melphalan and Neuroblastoma

Spontaneous rupture of adrenal neuroblastoma is very rare in infants, in contrast to neonates. This report describes a 9-month-old boy presenting with acute hemorrhagic shock due to spontaneous rupture of adrenal neuroblastoma. MYCN oncogene amplification may be a predisposing factor for spontaneous rupture and bleeding of neuroblastoma. An appropriate surgical treatment for this condition must be discussed according to the patient's general state and the tumor features, such as staging, the origin, and local invasiveness.

Topics: Adrenal Gland Neoplasms; Antineoplastic Combined Chemotherapy Protocols; Cisplatin; Crystalloid Solutions; Cyclophosphamide; Doxorubicin; Erythrocyte Transfusion; Genes, myc; Hematopoietic Stem Cell Transplantation; Hemoperitoneum; Humans; Infant; Isotonic Solutions; Male; Melphalan; Neuroblastoma; Remission Induction; Risk Factors; Rupture, Spontaneous; Shock, Hemorrhagic; Thiotepa; Transplantation, Autologous; Vincristine

The MYCN oncogene encodes a transcription factor which is amplified in up to 40% of high risk neuroblastomas. MYCN amplification is a well-established poor prognostic marker in neuroblastoma, however the role of MYCN expression and the mechanisms by which it acts to promote an aggressive phenotype remain largely unknown. This review discusses the current evidence identifying the direct and indirect downstream transcriptional targets of MYCN from recent studies, with particular reference to how MYCN affects the cell cycle, DNA damage response, differentiation and apoptosis in neuroblastoma.

Topics: Apoptosis; Brain Neoplasms; Cell Cycle; Cell Differentiation; Cell Line, Tumor; DNA Damage; Drug Delivery Systems; Gene Expression Profiling; Gene Expression Regulation, Neoplastic; Humans; Immunoglobulin G; Melphalan; N-Myc Proto-Oncogene Protein; Neuroblastoma; Nuclear Proteins; Oncogene Proteins; Transcription Factors

To review the clinical pharmacology and clinical trials that have used intravenous (IV) high-dose melphalan (HDM).. We reviewed the mechanism of action, clinical pharmacology, and clinical studies of HDM with and without autologous bone marrow support (ABMT) or peripheral-blood progenitor cells (PBPCs) in the following disease areas: myeloma, ovarian cancer, malignant lymphoma, breast cancer, neuroblastoma, Ewing's sarcoma, and acute leukemia.. HDM has a distribution half-life (t1/2 alpha) of 5 to 15 minutes and an elimination half-life (t1/2 beta) of 17 to 75 minutes at doses of 140 to 180 mg/m2, with significant intrapatient variability. At these doses, a wide range of areas under the concentration/time curve (AUC) have been reported, ie, 146 to 1,515 mg/min/mL. HDM has significant clinical activity in patients with multiple myeloma in relapse or when used as consolidative therapy in relapsed ovarian cancer, relapsed Hodgkin's disease, breast cancer, and relapsed neuroblastoma. Additional studies are required to determine the activity of HDM in Ewing's sarcoma or acute leukemia. Toxicities of HDM include myelosuppression, moderate nausea and vomiting, moderate to severe mucositis and diarrhea, and, infrequently, hepatic venoocclusive disease.. HDM has become an established and effective salvage regimen for children with relapsed neuroblastoma, as well as an effective consolidative treatment for children with high-risk disease (stage IV). HDM is emerging as an active and effective mode of treatment in patients with stage II and III myeloma. The favorable toxicity profile of HDM and the availability of PBPCs allows for repetitive therapy.

Topics: Acute Disease; Administration, Oral; Antineoplastic Combined Chemotherapy Protocols; Breast Neoplasms; Female; Forecasting; Half-Life; Humans; Infusions, Intravenous; Leukemia; Lymphoma; Melphalan; Multiple Myeloma; Neuroblastoma; Ovarian Neoplasms; Sarcoma, Ewing

Topics: Antineoplastic Agents; Bone Marrow Transplantation; Child; Combined Modality Therapy; Humans; Melphalan; Neoplasms; Neuroblastoma; Randomized Controlled Trials as Topic; Rhabdomyosarcoma; Sarcoma, Ewing

Studies are described of high-dose therapy in metastatic breast cancer, early stage breast cancer, stage IV neuroblastoma, recurrent or bulky disease testicular cancer and Ewing's sarcoma. The outcome in these subgroups with conventional therapy is described for comparison. The results of these studies suggest that high-dose therapy with autologous marrow support increases the proportion of patients with long-term survival without evidence of disease. Newer supportive care and recurrent high-dose therapy cycles of non-cross resistant regimens may improve outcome further in these diseases and increase the application to more resistant tumors.

Topics: Adult; Antineoplastic Combined Chemotherapy Protocols; Bone Marrow Transplantation; Breast Neoplasms; Child; Combined Modality Therapy; Cyclophosphamide; Humans; Melphalan; Neoplasm Metastasis; Neoplasms; Neuroblastoma; Prednisone; Prognosis; Remission Induction; Survival Rate; Transplantation, Autologous; Treatment Outcome; Vincristine

Patients received. Thirty patients were enrolled from November 2008 to June 2015. Median age at diagnosis was 5.5 years (2-20). Twenty-one had very high-risk NBL (VHR-NBL), that is, stage 4 NBL at diagnosis or at relapse, with insufficient response (i.e., less than a partial response of metastases and more than three mIBG spots) after induction chemotherapy; nine had progressive metastatic relapse. Median Curie score at inclusion was 6 (1-26). Median number of prior lines of treatment was 3 (1-7). Objective response rate was 13% (95% confidence interval [CI]: 4-31) for the whole population, 19% for VHR-NBL, and 0% for progressive relapses. Immediate tolerance was good, with nonhematologic toxicity limited to grade-2 nausea/vomiting in eight patients. Two-year event-free survival was 17% (95% CI: 6-32). Among the 16 patients with VHR-NBL who had not received prior myeloablative busulfan-melphalan consolidation, 13 had at least stable disease after MIITOP; 11 subsequently received busulfan-melphalan; four of them were alive (median follow-up: 7 years).. MIITOP showed acceptable tolerability in this heavily pretreated population and encouraging survival rates in VHR-NBL when followed by busulfan-melphalan.

Topics: 3-Iodobenzylguanidine; Adolescent; Busulfan; Child; Child, Preschool; Chronic Disease; Humans; Melphalan; Neoplasm Recurrence, Local; Neuroblastoma; Topotecan; Young Adult

Topics: Autografts; Child, Preschool; Disease-Free Survival; Female; Humans; Infant; Male; Melphalan; Neuroblastoma; Stem Cell Transplantation; Survival Rate

The prognosis of resistant or relapsing children with neuroblastoma remains very poor, and the search for new therapies is ongoing. In this analysis, we assessed the toxicity of a treosulfan, melphalan, and thiotepa (TMT) regimen in 17 children with recurrent or refractory neuroblastoma who underwent stem cell transplantation (SCT). For allogeneic SCT, fludarabine and antithymocyte globulin were added. The stem cell source was autologous in 8 patients, haploidentical in 8 patients, and a matched unrelated donor in 1 patient. The reported nonhematologic toxicities included grade 3 mucositis, grade 1 to 3 hypertransaminasemia, and in 3 patients, veno-occlusive disease. No neurologic, cardiac, or dermatologic toxicities were observed. The probability of overall survival (OS) in patients with primary resistance was superior to that in patients with relapsed disease (100% versus 22.6%; P = .046). Post-transplantation dinutuximab beta immunotherapy was associated with superior 5-year OS (66.7% versus 11.4%; P = .0007). The use of an allogeneic donor, previous autologous SCT with busulfan and melphalan, and pretreatment with high-dose metaiodobenzylguanidine therapy demonstrated no effect on outcomes. In 4 patients, TMT megatherapy alone was enough to achieve complete remission. The TMT conditioning regimen was well tolerated in heavily pretreated patients with neuroblastoma. The manageable toxicity and addition of new anticancer drugs with optional post-SCT immunotherapy or chemotherapy support further trials with the TMT regimen in patients with neuroblastoma.

