High-dose Chemotherapy In Children Research Articles

High-Dose Chemotherapy in Children with Newly Diagnosed Medulloblastoma.

Simple SummaryMedulloblastoma is the most common malignant central nervous system tumor in the pediatric population. Treatment modalities are stratified by age, extent of resection, metastatic status, histology, and more recently, tumor biology. Maximal surgical resection followed by risk-adapted craniospinal irradiation and adjuvant chemotherapy have produced the best survival for medulloblastoma. Although survival is, in general, quite high, some caveats and drawbacks argue for continuous adaptations of this treatment strategy. Clearly, for children with metastatic disease, there is no established standard chemotherapy regimen, even if there is a consensus that chemotherapy brings additional benefit. The treatment of infants and very young children is particularly challenging, as irradiation of the developing brain leads to substantial neurocognitive impairment. Some clinical trials have explored the possible efficacy of high-dose chemotherapy in childhood medulloblastoma, and here we have focused on clinical trials for infants and children with newly diagnosed medulloblastoma.High-dose chemotherapy with stem cell rescue has been used as an adjuvant therapy or as salvage therapy to treat pediatric patients with brain tumors, and to avoid deleterious side effects of radiotherapy in infants and very young children. Here, we present the most recent trials using high-dose chemotherapy regimens for medulloblastoma in children, and we discuss their contribution to improved survival and describe their toxicity profile and limitations.

Safety and Cost-effectiveness of Outpatient Administration of High-dose Chemotherapy in Children With Ewing Sarcoma.

Children with Ewing sarcoma (ES) are subjected to an interval-compressed regimen with cycles of chemotherapy given every 2 weeks, which is nowadays considered to be the standard of care for individuals with such a case. We developed institutional clinical practice guidelines (CPG) applying outpatient administration in regard to this regimen. This study intends to evaluate our institutional experience with this regimen. We conducted a retrospective review of patients with ES who were treated using interval-compressed protocol of 14 cycles consisting of alternating cyclophosphamide, doxorubicin, vincristine (VDC) and ifosfamide, etoposide (IE) with a maximum dose of doxorubicin of 375 mg/m. Cycles were subsequently followed by G-CSF administration until count recovery was recorded. Patients treated using our guidelines from June 2013 to June 2015 were eligible for these guidelines. Patients younger than 3 years at the time of diagnosis were not eligible for outpatient administration of chemotherapy. In total 12 patients with localized ES or lung-only metastasis were eligible. By the time of analysis, 153 cycles were administered to these patients. Eight cycles for 6 patients were administered on an inpatient basis while the rest (N=145) were administered in the outpatient chemotherapy unit. The median number of cycles per patient were 14 (with a range of 5 to 14). Ninety cycles (59%) were administered on time per CPG. The median interval between these cycles were 16 days (range, 12 to 36 days). The median interval between induction and consolidation cycles were 14 and 17 days, respectively. Neutropenia was reported at the time of each next cycle for 12 cycles. Transient gross hematuria was reported in 1 patient only. In addition, a cost saving of 21% (approximately US$ 4500) were achieved per patient. Our study showed that the outpatient administration of interval-compressed regimen is safe and associated with acceptable adherence to this regimen.

Toxicity of 131I-MIBG combined with high-dose chemotherapy in children with refractory neuroblastoma.

