement, MYCN status, and multifocality of soft tissue relapse. Results Median age at diagnosis was 3.0 (range: 1–10.7) years. Median time to first relapse or progression was 1.2 (range: 0.1–4.5) years after complete remission or minimal stable residual disease. Twelve (29%) patients had concomitant bone or marrow involvement at progression/relapse. There were 11 (26%) patients with International Neuroblastoma Staging System stage 3 disease (all with MYCN amplification), and 31 (74%) with stage 4 disease (12 with MYCN amplification). Nine (21%) patients had multifocal soft tissue progression. R1 resection was achieved in 41 children (95%), 38 (95%) of whom also received salvage radiation therapy. Five-year OS postprogression was 35% (95% CI: 19–51%), 5-year LDFS was 52% (95% CI: 32–72%), and 5-year PFS postprogression was 20% (95% CI: 6–34%). Conclusion Among children with high-risk neuroblastoma who underwent aggressive treatment of a first soft-tissue recurrence, 5-year postprogression overall survival was 34%. Multifocality and MYCN amplification were the predominant prognostic correlates for worse survival.
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- 2015
38. Lack of survival advantage with autologous stem-cell transplantation in high-risk neuroblastoma consolidated by anti-GD2 immunotherapy and isotretinoin
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Deborah Kuk, Ellen M. Basu, Shakeel Modak, Irene Y. Cheung, Karima Yataghene, Kim Kramer, Irina Ostrovnaya, Stephen S. Roberts, Brian H. Kushner, and Nai-Kong V. Cheung
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0301 basic medicine ,Oncology ,Male ,medicine.medical_treatment ,anti-GD2 antibody ,Immunoenzyme Techniques ,Neuroblastoma ,0302 clinical medicine ,Autologous stem-cell transplantation ,Gangliosides ,Child ,Isotretinoin ,Antibodies, Monoclonal ,pediatric oncology ,Prognosis ,Combined Modality Therapy ,3. Good health ,Survival Rate ,030220 oncology & carcinogenesis ,Child, Preschool ,Female ,immunotherapy ,medicine.drug ,Research Paper ,medicine.medical_specialty ,Adolescent ,autologous stem-cell transplantation ,Transplantation, Autologous ,03 medical and health sciences ,Internal medicine ,medicine ,Humans ,Survival rate ,Neoplasm Staging ,business.industry ,Infant, Newborn ,Cancer ,Granulocyte-Macrophage Colony-Stimulating Factor ,Infant ,Immunotherapy ,medicine.disease ,Minimal residual disease ,Transplantation ,030104 developmental biology ,Immunology ,minimal residual disease ,Dermatologic Agents ,Neoplasm Recurrence, Local ,business ,Stem Cell Transplantation - Abstract
// Brian H. Kushner 1 , Irina Ostrovnaya 2 , Irene Y. Cheung 1 , Deborah Kuk 2 , Shakeel Modak 1 , Kim Kramer 1 , Stephen S. Roberts 1 , Ellen M. Basu 1 , Karima Yataghene 1 , Nai-Kong V. Cheung 1 1 Department of Pediatrics, Memorial Sloan Kettering Cancer Center, New York, NY 10065, USA 2 Department of Epidemiology and Biostatistics, Memorial Sloan Kettering Cancer Center, New York, NY 10065, USA Correspondence to: Brian H. Kushner, e-mail: kushnerb@mskcc.org Keywords: immunotherapy, anti-G D2 antibody, minimal residual disease, autologous stem-cell transplantation, pediatric oncology Received: September 08, 2015 Accepted: November 09, 2015 Published: November 26, 2015 ABSTRACT Since 2003, high-risk neuroblastoma (HR-NB) patients at our center received anti-G D2 antibody 3F8/GM-CSF + isotretinoin – but not myeloablative therapy with autologous stem-cell transplantation (ASCT). Post-ASCT patients referred from elsewhere also received 3F8/GM-CSF + isotretinoin. We therefore accrued a study population of two groups treated during the same period and whose consolidative therapy, aside from ASCT, was identical. We analyzed patients enrolled in 1st complete/very good partial remission (CR/VGPR). Their event-free survival (EFS) and overall survival (OS) were calculated from study entry. Large study size allowed robust statistical analyses of key prognosticators including MYCN amplification, minimal residual disease (MRD), FCGR2A polymorphisms, and killer immunoglobulin-like receptor genotypes of natural killer cells. The 170 study patients included 60 enrolled following ASCT and 110 following conventional chemotherapy. The two cohorts had similar clinical and biological features. Five-year rates for ASCT and non-ASCT patients were, respectively: EFS 65% vs. 51% ( p = .128), and OS 76% vs. 75% ( p = .975). In multivariate analysis, ASCT was not prognostic and only MRD-negativity after two cycles of 3F8/GM-CSF correlated with significantly improved EFS and OS. Although a trend towards better EFS is seen with ASCT, OS is near identical. Cure rates may be similar, as close surveillance detects localized relapse and effective salvage treatments are applied. ASCT may not be needed to improve outcome when anti-G D2 immunotherapy is used for consolidation after dose-intensive conventional chemotherapy.