Topics: Allografts; Antineoplastic Combined Chemotherapy Protocols; Autografts; Busulfan; Child; Child, Preschool; Disease-Free Survival; Female; Humans; Male; Melphalan; Neuroblastoma; Recurrence; Stem Cell Transplantation; Survival Rate; Thiotepa

High-risk neuroblastoma is characterized by poor long-term survival, especially for very high-risk (VHR) patients (poor response of metastases after induction therapy). The benefits of a tandem high-dose therapy and hematologic stem cell reinfusion (HSCR) have been shown in these patients. Further dose escalation will be limited by toxicity. It is thus important to evaluate the efficacy and tolerability of the addition of new agents such as I-MIBG (131Iode metaiodobenzylguanidine) to be combined with high-dose therapy in the consolidation phase. We report the feasibility of busulfan/melphalan (BuMel) after I-MIBG therapy with HSCR in patients with refractory or relapsed metastatic neuroblastoma. From November 2008 to March 2015, 9 patients received BuMel after I-MIBG therapy and topotecan. The main toxicity was digestive with only 1 patient developing grade 4 sinusoidal obstructive syndrome. Seven patients are alive at a median follow-up of 25 months. Among them, 2 are in ongoing complete remission and 1 in ongoing stable disease. These results suggest that BuMel with HSCR can be administered safely 2 months after I-MIBG therapy associated with topotecan for VHR patients. This strategy will be compared with tandem high-dose chemotherapy (thiotepa and busulfan-melphalan), followed by HSCR in the upcoming SIOPEN VHR Neuroblastoma Protocol.

Topics: 3-Iodobenzylguanidine; Adolescent; Antineoplastic Combined Chemotherapy Protocols; Busulfan; Child; Child, Preschool; Female; France; Hematopoietic Stem Cell Transplantation; Humans; Male; Melphalan; Neoplasm Metastasis; Neuroblastoma; Risk Factors; Topotecan

Transplant-associated thrombotic microangiopathy (TA-TMA) is an increasingly recognized complication of hematopoietic cell transplant that can result in multi-organ failure (MOF). Patients undergoing high-dose chemotherapy with autologous stem cell transplant (aHCT) for neuroblastoma require good organ function to receive post-transplant radiation and immunotherapy. We examined TA-TMA incidence and transplant outcomes in patients with neuroblastoma receiving different transplant preparative regimens. Sixty patients underwent aHCT using high-dose chemotherapy: 41 patients received carboplatin/etoposide/melphalan (CEM), 13 patients busulfan/melphalan (Bu/Mel) and six patients received tandem transplant (cyclophosphamide/thiotepa and CEM). TA-TMA with MOF was diagnosed in 13 patients (21.7%) at a median of 18 days after aHCT. TA-TMA occurred in 12 patients receiving CEM and in 1 after cyclophosphamide/thiotepa. There were no incidences of TA-TMA after Bu/Mel regimen. Six of 13 patients with TA-TMA and MOF received terminal complement blocker eculizumab for therapy. They all recovered organ function and received planned post-transplant therapy. Out of seven patients who did not get eculizumab, two died from TA-TMA complications and four progressed to ESRD. We conclude that the CEM regimen is associated with a high incidence of clinically significant TA-TMA after aHCT and eculizumab can be safe and effective treatment option to remediate TA-TMA associated MOF.

Topics: Antibodies, Monoclonal, Humanized; Antineoplastic Combined Chemotherapy Protocols; Carboplatin; Child; Child, Preschool; Disease-Free Survival; Etoposide; Female; Hematopoietic Stem Cell Transplantation; Humans; Male; Melphalan; Neuroblastoma; Retrospective Studies; Survival Rate; Thrombotic Microangiopathies; Transplantation, Autologous

The Japanese Children's Cancer Group (JCCG) Neuroblastoma Committee (JNBSG) conducted a phase II clinical trial for high-risk neuroblastoma treatment. We report the result of the protocol treatment and associated genomic aberration studies.. JN-H-07 was a single-arm, late phase II trial for high-risk neuroblastoma treatment with open enrollment from June 2007 to February 2009. Eligible patients underwent five courses of induction chemotherapy followed by high-dose chemotherapy with hematopoietic stem cell rescue. Surgery for the primary tumor was scheduled after three or four courses of induction chemotherapy. Radiotherapy was administered to the primary tumor site and to any bone metastases present at the end of induction chemotherapy.. The estimated 3-year progression-free and overall survival rates of the 50 patients enrolled were 36.5 ± 7.0 and 69.5 ± 6.6%, respectively. High-dose chemotherapy caused severe toxicity including three treatment-related deaths. In response to this, the high-dose chemotherapy regimen was modified during the trial by infusing melphalan before administering carboplatin and etoposide. The modified high-dose chemotherapy regimen was less toxic. Univariate analysis revealed that patients younger than 547 days and patients whose tumor showed a whole chromosomal gains / losses pattern had a significantly poor prognosis. Notably, the progression-free survival of cases with MYCN amplification were not inferior to those without MYCN amplification.. The outcome of patients treated with the JN-H-07 protocol showed improvement over the results reported by previous studies conducted in Japan. Molecular and genetic profiling may enable a more precise stratification of the high-risk cohort.

Topics: Adolescent; Antineoplastic Combined Chemotherapy Protocols; Biomarkers, Tumor; Carboplatin; Child; Child, Preschool; Comparative Genomic Hybridization; Etoposide; Female; Humans; Induction Chemotherapy; Infant; Japan; Male; Melphalan; Neuroblastoma; Prospective Studies; Survival Rate; Treatment Outcome

In our previous SMC NB-2004 study of patients with high-risk neuroblastomas, which incorporated total-body irradiation (TBI) with second high-dose chemotherapy and autologous stem cell transplantation (HDCT/auto-SCT), the survival rate was encouraging; however, short- and long-term toxicities were significant. In the present SMC NB-2009 study, only TBI was replaced with. ClinicalTrials.gov NCT03061656.

Topics: 3-Iodobenzylguanidine; Adolescent; Antineoplastic Agents; Antineoplastic Combined Chemotherapy Protocols; Carboplatin; Child; Child, Preschool; Combined Modality Therapy; Cyclophosphamide; Etoposide; Humans; Induction Chemotherapy; Infant; Melphalan; Neuroblastoma; Stem Cell Transplantation; Thiotepa; Transplantation, Autologous; Young Adult

The treatment of pediatric high-risk neuroblastoma is intensive and multimodal. Despite the introduction of immunotherapy for minimal residual disease, survival rates remain suboptimal and new therapies are needed. As part of a phase 2 trial, we are using a consolidation therapy regimen that combines a busulfan/melphalan conditioning schema, autologous hematopoietic cell transplantation (AHCT), and experimental immunotherapy with hu14.18K322A (a humanized anti-GD2 monoclonal antibody), granulocyte-macrophage colony-stimulating factor (GM-CSF), and IL-2, with or without the adoptive transfer of haploidentical natural killer cells (NKs). Here we report on 30 patients who have undergone AHCT with this experimental immunotherapy regimen, 21 of whom received haploidentical NKs. The median time to neutrophil engraftment was 13 days (range, 10 to 28 days) and to platelet engraftment of at least 20  ×  103/mm

Topics: Antineoplastic Combined Chemotherapy Protocols; Busulfan; Child, Preschool; Consolidation Chemotherapy; Female; Granulocyte-Macrophage Colony-Stimulating Factor; Hematopoietic Stem Cell Transplantation; Humans; Infant; Infant, Newborn; Interleukin-2; Killer Cells, Natural; Male; Melphalan; Neuroblastoma; Prospective Studies; Transplantation, Autologous

High-risk neuroblastoma is characterised by poor long-term survival, especially for very high-risk (VHR) patients (poor response of metastases after induction therapy). We report the results of an intensified high-dose chemotherapy (HDC) strategy to improve the prognosis of VHR patients. This strategy was based on tandem HDC with thiotepa and busulfan-melphalan (Bu-Mel) followed by autologous stem cell transplantation (ASCT). All data were prospectively recorded in the Gustave Roussy Paediatric ASCT database. From April 2004 to August 2011, 26 patients were eligible for tandem HDC. The median age at diagnosis was 4.4 years (1-15.9). All patients had metastatic disease. MYCN was amplified in 5/26 tumours. Despite the cumulative toxicity of alkylating agents, the toxicity of the intensified HDC strategy was manageable. Thiotepa-related toxicity was mainly digestive, whereas sinusoidal obstruction syndrome was the main toxicity observed after Bu-Mel. The 3-year event-free survival of this cohort was 37.3% (21.3-56.7). This strategy will be compared with combined (131)I-mIBG/Bu-Mel in the upcoming SIOPEN VHR Neuroblastoma Protocol.