9549 Background: More effective regimens with acceptable toxicity are needed to improve prognosis of children with high-risk neuroblastoma. Iodine-131–metaiodobenzylguanidine (131I-MIBG) has been used for targeted radiotherapy of neural crest tumors, including neuroblastoma. By this retrospective study, we have evaluated feasibility and toxicity of 131I-MIBG combined to myeloablative chemotherapy (HD-CHT) with peripheral blood stem cell (PBSC) rescue in children with refractory neuroblastoma. Methods: Between October 1983 and October 2005 a total of 53 patients with refractory neuroblastoma received therapeutic 131I-MIBG combined with HD-CHT. Patients were divided in 2 cohorts. First cohort (FC) patients (n=34) received 131I-MIBG before HD-CHT. Second cohort (SC) patients (n=19) received 131I-MIBG after HD-CHT. Median age at diagnosis was 39 months (range, 7-198). FC patients received 131I-MIBG at the median dose of 7.26 mCi/kg (range, 3.75-16.66), at 16-45 days (median, 20) before HD-CHT. SC patients received 131I-MIBG at the median dose of 6 mCi/kg (range, 2.28-10), at 27-103 days (median, 57) after HD-CHT. Ten types of regimens were used as HD-CHT. Results: Both 131I-MIBG infusion and HD-CHT were well tolerated. Hematologic toxicity was comparable for the 2 cohorts. Median times to neutrophil (>0.5 x 103/µL) and platelet (> 50 x 103/µL) engraftment were 13 days (range, 8-30) and 21 days (range, 12->60), respectively. The predominant non hematopoietic toxicity was oral mucositis, of grade 4 in 23 patients (16 in the FC and 7 in the SC patients) and grade 3 in 9 (3 in the FC and 6 in the SC). Pulmonary complications occurred in 2 children. The predominant long-term toxicity was hypothyroidism which occurred in 9 FC and 6 SC patients. Conclusions: Treatment with 131I-MIBG in combination to HD-CHT was feasible with acceptable toxicity. Future studies are warranted to evaluate the efficacy of this combination.

High-dose chemotherapy for children and young adults with stage IV rhabdomyosarcoma

Rhabdomyosarcoma is the most common soft tissue sarcoma of childhood. Prognosis for patients with metastatic disease has not improved significantly in the past decades. High-dose chemotherapy (HDC) seems to be an attractive option to treat minimal residual disease in metastatic rhabdomyosarcoma patients. The objective of the review was to assess the effectiveness of HDC with stem cell rescue (SRC) versus standard-dose chemotherapy in improving event-free survival (EFS) and overall survival (OS) of children and young adults with metastatic rhabdomyosarcoma. We searched the databases of MEDLINE (1966 to December 2009), EMBASE (1980 to December 2009) and CENTRAL (The Cochrane Library Issue 1, 2009). In addition, we handsearched the reference lists of selected papers and conference proceedings of the SIOP, ASPHO and ASCO meetings (all 2000 to 2009). Randomised controlled trials (RCT), prospective or historical controlled clinical trials (CCT), in which HDC with SCR was compared to conventional chemotherapy and prospective case series (non-controlled clinical trials) including at least 20 naive metastatic rhabdomyosarcoma patients Two review authors independently performed the study selection, quality assessment and data extraction. No RCTs could be identified. We identified one prospective CCT, one retrospective CCT and one non-controlled clinical trial. Another CCT has been published as an abstract. All studies have severe methodological limitations, in particular selection bias could not be excluded. One CCT reported a significantly worse OS compared to oral maintenance therapy, however in a subgroup of high-risk patients no difference could be found. The retrospective CCT reported a similar survival for HDC compared to conventional chemotherapy. The non-controlled clinical trial and the CCT reported as a conference proceeding reported survival outcomes comparable to previous studies. Data on toxicity showed more grade 3-4 toxicity in the HDC group. However, there was no difference in the number of toxic deaths. Overall, the results of this review do not justify the use of HDC with SCR as a standard therapy for children with metastatic rhabdomyosarcoma. However, all reported studies were possibly subject to significant bias, especially selection bias. This might have underestimated the measured effect of HDC. As a result, a clinically important excess of adverse risk patients in the HDC arms may explain the non-beneficial effect of HDC. Only a large prospective RCT will be able to answer the question of whether HDC with SCR adds to survival or not definitively.