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- 2015
39. Irinotecan Plus Temozolomide for Relapsed or Refractory Neuroblastoma
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Shakeel Modak, Brian H. Kushner, Nai-Kong V. Cheung, and Kim Kramer
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Male ,Cancer Research ,medicine.medical_specialty ,Adolescent ,Dacarbazine ,Irinotecan ,Gastroenterology ,Drug Administration Schedule ,Neuroblastoma ,Refractory ,Internal medicine ,Antineoplastic Combined Chemotherapy Protocols ,Temozolomide ,medicine ,Humans ,Child ,business.industry ,Infant ,medicine.disease ,Surgery ,Regimen ,Treatment Outcome ,Oncology ,Child, Preschool ,Quality of Life ,Absolute neutrophil count ,Camptothecin ,Female ,Neoplasm Recurrence, Local ,business ,medicine.drug - Abstract
Purpose To report on an irinotecan and temozolomide regimen for neuroblastoma (NB). Quality of life and minimizing toxicity were major considerations. Patients and Methods The plan stipulated 5-day courses of irinotecan 50 mg/m2 (1-hour infusion) and temozolomide 150 mg/m2 (oral) every 3 to 4 weeks, with a pretreatment platelet count more than 30,000/μL. Granulocyte colony-stimulating factor was used when the absolute neutrophil count was less than 1,000/μL. Results Forty-nine NB patients received 1 to 15 courses (median, 5). Gastrointestinal and myelosuppressive toxicities were readily managed. Lymphocyte responses to phytohemagglutinin after 2 to 10 courses (median, 3.5) were normal in 10 of 10 patients treated after nonimmunosuppressive therapy, and normalized in five of seven patients first treated less than 2 months after high-dose alkylators. Of 19 patients treated for refractory NB and assessable for response, nine showed evidence of disease regression, including two complete responses and seven objective responses. Of 17 patients treated for progressive disease, three showed evidence of disease regression, including one partial response and two objective responses. Multiple courses entailed no cumulative toxicity and controlled disease for prolonged periods in many patients, including some who were unable to complete prior treatments because of hematologic, infectious, cardiac, or renal problems. Conclusion This regimen has anti-NB activity, spares vital organs, is feasible with poor bone marrow reserve, causes limited immunosuppression, and allows good quality of life.
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- 2006
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40. Topotecan, thiotepa, and carboplatin for neuroblastoma: failure to prevent relapse in the central nervous system
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Nancy A. Kernan, L Reich, N.-K. V. Cheung, Karen E Danis, Kim Kramer, Shakeel Modak, and Brian H. Kushner
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Male ,medicine.medical_specialty ,Adolescent ,Antineoplastic Agents ,ThioTEPA ,Gastroenterology ,Carboplatin ,Central Nervous System Neoplasms ,Central nervous system disease ,Neuroblastoma ,chemistry.chemical_compound ,Internal medicine ,Antineoplastic Combined Chemotherapy Protocols ,medicine ,Mucositis ,Humans ,Treatment Failure ,Child ,Etoposide ,Transplantation ,business.industry ,Hematology ,medicine.disease ,Combined Modality Therapy ,Surgery ,Regimen ,chemistry ,Child, Preschool ,Female ,Topotecan ,Neoplasm Recurrence, Local ,business ,Thiotepa ,medicine.drug - Abstract
We report on a three-drug myeloablative regimen designed to consolidate remission and to prevent central nervous system (CNS) relapse of high-risk neuroblastoma (NB). Sixty-six NB patients received topotecan 2 mg/m2/day, x 4 days; thiotepa 300 mg/m2/day, x 3 days; and carboplatin approximately 500 mg/m2/day, x 3 days. Post-SCT treatments included radiotherapy, immunotherapy, 13-cis-retinoic acid, +/-oral etoposide. Significant nonhematologic toxicities were mucositis and skin-related in all patients, convulsions in three patients, and cardiac failure and venocclusive disease of liver in one patient each. Grade 2 hepatotoxicity led to truncating cytoreduction in two patients; both later relapsed in brain. Among 46 patients transplanted in first complete/very good partial remission (CR/VGPR), event-free survival is 54% (s.e.+/-8%) at 36 months post-SCT; notable events were three non-NB-related deaths (adenovirus on day +9, bowel necrosis at 5 months, multiorgan failure at seven months) and four relapses in brain. Of 12 patients transplanted with evidence of NB, two became long-term event-free survivors and two relapsed in the brain. Of eight patients transplanted in second or greater CR/VGPR, one became a long-term event-free survivor and seven relapsed though not in the CNS. This regimen has manageable toxicity but does not prevent CNS relapse.