Topics: Adolescent; Antineoplastic Combined Chemotherapy Protocols; Autografts; Busulfan; Child; Child, Preschool; Disease-Free Survival; Female; Humans; Infant; Male; Melphalan; Neuroblastoma; Retrospective Studies; Stem Cell Transplantation; Survival Rate; Thiotepa

Myeloablative therapy for high-risk neuroblastoma commonly includes melphalan. Increased cellular glutathione (GSH) can mediate melphalan resistance. Buthionine sulfoximine (BSO), a GSH synthesis inhibitor, enhances melphalan activity against neuroblastoma cell lines, providing the rationale for a Phase 1 trial of BSO-melphalan.. Patients with recurrent/resistant high-risk neuroblastoma received BSO (3 gram/m(2) bolus, then 24 grams/m(2) /day infusion days -4 to -2), with escalating doses of intravenous melphalan (20-125 mg/m(2) ) days -3 and -2, and autologous stem cells day 0 using 3 + 3 dose escalation.. Among 28 patients evaluable for dose escalation, one dose-limiting toxicity occurred at 20 mg/m(2) melphalan (grade 3 aspartate aminotransferase/alanine aminotransferase) and one at 80 mg/m(2) (streptococcal bacteremia, grade 4 hypotension/pulmonary/hypocalcemia) without sequelae. Among 25 patients evaluable for response, there was one partial response (PR) and two mixed responses (MRs) among eight patients with prior melphalan exposure; one PR and three MRs among 16 patients without prior melphalan; one stable disease with unknown melphalan history. Melphalan pharmacokinetics with BSO were similar to reports for melphalan alone. Melphalan Cmax for most patients was below the 10 μM concentration that showed neuroblastoma preclinical activity with BSO.. BSO (75 gram/m(2) ) with melphalan (125 mg/m(2) ) is tolerable with stem cell support and active in recurrent/refractory neuroblastoma. Further dose escalation is feasible and may increase responses.

Topics: Adolescent; Antimetabolites, Antineoplastic; Antineoplastic Agents, Alkylating; Antineoplastic Combined Chemotherapy Protocols; Buthionine Sulfoximine; Child; Child, Preschool; Drug Synergism; Female; Glutamate-Cysteine Ligase; Glutathione; Hematopoietic Stem Cell Transplantation; Hematopoietic Stem Cells; Humans; Male; Melphalan; Myeloablative Agonists; Neoplasm Recurrence, Local; Neuroblastoma

To evaluate BSO-mediated glutathione (GSH) depletion in combination with L-PAM for children with recurrent or refractory high-risk neuroblastoma (NB) as a means to enhance alkylator sensitivity.. This pilot study (NCI #T95-0092) administered L-S,R-buthionine sulfoximine (BSO) as a bolus followed by 72 hr continuous infusion of either 0.75 g/m(2)/hr (level 1) or 1.0 g/m(2)/hr (level 2) and melphalan (L-PAM) (15 mg/m(2) bolus at hour 48 of BSO infusion). GSH in blood mononuclear cells and bone marrow was measured by enzymatic assay, BSO in plasma by HPLC.. Thirty two patients received 58 courses of therapy (median 1, range 1-4 courses). Blood mononuclear cell GSH decreased (48 hr) to 47% ± 15.7%. Level 2 mean steady-state concentration (Css) for BSO = 524 ± 207 μM and peak L-PAM concentration = 3.32 ± 1.2 μM. Grade 3-4 leukopenia and thrombocytopenia were common. There were two deaths from CNS toxicity and acute tubular necrosis; one had a large, intracranial mass, both were receiving cephalosporin antibiotics. No other significant toxicities were seen. There were six responses (five partial and, one mixed) representing an 18% response rate; four/six responses occurred in patients that relapsed following myeloablative therapy and included a 98% reduction in volume (cm(3)) of a pelvic mass, and three/five patients with >3 log reduction of tumor in marrow as measured by immunocytology (sensitivity 1/10(5)).. BSO/L-PAM has activity against recurrent high-risk NB. Exclusion of cephalosporin antibiotics in future clinical trials of BSO may diminish the potential for serious renal and CNS toxicity.

Topics: Antineoplastic Combined Chemotherapy Protocols; Buthionine Sulfoximine; Child; Chromatography, High Pressure Liquid; Female; Glutathione; Humans; Infusions, Intravenous; Injections, Intravenous; Male; Melphalan; Neoplasm Recurrence, Local; Neuroblastoma; Pilot Projects

To evaluate long-term survival of the first cohort of stage-4 neuroblastoma patients treated with the N7 induction chemotherapy, surgery of the primary tumor and high-dose chemotherapy (HDC) containing Busulfan-Melphalan (Bu-Mel) followed by autologous stem cell transplantation (ASCT).. From 1998 to 1999, 47 children were included in the NB97 trial and treated with induction chemotherapy according to the N7 protocol, followed by surgery of the primary tumor. HDC (Busulfan, 600 mg/m(2) Melphalan, 140 mg/m(2) ) was administered in patients with partial response of metastases with no more than 3 mIBG spots. Radiotherapy was delivered to the primary tumor site when tumors displayed MYCN amplification.. Thirty-nine patients received Bu-Mel (83%): 23 who had achieved complete response (CR) of metastases, 20 after induction treatment and 3 after second-line chemotherapy, and 16 in partial response (PR). The toxicity of the whole treatment was manageable. The main HDC related-toxicity was hepatic veno-occlusive disease grade > 2 occurring in 15% of the patients. The 8-year EFS of the whole cohort was 34% (95% CI, 22-48%). The 8-year EFS of the 39 patients who received Bu-Mel and ASCT was 41% (95% CI, 27-57%). Patients who achieved a CR of metastases at the end of induction chemotherapy had a significantly better outcome than the others (8-year EFS, 52% vs. 20%; P = 0.02).. The long-term results of this first prospective cohort of patients with metastatic disease treated with the N7 induction chemotherapy and HDC (Bu-Mel) confirm published data with stable survival curves but with a longer follow-up.

Topics: Abdominal Neoplasms; Antineoplastic Combined Chemotherapy Protocols; Busulfan; Child; Child, Preschool; Combined Modality Therapy; Consolidation Chemotherapy; Disease-Free Survival; Follow-Up Studies; Gene Amplification; Genes, myc; Hematopoietic Stem Cell Transplantation; Hepatic Veno-Occlusive Disease; Humans; Infant; Kaplan-Meier Estimate; Melphalan; Myeloablative Agonists; Neuroblastoma; Proportional Hazards Models; Remission Induction; Thoracic Neoplasms; Transplantation Conditioning; Transplantation, Autologous; Treatment Outcome

Although high-dose chemotherapy (HDC) represents the standard of treatment for high-risk neuroblastoma (NBL), the most effective conditioning regimen still remains to be identified.. Forty-one high-risk NBL entered into local protocol based on induction chemotherapy, surgery and HDC with either etoposide/thiotepa/cyclophophamide (ETC) or i.v. busulfan and L-PAM (Bu/L-PAM).. Thirty-seven patients underwent HDC; 29 with ETC and 8 with Bu/L-PAM. No toxic deaths were recorded. The 5-year progression-free survival (PFS) of patients given ETC was 21% (95% confidence interval CI (9-36%), while PFS for patients given Bu/L-PAM was 88% (95% CI=39-98%) (p<0.05). In multivariate analysis, treatment with the ETC regimen predicted progression/recurrence with a hazard ratio (HR) of 16.8 (p<0.05), as well as MYCN amplification which had an HR of 4.4 (p<0.05).. Although the number of studied cases is limited, our data suggest that in high-risk NBL the combination of Bu/L-PAM is superior to the ETC regimen.

Topics: Adolescent; Antineoplastic Combined Chemotherapy Protocols; Busulfan; Child; Child, Preschool; Combined Modality Therapy; Cyclophosphamide; Disease-Free Survival; Etoposide; Female; Gene Amplification; Hematopoietic Stem Cell Transplantation; Humans; Infant; Male; Melphalan; N-Myc Proto-Oncogene Protein; Neuroblastoma; Nuclear Proteins; Oncogene Proteins; Risk Factors; Thiotepa; Transplantation Conditioning

Graft contamination has been blamed for causing relapse in children with high-risk neuroblastoma (HRNB) after autologous hematopoietic stem cell transplantation (HSCT).. We report the long-term results of hematopoietic reconstitution, post-transplant complications, and clinical outcome of 44 children with HRNB treated with busulfan/melphalan high-dose chemotherapy followed by transplantation of purged CD34+ immunoselected autologous peripheral HSCT. Minimal residual disease (MRD) of grafts was evaluated by anti-GD2 immunofluorescence or tyrosine hydroxylase reverse transcriptase-polymerase chain reaction (RT-PCR).. Contaminating neuroblasts were found in 19/38 grafts (50%) before CD34+ positive selection, and none after (technique sensitivity of one cell in 10(5)). A median of 6.5 × 10(6) CD34+ cells/kg (range 0.8-23.7) were transplanted with only 2% of TRM. Neutrophils and platelet recovery occurred within a median of 12 days (range 9-47) and 44 days (range 12-259), respectively, without any secondary graft failure. Twenty-three percents of patients experienced a sepsis (10/44) and 14% a pyelonephritis (6/44). Recurrence of varicella zoster virus occurred in 21% of patients (9/44). Negative RT-PCR MRD within the leukapheresis product and cis-retinoic acid therapy were significantly and independently associated to a better survival (P < 0.05). Overall and event-free survivals at 5 years post-transplant were at 59.3% and 48.3% respectively.. Besides high rates of manageable infections due to late immune recovery, transplantation with CD34+ immunoselected grafts in HRNB children was feasible and did not affect long-term hematopoiesis.