Hepatic Veno-Occlusive Disease

Hepatic veno-occlusive disease (VOD) is a major manifestation of liver toxicity associated with conventional and high-dose chemotherapy in children affected by hematologic malignancies and certain solid tumors. Clinically, patients present with jaundice, painful hepatomegaly, and fluid retention, which may evolve into multi-organ failure, a hallmark of severe disease. The pathogenesis is complex and not completely understood, but the damage to sinusoidal endothelium, typically caused by toxic metabolites released from antineoplastic drugs, is thought to play a crucial role, together with cytokine activation, immune deregulation, and coagulopathy. Diagnosis is based on clinical criteria supported by characteristic ultrasound findings, with the gold standard investigation being hepatic-venous pressure gradient measurement and biopsy. Several treatment options have been tested; the most convincing approach to date is the use of defibrotide, a novel oligonucleotide with antithrombotic and antiplatelet aggregating properties, as well as endothelial-stabilizing effects. This agent, together with other specific forms of supportive care, has shown efficacy in the treatment of established VOD and promising results in the prevention of VOD in pediatric patients receiving chemotherapy.

High-dose chemotherapy in children with newly-diagnosed medulloblastoma

High-dose chemotherapy in children with newly-diagnosed medulloblastoma

Platelet Transfusion Containing ABO-Incompatible Plasma and Hepatic Veno-occlusive Disease after Hematopoietic Transplantation in Young Children

Hepatic veno-occlusive disease is a major limiting factor of high-dose chemotherapy in children. The cells lining the hepatic vascular endothelium express blood group A and/or B antigens according to the patient's blood group. We designed a study evaluating the impact of platelet concentrates containing ABO-incompatible plasma transfused to young children with a high risk of hepatic veno-occlusive disease. In all, 186 consecutive children (median age: 4 years, range: 0.75-17 years), treated with high-dose chemotherapy containing busulfan followed by hematopoietic stem cell transplantation for neuroblastoma (n=112) or brain tumor (n=74) between 1988 and 1998, were investigated. The main endpoint was the occurrence of hepatic veno-occlusive disease. Multivariate analysis was performed using a Cox's regression model with transfusion of platelet concentrates containing ABO-incompatible plasma as a time-dependent covariate. We found that 73 out of 186 (39%) children developed hepatic veno-occlusive disease after transplantation. Multivariate analysis demonstrated that two factors significantly increased the risk of hepatic veno-occlusive disease occurrence: transfusion of platelet concentrates containing ABO-incompatible plasma (P=0.003) and use of melphalan in the conditioning regimen (P=0.006). Conversely, the number of platelet concentrates transfusions per week, child's age, weight, sex, and use of cyclophosphamide in the conditioning regimen had no effect. Transfusion of platelet concentrates containing ABO-incompatible plasma increases the risk of hepatic veno-occlusive disease in young children treated with a busulfan-containing regimen. Binding of A and/or B antigens expressed on the surface of hepatic endothelial cells may promote this complication. Transfusion of platelet concentrates containing ABO-incompatible plasma should be avoided in these children.

White Matter Lesions Detected by Magnetic Resonance Imaging After Radiotherapy and High-Dose Chemotherapy in Children With Medulloblastoma or Primitive Neuroectodermal Tumor

White matter lesions (WMLs) have been described as a delayed effect of cranial irradiation in children with brain tumors, or a transient subacute effect characterized by an intralesional or perilesional reaction. We report the occurrence of subacute WMLs detected by magnetic resonance imaging (MRI) in children treated for medulloblastoma or primitive neuroectodermal tumor (PNET) and document the associated clinical, radiologic, and neurocognitive findings. Among 134 patients with medulloblastoma or supratentorial PNET treated prospectively with risk-adjusted craniospinal irradiation and conformal boost to the tumor bed, followed by four high-dose chemotherapy (HDC) cycles with stem-cell rescue, 22 developed WMLs on T1-weighted imaging with and without contrast and/or T2-weighted imaging on MRI. Patients had > or = 12 months of follow-up. Neurocognitive assessments included intelligence quotient (IQ) tests and tests of academic achievement. Twenty-two patients developed WMLs at a median of 7.8 months after starting therapy (range, 1.9 to 13.0 months). Lesions were predominantly in the pons (n = 8) and cerebellum (n = 6). Sixteen patients (73%) had WML resolution at a median of 6.2 months (range, 1.68 to 23.5 months) after onset; two patients developed necrosis and atrophy. Three developed persistent neurologic deficits. Cumulative incidence of WMLs at 1 year was 15% +/- 3%. Patients with WMLs had a significant decline in estimated IQ (-2.5 per year; P = .03) and math (-4.5 per year; P = .003) scores. WMLs in medulloblastoma or PNET patients treated with conformal radiotherapy and HDC are typically transient and asymptomatic, and may mimic early tumor recurrence. A minority of patients with WMLs develop permanent neurologic deficits and imaging changes. Overall, the presence of WMLs is associated with greater neurocognitive decline.