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- 2006
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41. Ototoxicity from high-dose use of platinum compounds in patients with neuroblastoma
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Shakeel Modak, Amy Budnick, Brian H. Kushner, Nai-Kong V. Cheung, and Kim Kramer
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Male ,Cancer Research ,medicine.medical_specialty ,Hearing loss ,Antineoplastic Agents ,Neuroblastoma ,Ototoxicity ,Internal medicine ,medicine ,Humans ,Hearing Loss ,Etoposide ,Cisplatin ,Dose-Response Relationship, Drug ,business.industry ,Cancer ,medicine.disease ,Surgery ,Clinical trial ,Regimen ,Oncology ,Child, Preschool ,Female ,medicine.symptom ,business ,medicine.drug - Abstract
BACKGROUND. The young age of neuroblastoma patients makes them especially prone to the ototoxic effects of widely used treatments that feature aggressive use of platinum compounds. We present data defining the extent of the problem in a large series of neuroblastoma patients whose induction included high-dose cisplatin/etoposide (HD-P/E) as used in both the Memorial Sloan-Kettering Cancer Center N7 regimen and the Children's Oncology Group A3973 study. METHODS. N7/A3973 patients were divided into 3 groups: Group 1 had hearing tested after induction, that included 2 cycles of HD-P/E (cumulative cisplatin = 400 mg/m2); Group 2 had hearing tested after induction, that included 3 cycles of HD-P/E (cumulative cisplatin = 600 mg/m2); and Group 3 had hearing tested following carboplatin-containing myeloablative therapy administered after induction, that included 2 cycles of HD-P/E. Ototoxicity was scored by the Brock method. RESULTS. All 3 groups had similar clinical characteristics, including median age at diagnosis of about 3 years. Little or no hearing loss in the speech range (Grade 0/1) was documented in 21 (32%) of the 65 Group 1 patients, 5 (10%) of the 50 Group 2 patients, and 9 (15.5%) of the 58 Group 3 patients. Severe (Grade 3/4) deficits affected 25% of Group 1, 54% of Group 2, and 50% of Group 3 patients. Patients < 5 years at diagnosis had greater ototoxicity than older patients had, with adolescents/adults being the least affected. Findings were stable in repeated assessments over 2 or more years. CONCLUSIONS. Ototoxicity is a serious and pervasive problem in this patient population. Strategies to ameliorate ototoxicity without compromising on antitumor activity of treatments are urgently needed. Cancer 2006. © 2006 American Cancer Society.