Topics: Antigens, CD34; Busulfan; Child; Follow-Up Studies; Hematopoiesis; Hematopoietic Stem Cell Transplantation; Hematopoietic Stem Cells; Humans; Immunomagnetic Separation; Infections; Leukapheresis; Melphalan; Neoplasm, Residual; Neuroblastoma; Survival Analysis; Transplantation, Autologous

The aim of this study was to clarify the feasibility of a novel treatment strategy consisting of postponed primary surgery till the end of systemic chemotherapy including HDC without interruption by local therapy for neuroblastoma patients at a high risk for relapse. After induction chemotherapy, patients received double conditioning HDC consisting of thiotepa and melphalan. Radical surgery was applied to local lesions. Irradiation was not applied to any lesions. Eleven consecutive pediatric neuroblastoma patients were treated according to this strategy. Seven of 11 patients remained in complete remission for 21-171 months. This treatment strategy seems feasible and a further study is warranted.

Topics: Adult; Child; Combined Modality Therapy; Female; Hematopoietic Stem Cell Transplantation; Humans; Male; Melphalan; Middle Aged; Neuroblastoma; Thiotepa; Transplantation Conditioning; Transplantation, Homologous; Treatment Outcome

Limited information is available regarding the use of amifostine in pediatric hematopoietic stem cell transplant (HSCT) patients. Melphalan, carboplatin, etoposide +/- cyclophosphamide is a commonly used preparatory regimen in pediatric solid tumor HSCT. Therefore, we decided to determine the feasibility of the addition of amifostine (750 mg/m b.i.d. x 4 d) to melphalan (200 mg/m), carboplatin (1200 mg/m), and etoposide (800 mg/m) (level 1) and escalating doses of cyclophosphamide (3000 mg/m and 3800 mg/m, levels 2 and 3, respectively) followed by autologous HSCT. Thirty-two patients with a variety of pediatric solid tumors were studied. Seventeen patients were accrued at level 1, 9 at level 2, and 6 at level 3. Major toxicities during the administration of the preparatory regimen were hypocalcemia, emesis, and hypotension. Hypocalcemia required aggressive calcium supplementation during the conditioning phase. No dose limiting toxicities were encountered at level 3. Amifostine at 750 mg/m b.i.d. for 4 days can be administered with a double alkylator regimen consisting of melphalan (200 mg/m), cyclophosphamide (up to 3800 mg/m), carboplatin (1200 mg/m), and etoposide (800 mg/m) with manageable toxicities.

Topics: Adolescent; Adult; Amifostine; Antineoplastic Combined Chemotherapy Protocols; Bone Marrow Transplantation; Bone Neoplasms; Carboplatin; Central Nervous System Neoplasms; Child; Child, Preschool; Combined Modality Therapy; Cyclophosphamide; Dose-Response Relationship, Drug; Drug Administration Schedule; Drug-Related Side Effects and Adverse Reactions; Etoposide; Feasibility Studies; Hematopoietic Stem Cell Transplantation; Hodgkin Disease; Humans; Hypocalcemia; Kidney Neoplasms; Melphalan; Neoplasms; Neuroblastoma; Pilot Projects; Recurrence; Risk Factors; Sarcoma; Transplantation, Autologous; Transplantation, Homologous; Treatment Outcome; Wilms Tumor

To determine the maximum-tolerated dose (MTD) and toxicity of iodine-131-metaiodobenzylguanidine ((131)I-MIBG) with carboplatin, etoposide, melphalan (CEM) and autologous stem-cell transplantation (ASCT) in refractory neuroblastoma.. Twenty-four children with primary refractory neuroblastoma and no prior ASCT were entered; 22 were assessable for toxicity and response. (131)I-MIBG was administered on day -21, CEM was administered on days -7 to -4, and ASCT was performed on day 0, followed by 13-cis-retinoic acid. (131)I-MIBG was escalated in groups of three to six patients, stratified by corrected glomerular filtration rate (GFR).. The MTD for patients with normal GFR (> or = 100 mL/min/1.73 m2) was 131I-MIBG 12 mCi/kg, carboplatin 1,500 mg/m2, etoposide 1,200 mg/m2, and melphalan 210 mg/m2. In the low-GFR cohort, at the initial dose level using 12 mCi/kg of 131I-MIBG and reduced chemotherapy, one in six patients had dose limiting toxicity (DLT), including veno-occlusive disease (VOD). Three more patients in this group had grade 3 or 4 hepatotoxicity, and two had VOD, without meeting DLT criteria. There was only one death as a result of toxicity among all 24 patients. All assessable patients engrafted, with median time for neutrophils > or = 500/microL of 10 days and median time for platelets > or = 20,000/microL of 26 days. Six of 22 assessable patients had complete or partial response, and 15 patients had mixed response or stable disease. The estimated probability of event-free survival and survival from the day of MIBG infusion for all patients at 3 years was 0.31 +/- 0.10 and 0.58 +/- 0.10, respectively.. 131I-MIBG with myeloablative chemotherapy is feasible and effective for patients with neuroblastoma exhibiting de novo resistance to chemotherapy.

Topics: 3-Iodobenzylguanidine; Adolescent; Antineoplastic Agents; Carboplatin; Child; Child, Preschool; Disease-Free Survival; Drug Administration Schedule; Etoposide; Female; Hematopoietic Stem Cell Transplantation; Humans; Male; Melphalan; Neuroblastoma; Survival Analysis; Transplantation, Autologous; Treatment Outcome

Normalized glomerular filtration rate (nGFR) <60 mL/min/1.73 m(2) often precludes hematopoietic stem cell transplant (HSCT) in pediatric patients. Three patients with nGFR < 60 mL/min/1.73 m(2) enrolled on an institutional phase I trial of HSCT preparative therapy for advanced and recurrent solid tumors with escalating melphalan, ranging from 135 to 180 mg/m(2), thiotepa (600 mg/m(2)), and vincristine (2 mg/m(2)). An additional patient with low nGFR was treated with the same preparative therapy. None of the patients developed acute renal failure, excess toxicities during HSCT or delayed engraftment. These cases demonstrate that it is feasible and safe to perform HSCT in pediatric patients with low nGFR using melphalan- and thiotepa-based preparative therapy.

Topics: Antineoplastic Agents, Alkylating; Child, Preschool; Combined Modality Therapy; Drug Therapy, Combination; Female; Glomerular Filtration Rate; Hematopoietic Stem Cell Transplantation; Humans; Infant; Kidney Neoplasms; Melphalan; Neuroblastoma; Thiotepa; Transplantation, Autologous; Treatment Outcome; Wilms Tumor

High dose myeloablative chemotherapy ("megatherapy"), with haematopoietic stem cell support, is now widely used to consolidate response to induction chemotherapy in patients with advanced neuroblastoma.. In this study (European Neuroblastoma Study Group, ENSG1), the value of melphalan myeloablative "megatherapy" was evaluated in a randomised, multi-centre trial. Between 1982 and 1985, 167 children with stages IV and III neuroblastoma (123 stage IV > 1 year old at diagnosis and 44 stage III and stage IV from 6 to 12 months old at diagnosis) were treated with oncovin, cisplatin, epipodophyllotoxin, and cyclophosphamide (OPEC) induction chemotherapy every 3 weeks. After surgical excision of primary tumour, the 90 patients (69% of the total) who achieved complete response (CR) or good partial response (GPR) were eligible for randomisation either to high dose melphalan (180 mg per square meter) with autologous bone marrow support or to no further treatment.. Sixty-five (72%) of eligible children were actually randomised and 21 of these patients were surviving at time of this analysis, with median follow-up from randomisation of 14.3 years. Five year event-free survival (EFS) was 38% (95% confidence interval (CI) 21-54%) in the melphalan-treated group and 27% (95% CI 12-42%) in the "no-melphalan" group. This difference was not statistically significant (P = 0.08, log rank test) but for the 48 randomised stage IV patients aged >1 year at diagnosis outcome was significantly better in the melphalan-treated group-5 year EFS 33% versus 17% (P = 0.01, log rank test).. In this trial, high dose melphalan improved the length of EFS and overall survival of children with stage IV neuroblastoma >1 year of age who achieved CR or GPR after OPEC induction therapy and surgery. Multi-agent myeloablative regimens are now widely used as consolidation therapy for children with stage IV disease and in those with other disease stages when the MYCN gene copy number in tumour cells is amplified. Because they are more toxic, complex, and costly these combination megatherapy regimens should be compared with single agent melphalan in randomised clinical trials.