High dose chemotherapy in children with malignant lymphoma

High dose chemotherapy in children with malignant lymphoma

Radiotherapy followed by high dose busulfan and thiotepa: a prospective assessment of high dose chemotherapy in children with diffuse pontine gliomas.

The role of high dose chemotherapy (HDC) in patients with pediatric brain tumors currently is ill-defined. The purpose of this pilot study was to assess the feasibility and the benefit of HDC after radiotherapy in a group of children with newly diagnosed diffuse pontine gliomas. Patients eligible for study were ages 3-18 years with diffuse intrinsic tumors arising in the pons, who were not treated previously with radiotherapy or chemotherapy. Histologic confirmation was not mandatory, provided clinical findings and magnetic resonance imaging were typical. Patients were given focal radiotherapy followed 2-3 months later by HDC. Busulfan (150 mg/m(2) on Days 8, 7, 6, and 5) and thiotepa (300 mg/m(2) on Days 4, 3, and 2) were administered prior to autologous bone marrow transplantation. Survival was the endpoint, and the statistical procedure was based on sequential subgroup analysis. Thirty-six patients were entered on to the study, 12 of whom underwent stereotactic biopsy or open surgery at the time of diagnosis. One patient eventually was excluded due to inappropriate eligibility criteria. All 35 eligible patients received irradiation. Early progression (9 patients) and parental refusal (2 patients) precluded the use of HDC in 11 patients. Three patients died of HDC-related complications. All 21 patients who survived HDC eventually died of disease progression. The median survival time was 10 months for the study group. The median survival time in the subgroup of patients who received HDC was 10 months (range, 3-26 months). Statistical analysis did not suggest any evidence of survival benefit. For patients with diffuse pontine gliomas, survival using this aggressive treatment modality does not appear to be any better than that reported for conventional radiotherapy.

Autologous bone marrow transplantation for pediatric Wilms' tumor: The experience of the European bone marrow transplantation solid tumor registry

This survey includes 25 children with Wilms' tumor undergoing high-dose chemotherapy associated with autologous bone marrow transplantation (ABMT) in the period June 1984-December 1991 and enrolled in the European Bone Marrow Transplantation Registry for Solid Tumors. At diagnosis, 12 children presented stage IV disease, 5 stage III, 3 stage II, and 5 stage I. Before ABMT, 21 children had 1 to 4 relapses (median 1); 13 achieved a second or subsequent complete remission (CR), four stage IV children failed to respond to first line treatment and achieved either CR (3 patients), or partial remission (PR) after second line therapy. At high-dose chemotherapy, 17 children were in CR and 8 had measurable disease. Seven different high-dose regimens were administered, even if 20 children received melphalan mostly associated with vincristine and 8 involved field radiotherapy. Three children died early of pneumonitis; 2 developed an acute transient renal failure, 1 a chronic renal failure. Out of the 8 children with target disease at graft, 2 died of toxicity, 5 achieved CR, 1 obtained PR, and only 1 is presently alive in CCR at 39 months after ABMT. Of the 17 children grafted in CR, 8 are alive event-free at 14-90 months (median 34) from ABMT; 7 relapsed at 3-23 months (median 7 months); 1 died of toxicity and 1 was lost to follow-up in CR at 12 months. A salvage attempt with high-dose chemotherapy in children with resistant or poor prognosis recurrent Wilms' tumor seems to be justified. An international cooperative protocol taking into account the increased risk of lung and renal toxicity is necessary.