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- 2006
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42. Five-day courses of irinotecan as palliative therapy for patients with neuroblastoma
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Nai-Kong V. Cheung, Kim Kramer, Brian H. Kushner, and Shakeel Modak
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Adult ,Male ,Cancer Research ,medicine.medical_specialty ,Adolescent ,medicine.medical_treatment ,Nervous System Neoplasms ,Salvage therapy ,Irinotecan ,Neuroblastoma ,Quality of life ,Internal medicine ,Humans ,Medicine ,Child ,Infusions, Intravenous ,Retrospective Studies ,business.industry ,Palliative Care ,Cancer ,medicine.disease ,Antineoplastic Agents, Phytogenic ,Surgery ,Radiation therapy ,Regimen ,Treatment Outcome ,Oncology ,Child, Preschool ,Quality of Life ,Absolute neutrophil count ,Camptothecin ,Female ,business ,Progressive disease ,medicine.drug - Abstract
BACKGROUND The authors describe a large experience using short courses of irinotecan for palliative therapy in patients with neuroblastoma (NB). Quality of life was a major issue in choosing this regimen for patients whose disease was resistant to standard anti-NB therapies. METHODS A retrospective review was conducted of all patients who were followed by the Department of Pediatrics at Memorial Sloan-Kettering Cancer Center and treated for resistant NB with irinotecan at 50 mg/m2 per day for 5 days as a 1-hour intravenous infusion. Treatment was outpatient, and there was a minimum 2-week rest period between courses. Granulocyte colony-stimulating factor was used to keep the absolute neutrophil count > 500–1000/mL. RESULTS Forty-four patients had been treated aggressively and/or extensively before they received one or more five-day courses of irinotecan. Emetogenic, diarrheal, and myelosuppressive effects were readily managed. Hospitalizations were limited to three patients with bacteremia. Twenty-three patients had a change in therapy, although they did not have progressive disease (PD) after receiving 1 (n = 10), 2 (n = 3), 3 (n = 1), 4 (n = 6), 7 (n = 1 patient), 22 (n = 1 patient), or 24 (n = 1) courses. The most common reasons for changing treatment were to intensify retrieval therapy or to pursue immunotherapy. Of those 23 patients, 15 patients had stable disease, 7 were not evaluable for response because of concurrent radiotherapy, and 1 patient had a major response. Twenty-one patients had PD after 1 (n = 3, 2 (n = 9), 4 (n = 2), 5 (n = 1), 6 (n = 3), 7 (n = 1), 9 (n = 1), and 11 (n = 1) courses. CONCLUSIONS In heavily treated patients, the regimen studied was well tolerated, allowed patients to continue most normal life activities, and produced anti-NB effects. Its modest toxicity supported use with other antitumor agents. Cancer 2005. © 2005 American Cancer Society.
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- 2005
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43. Long-term complications in survivors of advanced stage neuroblastoma
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Suzanne L. Wolden, Shakeel Modak, James G. Gurney, Charles A. Sklar, Brian H. Kushner, Kirsten K. Ness, Kim Kramer, Michael P. LaQuaglia, Caroline Laverdière, and Nai-Kong V. Cheung
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Adult ,Male ,medicine.medical_specialty ,Adolescent ,Cyclophosphamide ,medicine.medical_treatment ,Population ,Antineoplastic Agents ,Endocrine System Diseases ,Neuroblastoma ,Internal medicine ,Humans ,Medicine ,Survivors ,Child ,Hearing Loss ,education ,Retrospective Studies ,Chemotherapy ,education.field_of_study ,Radiotherapy ,business.industry ,Infant, Newborn ,Late effect ,Infant ,Neoplasms, Second Primary ,Retrospective cohort study ,Hematology ,Combined Modality Therapy ,Surgery ,Radiation therapy ,Logistic Models ,Oncology ,Child, Preschool ,Multivariate Analysis ,Pediatrics, Perinatology and Child Health ,Cohort ,Female ,New York City ,medicine.symptom ,business ,Complication ,Follow-Up Studies ,medicine.drug - Abstract
Background Few studies have assessed late effects in neuroblastoma (NB) survivors, particularly those with advanced stage disease. Methods Retrospective analysis of a cohort of advanced stage NB survivors followed in a late effect clinic at a single institution. Screening tests to detect late effects were tailored depending on the individual's treatment exposures. Results The study included 63 survivors (31 males). The median age at diagnosis was 3.0 years. The median follow-up from diagnosis was 7.06 years. All patients had surgery and received chemotherapy, 89% received radiation therapy (RT), 62% immunotherapy, and 56% autologous stem cell transplant. Late complications were detected in 95% of survivors and included: hearing loss (62%), primary hypothyroidism (24%), ovarian failure (41% of females), musculoskeletal (19%), and pulmonary (19%) abnormalities. The majority of complications were moderate, with only 4% being life-threatening. Survivors who received cisplatin were at greater risk to develop hearing loss compared to those not so treated (OR 9.74; 95% CI: 0.9–101.6). A total dose of cyclophosphamide greater than 7.4 g was associated with ovarian failure (P = 0.02). Conclusions Late complications occur frequently in survivors of advanced stage NB. The majority of these problems are of mild-moderate severity. Long-term follow-up (LFTU) and screening of this population is essential. © 2005 Wiley-Liss, Inc.