Topics: Antineoplastic Agents, Alkylating; Child, Preschool; Combined Modality Therapy; Disease-Free Survival; Europe; Female; Humans; Infant; Life Tables; Male; Melphalan; Neuroblastoma; Survival Rate

The Lyon-Marseille-Curie-Est (LMCE) of France cooperative group has previously reported successive series of unselected stage four children older than 1 year at diagnosis with metastatic neuroblastoma (LMCE 1 and 3). The goal of LMCE 5 study was to increase progression free survival rate as compared to LMCE 1 and 3. Based on improvements reported with post induction chemotherapy, the LMCE 5 used post induction for all children, but omitted total body irradiation and immunomagnetic purging in megatherapy regimen for all children. Twenty-five sequentially diagnosed children received an induction regimen which compared with previous induction included an increased dose of etoposide and cyclophosphamide, delivered similar dose of cisplatinum, and deleted doxorubicin and vincristin. After surgery treatment was stratified based on response and eligible children received etoposide carboplatin (LMCE 5A : n=10)+/-doxorubicin (LMCE 5B-C n=13) followed by megatherapy (melphalan without total body irradiation and unpurged peripheral blood stem cell rescue). The increase in drug doses during induction did not improve remission rate. The progression free survival at 6 years is 8%. It is significantly worse than LMCE 3, and equivalent to LMCE 1 study though toxic death rate has decreased with increasing experience. Failure to improve the response rate during induction and reducing the megatherapy regimen may be the main factors in this disappointing result. Modified strategies for induction, non toxic alternative to total body irradiation, and post megatherapy regimen should be developed.

Topics: Adolescent; Antineoplastic Combined Chemotherapy Protocols; Carboplatin; Child; Child, Preschool; Cisplatin; Cohort Studies; Cyclophosphamide; Disease-Free Survival; Doxorubicin; Etoposide; Female; Humans; Infant; Male; Melphalan; Neuroblastoma; Peripheral Blood Stem Cell Transplantation; Treatment Outcome

The survival for children with relapsed or metastatic neuroblastoma remains poor. More effective regimens with acceptable toxicity are required to improve prognosis. Iodine-131-metaiodobenzylguanidine ((131)I-MIBG) selectively targets radiation to catecholamine-producing cells, including neuroblastoma cells. A pilot study was performed to examine the feasibility of a novel regimen combining (131)I-MIBG and myeloablative chemotherapy with autologous stem-cell rescue.. Twelve patients with neuroblastoma were treated after relapse (five patients) or after induction therapy (seven patients). Eight patients had metastatic and four had localized disease at the time of therapy. All patients received (131)I-MIBG 12 mCi/kg on day -21, followed by carboplatin (1,500 mg/m(2)), etoposide (800 mg/m(2)), and melphalan (210 mg/m(2)) administered from day -7 to day -4. Autologous peripheral-blood stem cells or bone marrow were infused on day 0. Engraftment, toxicity, and response rates were evaluated.. The (131)I-MIBG infusion and myeloablative chemotherapy were both well tolerated. Grade 2 to 3 oral mucositis was the predominant nonhematopoietic toxicity, occurring in all patients. The median times to neutrophil (> or = 0.5 x 10(3)/microL) and platelet (> or = 20 x 10(3)/microL) engraftment were 10 and 28 days, respectively. For the eight patients treated with metastatic disease, three achieved complete response and two had partial responses by day 100 after transplantation.. Treatment with (131)I-MIBG in combination with myeloablative chemotherapy and hematopoietic stem-cell rescue is feasible with acceptable toxicity. Future study is warranted to examine the efficacy of this novel therapy.

Topics: 3-Iodobenzylguanidine; Antineoplastic Combined Chemotherapy Protocols; Carboplatin; Child; Child, Preschool; Combined Modality Therapy; Etoposide; Feasibility Studies; Hematopoietic Stem Cell Transplantation; Humans; Melphalan; Neuroblastoma; Pilot Projects; Radiopharmaceuticals; Transplantation, Autologous

Repeated high-dose (HD) chemotherapy with peripheral blood stem cell (PBSC) transplantation is a new modality aimed at increasing both the dose and its intensity in the treatment of chemosensitive tumours. The aim of this study was to evaluate the tolerance, pharmacokinetics (PK) and pharmacodynamics (PD) of HD single-agent melphalan administered over two consecutive courses (C1 and C2) in children. Twenty-one patients (10 girls) with a median age of 4.1 years (range 8 months-14 years) were entered into this study. Five had metastatic neuroblastoma (NB) and 16 a cerebral primitive neuroectodermal tumour (PNET). Melphalan was given at a dose of 100 mg/m(2) every 21 days. PBSCs were infused at a median number of 2.98 x 10(6) CD34(+) cells/kg. Forty courses, ie 21 C1 and 19 C2, were administered. Both courses were well tolerated. The median duration of ANC < 500/microl was 7 and 6 days after C1 and C2, respectively. Platelet recovery (not mandatory to continue the HD strategy) was achieved in 52% of courses. GI toxicity was mild to moderate. The melphalan AUC ranged from 177 to 475 microg small middle dotmin/ml (no difference between C1 and C2). Prolonged neutropenia was associated with a young age (P < 0.001) and a low amount of CFU-GM (P = 0.002). A long time to platelet recovery was associated with a high AUC (P = 0.004) and a young age (P = 0.02). Grade 1 or 2 GI toxicity was associated with a high AUC (P = 0.015). Partial remission was observed in 11/14 patients with measurable cerebral PNET. In conclusion, tandem HD melphalan is feasible and safe in children, and achieved a high response rate in cerebral PNET. The observed PK-PD relationships may help us design PK-guided outpatient treatment.

Topics: Adolescent; Antineoplastic Agents, Alkylating; Area Under Curve; Cerebellar Neoplasms; Child; Child, Preschool; Dose-Response Relationship, Drug; Drug Administration Schedule; Female; Hematopoietic Stem Cell Transplantation; Humans; Infant; Male; Medulloblastoma; Melphalan; Metabolic Clearance Rate; Neuroblastoma; Transplantation Conditioning

The early biological response has been proved an excellent predictor in acute lymphoblastic leukemia and nephroblastoma. We asked whether catecholamine metabolites, mIBG scan, and bone marrow evaluation might be relevant response markers in disseminated neuroblastoma.. Three hundred sixty-seven unselected stage 4 neuroblastoma patients treated according the German cooperative trial NB90 were entered into the study. Catecholamine plasma and urine levels were centrally determined by gas chromatography/ mass spectrometry. Bone marrow cytology and mIBG scans were evaluated by local investigators.. At diagnosis, mIBG scan was positive in 306 patients (92%), borderline in seven patients (2%), and negative in 19 patients (6%). Bone marrow aspirates were cytologically positive in 292 patients (84%) and negative in 57 patients (16%). Plasma catecholamine levels were elevated in 79% (206 of 260 patients.), urinary levels in 91% (307 of 338 patients). The outcome of patients with normalized mIBG scan after four courses of chemotherapy [5 year EFS (event free survival) 0.22 +/- 0.07] was not superior to the outcome of patients with still abnormal uptake (5 year EFS 0.30 +/- 0.05). The event free survival of patients with still positive bone marrow aspirates after four courses (0.16 +/- 0.06) was inferior to the EFS of patients with negative bone marrow aspirates (0.26 +/- 0.04, P = 0.0054). Urinary catecholamine normalization after four cycles of chemotherapy (5 year EFS 0.35 +/- 0.06 versus 0.26 +/- 0.10) had no influence on outcome, whereas plasma catecholamine normalization after the first (5 year EFS 0.40 +/- 0.09 versus 0.14 +/- 0.07, P= 0.0364) or the fourth cycle (5 year EFS 0.35 +/- 0.06 versus 0.26 +/- 0.10, P = 0.0242) indicated a better outcome.. These data show that serial plasma catecholamine levels and bone marrow aspirates in the course of the disease are useful tools in predicting outcome.

Topics: 3-Iodobenzylguanidine; Antineoplastic Combined Chemotherapy Protocols; Biomarkers, Tumor; Bone Marrow Examination; Chemotherapy, Adjuvant; Cisplatin; Combined Modality Therapy; Cyclophosphamide; Dacarbazine; Disease-Free Survival; Doxorubicin; Etoposide; Homovanillic Acid; Humans; Ifosfamide; Iodine Radioisotopes; Life Tables; Melphalan; Neoplasm Staging; Neuroblastoma; Radionuclide Imaging; Radiopharmaceuticals; Radiotherapy, Adjuvant; Survival Analysis; Treatment Outcome; Vanilmandelic Acid; Vincristine; Vindesine

One hundred and seventy-five children with Stage 3 or 4 neuroblastoma who had obtained a good response to conventional therapy were randomly allocated to 13-Cis retinoic acid at a dose of 0.75 mg/kg/day or placebo for up to 4 years. Toxicity was mild but no advantage in event-free survival was shown for the children receiving retinoic acid.

Topics: Adolescent; Adult; Antineoplastic Agents, Alkylating; Cheilitis; Child; Child, Preschool; Dose-Response Relationship, Drug; Double-Blind Method; Follow-Up Studies; Humans; Infant; Isotretinoin; Melphalan; Neoplasm Staging; Neoplasm, Residual; Neuroblastoma; Skin Diseases; Survival Analysis; Survival Rate; Treatment Outcome

We conducted a prospective pilot study to assess the feasibility and safety of high-dose busulfan/melphalan as conditioning therapy prior to autologous PBPC transplantation in pediatric patients with high-risk solid tumors. From January 1995 to January 1999, 30 patients aged 2-21 years (median 8) were entered into the study. There were 14 females and 16 males. Diagnoses included neuroblastoma in 10 patients; Ewing's sarcoma and peripheral neuroectodermal tumor (PNET) in 15 patients and rhabdomyosarcoma in five patients. Treatment consisted of busulfan 16 mg/kg, orally over 4 days (from days -5 to -2) in 6 hourly divided doses, and melphalan at a dose of 140 mg/m2 given by intravenous infusion over 5 min on day -1. G-CSF mobilized PBPC were used as autologous stem-cell rescue. One patient developed a single generalized convulsion during busulfan therapy. The most relevant non-hematologic toxicity was gastrointestinal, manifesting as grade 2-3 mucositis and diarrhea in 12 patients. Two patients died of procedure-related complications, one from veno-occlusive disease of liver and multiorgan failure and the other from adult respiratory distress syndrome. Probability of treatment-related mortality was 6.6 +/- 4.5%. With a median follow-up of 18 months (range, 1-48), 19 patients are alive and disease-free, the actuarial EFS at 4 years being 55 +/- 12% for the whole group. We conclude that high-dose busulfan/melphalan for autologous transplantation in children with solid tumors is feasible even in small patients. It is well-tolerated, with an acceptable transplant-related mortality and has proven antitumor activity.

Topics: Adolescent; Adult; Antigens, CD34; Antineoplastic Agents, Alkylating; Blood Cell Count; Bone Diseases; Bone Neoplasms; Busulfan; Child; Child, Preschool; Clonazepam; Disease-Free Survival; Female; Hematopoietic Stem Cell Transplantation; Humans; Male; Melphalan; Neoplasms; Neuroblastoma; Pilot Projects; Retrospective Studies; Rhabdomyosarcoma; Sarcoma, Ewing; Survival Rate; Transplantation Conditioning; Transplantation, Autologous

Between January 1993 and December 1996, 21 children with advanced solid tumors were entered in a dose-escalating study of high-dose sequential chemotherapy followed by autologous stem cell transplantation. The diagnoses included neuroblastoma (NB) for 13 patients; Ewing's sarcoma (ES) for six patients and osteosarcoma for two patients. Nine patients received therapy as consolidation for primary metastatic disease, and 12 patients had had previous relapses. Treatment consisted of CY given i.v. at a dose of 7 g/m2 on day 1, followed by G-CSF until myeloid recovery. After 3 weeks of rest, all patients were given thiotepa i.v. on days 22-24. The total dose of thiotepa was 450 mg/m2 in three patients, 600 mg/m2 in six patients, and 750 mg/m2 in 12 patients. Melphalan was given i.v. at a dose of 180 mg/m2 i.v. on day 27 followed by stem cell infusion on day 28. Major toxic reactions included stomatitis, esophagitis, diarrhea and dermatitis. Three patients died of treatment-related complications. Twelve patients have had a relapse. Six patients (five with NB and one with ES) are alive in continuous remission 5-50 months (median 36) after transplantation. The results of this study show that it is feasible to administer high-dose sequential chemotherapy to children with advanced solid tumors.

Topics: Adolescent; Antineoplastic Combined Chemotherapy Protocols; Bone Neoplasms; Child; Child, Preschool; Combined Modality Therapy; Cyclophosphamide; Digestive System Diseases; Drug Administration Schedule; Female; Granulocyte Colony-Stimulating Factor; Hematopoietic Stem Cell Mobilization; Hematopoietic Stem Cell Transplantation; Humans; Infant; Male; Melphalan; Neoplasms; Neuroblastoma; Osteosarcoma; Remission Induction; Salvage Therapy; Sarcoma, Ewing; Survival Analysis; Thiotepa; Treatment Outcome

The purpose of the study was to determine the maximum tolerated dose of continuous infusion of high-dose VP-16 in combination with high-dose melphalan (HDM) for conditioning before autologous bone marrow transplantation (ABMT). Thirteen children (median age 27 months) with stage IV neuroblastoma were treated with high-dose VP-16 and HDM followed by ABMT as consolidation treatment. All had previously received conventional chemotherapy with a mean number of six drugs. Surgery of the primary tumor had been performed in 12/13. We performed a dose-escalating study of VP-16 from 1800 mg/m2/72 h with 300 mg/m2/72 h dose increments according to toxicity. VP-16 was administered as a 72-h i.v. infusion. Melphalan (140 mg/m2/day) was administered once as an i.v. push. VP-16 pharmacokinetics were analyzed in 12 patients. Five children received 1800 mg/m2/72 h of VP-16, five received 2100 mg/m2/72 h and three, 2400 mg/m2/72 h. The mean duration of granulocytopenia (< 0.5 x 10(9)/1) was 24 days and thrombocytopenia (< 50 x 10(9)/1) was 36 days. No major infectious complications occurred. Gastrointestinal (GI) toxicity was the dose-limiting toxicity. Five severe manifestations of GI toxicity in three patients led us to consider 2400 mg/m2/72 h as the MTD. The mean VP-16 clearance rate was 17.3 ml/min/m2 with continuous infusion. A mean steady-state plasma concentration of 24.2 micrograms/ml (s.d. = 2) and 28.3 micrograms/ml (s.d. = 1.9) was achieved at the 1800 mg/ml and 2100 mg/m2 dose levels, respectively, GI toxicity is dose limiting when VP-16 at 2400 mg/m2/72 h, is associated with HDM. When given as a continuous i.v. infusion, at 2100 mg/m2/72 h, VP-16 associated with HDM is well tolerated before ABMT in young heavily pre-treated children.

Topics: Antineoplastic Combined Chemotherapy Protocols; Bone Marrow Transplantation; Child; Cisplatin; Combined Modality Therapy; Cyclophosphamide; Diarrhea; Dose-Response Relationship, Drug; Doxorubicin; Etoposide; Female; Humans; Infant; Infusions, Intravenous; Injections, Intravenous; Male; Melphalan; Neuroblastoma; Neutropenia; Remission Induction; Salvage Therapy; Stomatitis; Transplantation Conditioning; Vincristine

From October 87 to April 92, 172 children were admitted in the N-I-87 protocol of the Spanish Society of Pediatric Oncology for the diagnosis and treatment of neuroblastoma. Forty-eight were considered Evans stage III, 33 of them being older than 1 year. All children were treated with induction chemotherapy (IC) and surgery. IC consisted of three courses of high-dose cisplatin-VM-26 alternating with three further courses of cyclophosphamide-doxorubicin (CAD). Infants less than 1 year received the same drugs at lower doses. After surgery, maintenance chemotherapy was administered to all children during 14 months. It consisted of four pairs of drugs rotated every 4 weeks. Radiotherapy was administered exclusively to patients older than 1 year with residual tumor after IC and surgery. Response was evaluated after IC and surgery. In children older than 1 year, response was obtained in 28/33 (88%). Fifteen of them (47%) achieved complete remission (CR), seven (22%) good partial response (GPR), six (19%) partial response (PR); and in three patients (9%) there was progressive disease (PD). Actuarial survival at 48 months was 0.60 +/- 0.10 and EFS was 0.61 +/- 0.12. Audiologic impairment was considered the worst toxicity. In children less than 1 year the response rate to IC and surgery was 93% (14/15); nine infants obtained complete response and four had GPR. Only one patient experienced PD in the first 6 months of therapy and died. The other 14 are alive and well at a mean follow-up time of 48 months. Chemotherapy toxicity was mild and reversible.

Topics: Adolescent; Antineoplastic Combined Chemotherapy Protocols; Female; Humans; Infant; Lomustine; Male; Melphalan; Neuroblastoma; Remission Induction; Treatment Outcome; Vindesine

Twenty-six children with advanced neuroblastoma were consolidated with cisplatin, BCNU, etoposide, melphalan, 21 Gy of local radiotherapy, and bone marrow rescue in a multicenter study. All patients were over 1 year of age at diagnosis. Twenty-two patients were treated in first complete or partial remission and four in second complete or partial remission. Hematologic rescue was autologous (n = 23), allogeneic (n = 2), or syngeneic (n = 1). Extrahematological toxicity involved primarily the gastrointestinal mucosa. Among five fatal toxicities, three included intestinal hemorrhage. Fourteen patients relapsed after BMT, four of them at the primary site. Seven children survive progression-free after 16-56 months. These results are essentially not different from a single-center study with the same protocol or from other published studies. The value of megatherapy for patients with advanced neuroblastoma or for a subgroup of them can only be established on a larger number of patients than most national trials accrue.