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- 2005
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44. The impact of gross total resection on local control and survival in high-risk neuroblastoma
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Brian H. Kushner, Kim Kramer, Michael P. La Quaglia, Glenn Heller, Wendy Su, Nancy Rosen, Suzanne L. Wolden, Sara J. Abramson, and Nai-Kong V. Cheung
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Adult ,medicine.medical_specialty ,Adolescent ,medicine.medical_treatment ,Adrenal Gland Neoplasms ,Mediastinal Neoplasms ,Iodine Radioisotopes ,Neuroblastoma ,Unresected ,Antineoplastic Combined Chemotherapy Protocols ,medicine ,Humans ,Stage (cooking) ,Child ,Survival rate ,Neoplasm Staging ,Proportional Hazards Models ,Retrospective Studies ,Analysis of Variance ,Proportional hazards model ,business.industry ,Infant ,Retrospective cohort study ,General Medicine ,medicine.disease ,Primary tumor ,Surgery ,Survival Rate ,Radiation therapy ,Abdominal Neoplasms ,Child, Preschool ,Pediatrics, Perinatology and Child Health ,Disease Progression ,Radiotherapy, Adjuvant ,business - Abstract
Gross total resection of the primary tumor in treatment of high-risk neuroblastoma remains controversial. Furthermore, there are few reports of the effect of primary tumor resection on local control as opposed to overall survival. The authors reviewed their institutional experience to assess the effect of primary tumor resection on local control and overall survival.A total of 141 patients were treated on protocol between November 1, 1979 and June 25, 2002 and are the subject of this report. Gross total resection was assessed by review of operative notes, postoperative computerized axial tomograms, and postoperative meta-iodobenzyl guanidine (MIBG)1 scans when available.The median age was 3.3 years, and all patients were International Neuroblastoma Staging System (INSS) stage 4 with 79% having metastases to cortical bone. The primary site was the adrenal gland in 74%, the central abdominal compartment in 13%, the posterior mediastinum in 7%, and other sites in 6%. Gross total resection was accomplished in 103 (73%) but was more than 90% for the last 3 protocols. Five kidneys were lost overall. The probability of local progression was 50% in unresected patients compared with 10% in patients undergoing gross total resection (P.01). Overall survival rate in resected patients was 50% compared with 11% in unresected patients (P.01).Our data indicate that local control and overall survival rate are correlated with gross total resection of the primary tumor in high-risk neuroblastoma. Gross total resection should be part of the management of stage 4 neuroblastoma in patients greater than 1 year of age.
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- 2004
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45. Long-Term Event-Free Survival After Intensive Chemotherapy for Ewing’s Family of Tumors in Children and Young Adults
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Ha Thanh Vu, Caroline Laverdière, Andrew G. Huvos, Michael P. LaQuaglia, Leonard H. Wexler, Paul A. Meyers, Richard Gorlick, John H. Healey, Brian H. Kushner, E. Anders Kolb, Suzanne L. Wolden, and Jing Qin
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Adult ,Male ,Cancer Research ,Vincristine ,medicine.medical_specialty ,Adolescent ,Cyclophosphamide ,medicine.medical_treatment ,Bone Neoplasms ,Sarcoma, Ewing ,Gastroenterology ,Disease-Free Survival ,chemistry.chemical_compound ,Recurrence ,Internal medicine ,Antineoplastic Combined Chemotherapy Protocols ,Humans ,Medicine ,Ifosfamide ,Prospective Studies ,Child ,Prospective cohort study ,Etoposide ,Chemotherapy ,business.industry ,Remission Induction ,medicine.disease ,Nitrogen mustard ,Surgery ,Oncology ,chemistry ,Doxorubicin ,Child, Preschool ,Disease Progression ,Female ,Sarcoma ,business ,medicine.drug - Abstract
Purpose: To improve the long-term event-free survival of patients with Ewing’s family of tumors (EFTs) using high-dose, short-term chemotherapy. Patients and Methods: P6 was a prospective study of previously untreated patients with newly diagnosed EFTs. Patients received seven cycles of chemotherapy. Cycles 1, 2, 3, and 6 consisted of cyclophosphamide 2,100 mg/m2/d on days 1 and 2, and a 72-hour continuous infusion of doxorubicin 75 mg/m2 and vincristine 2 mg/m2 starting day 1. Cycles 4, 5, and 7 consisted of 5 consecutive days of ifosfamide 1,800 mg/m2/d and etoposide 100 mg/m2/d. Results: Sixty-eight patients were enrolled from 1991 to 2001 (median age, 18.7 years; range, 3.7 to 39.9 years). At diagnosis, 44 patients had local-regional disease, and 24 had distant metastases. The 4-year event-free survival (EFS) rate for patients with local-regional disease is 82%; overall survival (OS) is 89%. The 4-year EFS rate for patients with distant metastases is 12%; the OS rate is 17.8%. All events occurred within 51 months of diagnosis. Four patients with distant metastases had progressive disease during therapy, and no patient with local-regional disease experienced disease progression during therapy. Conclusion: Sustained EFS and OS can be achieved with intensive chemotherapy in children and young adults with local-regional EFTs. This therapy is relatively ineffective in the treatment of metastatic EFTs.