Topics: Antineoplastic Combined Chemotherapy Protocols; Bone Marrow Purging; Bone Marrow Transplantation; Carmustine; Child; Cisplatin; Combined Modality Therapy; Disease-Free Survival; Etoposide; Follow-Up Studies; Humans; Infant; Melphalan; Neoplasm Recurrence, Local; Neuroblastoma; Radiotherapy, High-Energy; Remission Induction; Survival Rate

In the LMCE1 study using a single course of megatherapy most of the relapses occurred during the first 2 years after autologous bone marrow transplantation. A second pilot study (LMCE2) was therefore set up using a double harvest/double graft approach with two different megatherapy regimens. Objectives were to test the role of increased dose intensity on response status, relapse pattern and overall survival. Thirty-three patients (20 boys, 13 girls) with a median age of 53 months at first megatherapy (range, 17-202 months) entered this study. They were cases either with refractory disease in partial response after second line treatment for stage 4 neuroblastoma (n = 25) or after relapse from stage 4 (n = 5) or stage 3 disease (n = 3). All patients received Etoposid and/or Cisplatinum (or Carboplatin) containing treatments before megatherapy. The first megatherapy regimen was a combination of Tenoposid, Carmustine and Cisplatinum (or Carboplatin), the second applied Vincristin, Melphalan and Total Body Irradiation. The first harvest was scheduled 4 weeks after the last chemotherapy, the second 60 to 90 days after megatherapy. All marrows were purged in vitro by an immunomagnetic technique. Median follow up time since first megatherapy is 56 months. Response rates for evaluable patients were 65% (complete response rate: 16%) for megatherapy 1 and 60% (complete response rate: 25%) for megatherapy 2. Considering that only patients with delayed response or relapse were eligible for this pilot study the overall survival was encouraging with 36% at 2 years and still 32% at 5 years. The costs for these survival rates were high in terms of morbidity (four early and four late toxic deaths; toxic death rate: 24%). Double harvesting may have the disadvantage of delayed engraftments related in part to a disturbance of marrow microenvironment by megatherapy 1. This double megatherapy approach achieved a prolonged relapse free interval (median 11 months, range 2-31 months) in patients reaching megatherapy 2 and justifies further evaluation of concepts with consecutive dose-escalation.

Topics: Adolescent; Antineoplastic Combined Chemotherapy Protocols; Bone Marrow Transplantation; Carboplatin; Carmustine; Child; Child, Preschool; Cisplatin; Combined Modality Therapy; Female; Follow-Up Studies; Humans; Infant; Male; Melphalan; Neuroblastoma; Pilot Projects; Teniposide; Vincristine

Topics: Adolescent; Child; Child, Preschool; Dose-Response Relationship, Drug; Europe; Humans; Infant; Melphalan; Neuroblastoma; Prospective Studies

Studies are described of high-dose therapy in metastatic breast cancer, early stage breast cancer, stage IV neuroblastoma, recurrent or bulky disease testicular cancer and Ewing's sarcoma. The outcome in these subgroups with conventional therapy is described for comparison. The results of these studies suggest that high-dose therapy with autologous marrow support increases the proportion of patients with long-term survival without evidence of disease. Newer supportive care and recurrent high-dose therapy cycles of non-cross resistant regimens may improve outcome further in these diseases and increase the application to more resistant tumors.

Topics: Adult; Antineoplastic Combined Chemotherapy Protocols; Bone Marrow Transplantation; Breast Neoplasms; Child; Combined Modality Therapy; Cyclophosphamide; Humans; Melphalan; Neoplasm Metastasis; Neoplasms; Neuroblastoma; Prednisone; Prognosis; Remission Induction; Survival Rate; Transplantation, Autologous; Treatment Outcome; Vincristine

We conducted a pilot protocol at seven Pediatric Oncology Group (POG) institutions to examine the feasibility, toxicity, and efficacy of using a common regimen of high-dose chemoradiotherapy (HD CT/RT) supported by autologous or allogeneic marrow infusions in children with metastatic neuroblastoma (NBL) in first or second remission. During a 57-month period, we accrued 101 patients. We report here results for the 81 who completed treatment at least 2 years ago. The HD CT/RT regimen consisted of melphalan 60 mg/m2/d for three doses, and total body irradiation (TBI) either 1.5 Gy (n = 27) or 2.0 Gy (n = 54) twice daily for six doses. Twenty-three patients also received irradiation consisting of 1.2 Gy twice daily for 10 doses to persisting disease sites. Seventy-four were given autologous and seven allogeneic marrow, 64 autologous marrows being purged immunomagnetically. Fifty-four children were in first complete (CR) or partial (PR) remission and 27 in second CR or PR. As of October 1, 1990, follow-up was from 32 to 72 months. Forty-seven of these 81 children relapsed, 10 died of complications, one of unknown cause, and 23 continue in remission, including 21 of the 54 treated in first remission, and 16 who completed treatment more than 3 years ago. The 2-year actuarial event-free survival (EFS) probabilities are first CR (CR1) 32% (SE 10%), first PR (PR1) 43% (SE 9%), second CR (CR2) 33% (SE 27%), and second PR (PR2) 5% (SE 5%). Probability of EFS correlated with remission number (first better than second, P less than .001), with interval from diagnosis to HD CT/RT (greater than 9 months better than less than 9 months, P = .055), and with TBI dose (12 Gy better than 9 Gy, P = .031). These encouraging results may partly reflect selection for this treatment of patients with NBL who have a slower disease pace.

Topics: Adolescent; Bone Marrow Transplantation; Child; Child, Preschool; Combined Modality Therapy; Feasibility Studies; Female; Follow-Up Studies; Humans; Infant; Male; Melphalan; Neuroblastoma; Pilot Projects; Radiotherapy Dosage; Remission Induction; Survival Rate

Despite the progress in current treatments, the event-free survival of high-risk neuroblastoma (HR-NB) patients does not exceed 40%-50%, and the prognosis of refractory or relapsed patients is poor, still representing a challenge for pediatric oncologist. Therapeutic Iodine-131 meta-iodobenzylguanidine (Th-. This retrospective study reports the outcomes of 28 MIBG-avid NB patients with advanced disease either refractory or relapsed, which was undertaken from 1996 to 2014. Th-. Th-

Topics: Antineoplastic Agents, Alkylating; Busulfan; Child; Child, Preschool; Female; Hematopoietic Stem Cell Transplantation; Humans; Infant; Iodine Radioisotopes; Male; Melphalan; Neuroblastoma; Retrospective Studies; Transplantation, Autologous

Consolidation using high-dose chemotherapy with autologous stem cell transplantation (ASCT) is an important component of frontline therapy for children with high-risk neuroblastoma. The optimal preparative regimen is uncertain, although recent data support a role for busulfan/melphalan (BuMel). The Children's Oncology Group (COG) conducted a trial (ANBL12P1) to assess the tolerability and feasibility of BuMel ASCT following a COG induction. Patients with newly diagnosed high-risk neuroblastoma who did not progress during induction therapy and met organ function requirements received i.v. busulfan (every 24 hours for 4 doses based on age and weight) and melphalan (140 mg/m

Topics: Busulfan; Child; Hematopoietic Stem Cell Transplantation; Humans; Induction Chemotherapy; Melphalan; Neuroblastoma; Transplantation, Autologous

The efficacy of tandem HDCT against high-risk neuroblastoma has been reported; however, an optimal regimen remains to be established. In this paper, we report our experience using tandem HDCT comprising the MEC and BuMel regimens in patients with high-risk neuroblastoma. We retrospectively analyzed four patients with stage M high-risk neuroblastoma who received HDCT with MEC followed by BuMel combined with autologous stem cell rescue. Although none of their metastatic lesions had disappeared after induction chemotherapy, three patients showed a CR after tandem HDCT. Gastrointestinal mucosal injuries and renal dysfunction were observed as non-hematologic adverse events of grade 3 or higher. Gastrointestinal mucosal injuries were observed in all four patients following the first HDCT and in one patient following the second HDCT and were treated with parenteral nutrition and analgesics. One patient experienced renal dysfunction during the first HDCT, which was alleviated by sufficient hydration and diuretics and resulted in the reduction of melphalan dosage for the second HDCT. SOS was not observed in any patient. The HDCT regimens examined in this study were observed to be feasible and did not result in any life-threatening adverse events. Our findings indicate that tandem HDCT comprising MEC and BuMel is a potentially effective regimen for patients with high-risk neuroblastoma, including for those who respond poorly to induction chemotherapy, although additional studies in a larger population should be conducted to verify any long-term outcomes and toxicity.