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- 2003
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46. Oral Topotecan for Refractory and Relapsed Neuroblastoma: A Retrospective Analysis
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Nai-Kong V. Cheung, Brian H. Kushner, and Kim Kramer
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Adult ,Male ,medicine.medical_specialty ,Adolescent ,medicine.medical_treatment ,Administration, Oral ,Antineoplastic Agents ,Gastroenterology ,Neuroblastoma ,Refractory ,Internal medicine ,medicine ,Humans ,Child ,Retrospective Studies ,Chemotherapy ,business.industry ,Retrospective cohort study ,Hematology ,medicine.disease ,Surgery ,Discontinuation ,Treatment Outcome ,Oncology ,Drug Resistance, Neoplasm ,Child, Preschool ,Radioimmunotherapy ,Pediatrics, Perinatology and Child Health ,Disease Progression ,Female ,Topotecan ,Neoplasm Recurrence, Local ,business ,Progressive disease ,medicine.drug - Abstract
Purpose Among patients with multiply relapsed neuroblastoma refractory to conventional chemotherapy, oral topotecan has often been used for palliation. Although toxicity was generally thought to be mild, the efficacy of such an approach remains unproven. Methods The authors retrospectively analyzed patients with multiply relapsed or refractory neuroblastoma who were treated with oral topotecan for palliation. Each course was generally 1 mg/m2/d in two divided doses, for 21 consecutive days, repeated after a 1-week rest in patients without symptoms of progressive disease. Disease status was assessed by radiographic studies, urine catecholamine levels, and multiple bone marrow aspirations and biopsies. Results Twenty patients between the ages of 3 and 34 (median 13 years) received 1 (n = 7), 2 (n = 3), 3 (n = 4), 4 (n = 2), 6 (n = 2), and 12 courses (n = 2). Prior treatments included multiple cycles of high-dose alkylator-based chemotherapy (n = 20), high-dose intravenous topotecan (n = 8), myeloablative chemotherapy or radioimmunotherapy (n = 10), or experimental biologic agents (n = 16). Anti-neuroblastoma effects were seen in five patients lasting 6 to 12 months; two additional patients remained stable for 4 months. Thirteen patients had progressive disease (11 after one or two cycles). Toxicity included diarrhea (n = 12) requiring a dose adjustment in three patients and discontinuation of the drug in a fourth, and myelosuppression (n = 11) requiring transfusion and/or granulocyte-colony stimulating factor support. Conclusions Oral topotecan therapy has antitumor activity in a small percentage of patients with relapsed or refractory neuroblastoma. Toxicities, including diarrhea and myelosuppression, may necessitate a dose adjustment in this patient population. Low-dose oral topotecan may have utility in the treatment of neuroblastoma.
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- 2003
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47. Curability of Recurrent Disseminated Disease After Surgery Alone for Local-Regional Neuroblastoma Using Intensive Chemotherapy and Anti-GD2 Immunotherapy
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Michael P. LaQuaglia, Kim Kramer, Brian H. Kushner, and Nai-Kong V. Cheung
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Male ,medicine.medical_specialty ,medicine.medical_treatment ,Population ,Iodine Radioisotopes ,Neuroblastoma ,medicine ,Humans ,Combined Modality Therapy ,Child ,education ,Chemotherapy ,education.field_of_study ,business.industry ,Granulocyte-Macrophage Colony-Stimulating Factor ,Infant ,Cancer ,Hematology ,Prognosis ,medicine.disease ,Recombinant Proteins ,Surgery ,Treatment Outcome ,medicine.anatomical_structure ,Oncology ,Child, Preschool ,Pediatrics, Perinatology and Child Health ,Cohort ,Female ,Immunotherapy ,Bone marrow ,Complication ,business - Abstract
Purpose A reluctance to treat local-regional neuroblastoma by surgery alone derives partly from concern that if widespread neuroblastoma develops, the chance for cure is small, and partly from hope that mild chemotherapy will prevent relapse. The authors report on a series of patients who had distant recurrences after surgery alone for local-regional neuroblastoma. Methods Seven patients treated with surgery alone for local-regional neuroblastoma had widespread relapses 2.5 to 25 (median 7) months later and were treated at Memorial Sloan-Kettering Cancer Center (MSKCC). During the period of this study (1995-1999), MSKCC patients with high-risk neuroblastoma received the N7 protocol (dose-intensive chemotherapy, immunotherapy with the anti-G(D2) 3F8 antibody, targeted radiotherapy using 131I-3F8, local radiotherapy) if they had assessable disease, or 3F8 plus granulocyte-macrophage colony-stimulating factor (GM-CSF) followed by 13-cis-retinoic acid if they were in remission after treatment elsewhere. Results Five patients were in complete remission 3 years 11 months to 7 years 4 months from the start of retrieval therapy, including three who received all of their N7 treatment of relapsed neuroblastoma at MSKCC, one who received two cycles of chemotherapy elsewhere before starting N7, and one who was referred for 3F8/GM-CSF because of neuroblastoma cells in pretransplantation bone marrow. Conclusions The encouraging survival results of our cohort are consistent with the concept that surgery alone for local-regional neuroblastoma might be beneficial to the overall neuroblastoma population because many patients will never need chemotherapy (and will therefore be spared its potential toxicities), and most of those who do have widespread relapses are likely to be cured with contemporary treatments.
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- 2003
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48. Myeloablative Chemotherapy with Autologous Stem Cell Transplant for Desmoplastic Small Round Cell Tumor
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Suzanne L. Wolden, Brian H. Kushner, Leonard H. Wexler, Heather Magnan, Christopher J. Forlenza, Farid Boulad, Shakeel Modak, Nancy A. Kernan, and Michael P. LaQuaglia
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medicine.medical_specialty ,Pathology ,Desmoplastic small-round-cell tumor ,Article Subject ,business.industry ,medicine.medical_treatment ,Induction chemotherapy ,ThioTEPA ,lcsh:Neoplasms. Tumors. Oncology. Including cancer and carcinogens ,medicine.disease ,lcsh:RC254-282 ,Carboplatin ,Surgery ,Radiation therapy ,chemistry.chemical_compound ,Oncology ,chemistry ,Clinical Study ,medicine ,Radiology, Nuclear Medicine and imaging ,Topotecan ,Stem cell ,business ,Prospective cohort study ,medicine.drug - Abstract
Desmoplastic small round cell tumor (DSRCT), a rare, aggressive neoplasm, has a poor prognosis. In this prospective study, we evaluated the role of myeloablative chemotherapy, followed by autologous stem cell transplant in improving survival in DSRCT. After high-dose induction chemotherapy and surgery, 19 patients with chemoresponsive DSRCT underwent autologous stem cell transplant. Myeloablative chemotherapy consisted of carboplatin (400–700 mg/m2/day for 3 days) + thiotepa (300 mg/m2/day for 3 days) ± topotecan (2 mg/m2/day for 5 days). All patients were engrafted and there was no treatment-related mortality. Seventeen patients received radiotherapy to sites of prior or residual disease at a median of 12 weeks after transplant. Five-year event-free and overall survival were 11 ± 7% and 16 ± 8%, respectively. Two patients survive disease-free 16 and 19 years after transplant (both in complete remission before transplant). 14 patients had progression and died of disease at a median of 18 months following autologous transplant. These data do not justify the use of myeloablative chemotherapy with carboplatin plus thiotepa in patients with DSRCT. Alternative therapies should be considered for this aggressive neoplasm.
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- 2015
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49. Chronic neuroblastoma
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Nai-Kong V. Cheung, Brian H. Kushner, and Kim Kramer
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Cancer Research ,Chemotherapy ,medicine.medical_specialty ,Pediatrics ,business.industry ,medicine.medical_treatment ,Disease ,Immunotherapy ,medicine.disease ,Metastasis ,Surgery ,Radiation therapy ,Oncology ,El Niño ,Medicine ,Stage (cooking) ,business ,Isotretinoin ,medicine.drug - Abstract
BACKGROUND. An indolent course is associated with neuroblastoma (NB) in adolescents and adults. In the current study, the authors analyzed this phenomenon in a large series of children with metastatic NB. METHODS. The authors studied 38 patients who were diagnosed with NB in the first decade of life and had metastatic disease 5 years or more from diagnosis. RESULTS. The median age at diagnosis was 3 years 10 months. MYCN was amplified in 2 of 28 patients tested. Of 30 patients with classic Stage 4 NB, 9 had a late first recurrence of disease (4.3-13 years from diagnosis). Of eight patients who had atypical cases at diagnosis (one isolated mandibular lesion, two Stage 4-N, five non-Stage 4), six had a late first distant recurrence of disease (4 years 11 months-38 years 8 months). Nineteen patients were off therapy continuously for 3 years or more before disease recurred a first or second time. Myeloablative therapy was used to consolidate a first or second response in 27 patients. High-dose conventional therapy helped to achieve a second remission of disease in 9 of 20 patients assessable for response of first recurrence but achieved no major responses of second or third relapse in 10 of 11 patients. The combination of anti-G D2 immunotherapy and/or cis-retinoic acid, targeted radiotherapy, and multiple cycles of chemotherapy with modest toxicity helped prolong survival. Twelve patients survive at 5 years 6 months- to 19 years 4 months+ from diagnosis (median, 6 years 10 months+), including four with complete remission of disease; 10 received anti-G D2 immunotherapy after recurrence. The other 26 patients died of disease (n = 22) or toxicity (n = 4) at 5 years-41 years 5 months from diagnosis (median, 6 years 5 months). CONCLUSIONS. The concept of indolent or smoldering NB should not be limited to adolescents/adults. The expanding repertoire of anti-NB treatments, including biologic therapies and chemotherapy regimens of modest toxicity, can convert childhood NB into a chronic disease with prolonged survival after recurrence.
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- 2002
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50. SCDT-38. SAFETY AND EFFICACY OF INTRAVENTRICULAR 131I-LABELED MONOCLONAL ANTIBODY 8H9 TARGETING THE SURFACE GLYCOPROTEIN B7-H3 IN PATIENTS WITH CNS/LM DISEASE
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Jorge A. Carrasquillo, Stephen S. Roberts, Pat Zanzonico, Ursula Tomlinson, Ellen M. Basu, Sophia Haque, Brian H. Kushner, Mark M. Souweidane, Kim Kramer, Nai-Kong V. Cheung, Serge K. Lyashchenko, Maria Donzelli, Jeffrey P. Greenfield, Neeta Pandit-Taskar, John L. Humm, Suzanne L. Wolden, Jason S. Lewis, Shakeel Modak, and Steven M. Larson
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Cancer Research ,medicine.medical_specialty ,business.industry ,Pharmacology ,medicine.disease ,Gastroenterology ,Abstracts ,Oncology ,Pharmacokinetics ,Internal medicine ,Neuroblastoma ,Toxicity ,medicine ,Vomiting ,Dosimetry ,Immunohistochemistry ,Neurology (clinical) ,medicine.symptom ,business ,Adverse effect ,Progressive disease - Abstract
Tumors metastasizing to the central nervous system (CNS) are associated with significant mortality. We tested the toxicity and dosimetry of intraventricular 131I-labeled monoclonal antibody 8H9 targeting surface glycoprotein B7-H3 in patients with CNS. Tumor B7-H3 expression was assessed by immunohistochemistry. CSF flow was determined by 111Indium-DTPA cisternography. 131 patients received 2 mCi tracer of intra-Ommaya 124I- or 131I-8H9 for nuclear imaging followed by a therapeutic injection (10-80 mCi, dose levels 1-8 in 10 mCi increments for phase I patients; expanded cohort 50 mCi/injection) 131I-8H9. Pharmacokinetics were studied by serial CSF and blood samplings over 48 hours. Dosimetry was based on pharmacokinetics and region of interest analyses on serial PET. Toxicity was defined by the CTCAE v.3.0. 8H9 dosimetry and therapy injections were repeated after 1 month if no serious adverse events or progressive disease ensued. Tumor response was determined by clinical, radiographic, cytologic criteria; overall survival was noted. 129 patients with primary or metastatic CNS tumors received 383 injections [median age 5.4 years (1.2- 53.6 years)] Injections were well tolerated and routinely administered in the outpatient setting. Rare self-limited adverse events included grade 1 or 2 fever, headache, vomiting, biochemical elevations in AST or ALT and 1 injection with grade 3 ALT elevation (dose level 3). Although not a dose limiting toxicity, myelosuppression occurred in patients who had received craniospinal radiation and at dose levels 6 and higher (>60 mCi). Of 93 patients treated for metastatic CNS neuroblastoma, an improved overall survival was noted compared to survival reported with conventional therapies. Interpatient variability for total absorbed dose to the CSF and blood was observed; mean absorbed CSF dose was 104.9 cGy/mCi by CSF sampling, and 2.6 cGy/mCi to the blood. We conclude that intraventricular 131I-8H9 is safe, has favorable dosimetry to CSF, and has clinical utility.
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- 2017
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