Topics: Adrenal Gland Neoplasms; Antineoplastic Agents, Alkylating; Antineoplastic Agents, Phytogenic; Antineoplastic Combined Chemotherapy Protocols; Busulfan; Carboplatin; Child; Child, Preschool; Dose-Response Relationship, Drug; Etoposide; Female; Follow-Up Studies; Hematopoietic Stem Cell Transplantation; Humans; Male; Melphalan; Neoplasm Staging; Neuroblastoma; Retrospective Studies; Transplantation, Autologous

Survival for high-risk neuroblastoma patients is still suboptimal. Although stem cell transplantation (SCT) is used, there is no consensus as to which conditioning regimen has the greatest efficacy and fewest toxicities. We assessed the incidence of and risk for hepatic veno-occlusive disease (VOD) for neuroblastoma patients who underwent autologous SCT with busulfan and melphalan (BuMel) at eight centers following Children's Oncology Group (COG)-based induction chemotherapy. Data regarding the patients, SCT characteristics, busulfan steady-state concentrations, incidence of VOD, and survival were evaluated. VOD was defined using the modified Seattle criteria. Possible factors associated with VOD (age, busulfan-pharmacokinetic parameters, history of hepatic dysfunction, and day of neutrophil engraftment) were evaluated. Seventy five patients were included and 23 children (31%) developed VOD at a median of 19 days after SCT (range 14-27 days). VOD was the cause of death in 4 patients (5%). In a multivariable analysis, young age (OR 1.7 (95% CI: 1.16-2.56; p = 0.012)) and early day of neutrophil engraftment (OR 1.4 (95% CI: 1.08-2.14; p = 0.041) were associated with the development of VOD. Initial or cumulative busulfan steady-state concentration were not associated with VOD. We found that despite the use of intravenous busulfan with adjusted serum levels, the incidence of VOD remains high in pediatric neuroblastoma patients.

Topics: Busulfan; Child; Hematopoietic Stem Cell Transplantation; Hepatic Veno-Occlusive Disease; Humans; Melphalan; Neuroblastoma; Transplantation Conditioning

Secondary hemophagocytic syndrome (HPS) has been described after autologous hematopoietic cell transplant (AutoHCT). We report two cases of secondary HPS after novel consolidation therapy for high-risk neuroblastoma as part of an institutional phase 2 trial incorporating immunotherapy into a "standard" AutoHCT regimen. Both patients developed liver dysfunction beyond expected course of hepatic veno-occlusive disease, coagulopathy, hyperferritinemia, and when evaluated, elevated soluble interleukin-2 receptor and hemophagocytosis. These cases highlight the need for clinicians to have a high index of suspicion for immune-related complications in patients receiving immune therapies.

Topics: Antineoplastic Agents, Immunological; Antineoplastic Combined Chemotherapy Protocols; Busulfan; Child, Preschool; Ferritins; Hepatic Veno-Occlusive Disease; Humans; Immunotherapy; Immunotherapy, Adoptive; Infant; Killer Cells, Natural; Liver Failure; Lymphohistiocytosis, Hemophagocytic; Male; Melphalan; Neuroblastoma; Peripheral Blood Stem Cell Transplantation; Systemic Inflammatory Response Syndrome; Transplantation Conditioning

Carboplatin dosage is calculated by using the estimated glomerular filtration rate (GFR) to achieve a target plasma area under the plasma concentration-time curve (AUC). The aims of the present study were to investigate factors that influence the pharmacokinetics of carboplatin in children with high-risk neuroblastoma, and whether target exposures for carboplatin were achieved using current treatment protocols.. Data on children receiving high-dose carboplatin, etoposide and melphalan for neuroblastoma were obtained from two study sites [European International Society for Paediatric Oncology (SIOP) Neuroblastoma study, Children's Hospital at Westmead; n = 51]. A population pharmacokinetic model was built for carboplatin to evaluate various dosing formulas. The pharmacokinetics of etoposide and melphalan was also investigated. The final model was used to simulate whether target carboplatin AUC (16.4 mg ml. Allometric weight was the only significant, independent covariate for the pharmacokinetic parameters of carboplatin, etoposide and melphalan. The paediatric Newell formula and modified Calvert formula were suitable for achieving the target AUC of carboplatin for children with a GFR <100 ml min. GFR did not appear to influence the pharmacokinetics of carboplatin after adjusting pharmacokinetic parameters for weight. This model-based approach validates the use of weight-based dosing as an appropriate alternative for carboplatin in children with either mild renal impairment or normal renal function.

Topics: Age Factors; Antineoplastic Agents; Area Under Curve; Body Weight; Carboplatin; Child; Child, Preschool; Dose-Response Relationship, Drug; Drug Dosage Calculations; Etoposide; Female; Glomerular Filtration Rate; Humans; Infant; Kidney; Male; Melphalan; Models, Biological; Neuroblastoma

High-dose chemotherapy with autologous stem cell rescue (HDC-ASCR) has improved event-free survival for children with high-risk neuroblastoma. Common regimens include carboplatin/etoposide/melphalan (CEM), busulfan/melphalan (BuMel), and tandem HDC-ASCR [thiotepa/cyclophosphamide (TC) followed by CEM]. To complement clinical trial data and to evaluate the clinical burden associated with these regimens, resource ultilization (RU) was evaluated. An administrative database was used to evaluate RU in a previously developed high-risk neuroblastoma cohort. Single CEM and BuMel patients were followed for 60 days from the first day of the HDC-ASCR preparative regimen or until death, whichever came first. Tandem patients were followed from the first day of the first HDC-ASCR preparative regimen through day 60 from the first day of the second HDC-ASCR. Resources compared included inpatient days, ICU-level care, and medications administered.. A cohort of 578 patients was evaluated; 422 patients underwent single HDC-ASCR with CEM, 67 received BuMel, 72 underwent TC/CEM, and 17 received only the first portion of tandem HDC-ASCR. The median number of inpatient days and days of exposure to antibiotics, opioids, and total parenteral nutrition were higher in the tandem group than in the CEM and BuMel groups. However, the rate of use of several ICU-level resources per 1000 hospital days was lower for the tandem group.. These data suggest that while patients undergoing tandem HDC-ASCR were hospitalized longer, the severity of illness during hospitalization was not greater in tandem patients.

Topics: Adolescent; Adult; Antineoplastic Combined Chemotherapy Protocols; Autografts; Busulfan; Carboplatin; Child; Child, Preschool; Databases, Factual; Etoposide; Female; Follow-Up Studies; Humans; Infant; Infant, Newborn; Length of Stay; Male; Melphalan; Neuroblastoma; Stem Cell Transplantation

High-dose chemotherapy with autologous stem-cell rescue (SCR) is a key component of high-risk neuroblastoma (HRNB) therapy. Carboplatin, etoposide, and melphalan (CEM) or busulfan and melphalan (Bu/Mel) are the most evaluated, effective high-dose chemotherapy for HRNB on the basis of results from major cooperative group studies. Toxicity profiles vary between these regimens, and practice variation exists regarding the preferred high-dose therapy (HDT). We sought to evaluate the safety of HDT and autologous SCR for HRNB in a resource-limited country (Egypt) compared with the resource-rich United States.. We performed a retrospective comparative review of single CEM-based HDT/SCR outcomes through day 100 for HRNB at the Fred Hutchinson Cancer Research Center (FH) in the United States (2005 to 2015) versus Bu/Mel-based HDT at El-Sheikh Zayed Specialized Hospital (SZ) in Egypt (2009 to 2015).. Forty-four patients at FH and 77 patients at SZ were reviewed. Pretransplant hepatic comorbidities were significantly higher at SZ (29 of 77 v nine of 44; P = .05), with 19 of 77 patients at SZ having hepatitis infection. Engraftment was delayed after SZ-Bu/Mel therapy compared with FH-CEM therapy for neutrophils (median 12 days v 10 days, respectively; P < .001) and platelets (median 20 days v 18 days, respectively; P < .001). Sinusoidal obstruction syndrome occurred later, after SZ-Bu/Mel therapy (median 19 days v 7 days; P = .033), and four of eight cases were fatal (six of eight patients had underlying hepatitis infection), whereas three of three cases after FH-CEM therapy were moderately severe. Resource utilization associated with the number of days with fever, antibiotic use, and the number of transfusions administered was significantly higher after FH-CEM therapy than after SZ-Bu/Mel therapy.. Use of autologous stem-cell transplantation is feasible in the context of a resource-limited country.

Topics: Adult; Aged; Antineoplastic Combined Chemotherapy Protocols; Autografts; Busulfan; Carboplatin; Combined Modality Therapy; Dose-Response Relationship, Drug; Egypt; Etoposide; Female; Humans; Male; Melphalan; Middle Aged; Neuroblastoma; Stem Cell Transplantation; Transplantation Conditioning

The outcome for advanced neuroblastoma has improved with combined modality therapy: induction chemotherapy, surgery, and consolidation with high-dose chemotherapy/autologous HSCT, followed by local radiation, cisretinoic acid, and recently antibody therapy. In the United States, the most common conditioning regimen is CEM, while in Europe/Middle East, Bu/Mel has been widely used; it remains unclear which regimen has the best outcome. Assess renal, hepatic, and infectious toxicity through Day+100 in 2 different regimens. Retrospective comparison between CEM-DFCHCC Boston and Bu/Mel- CCHE-57357. Thirty-five patients, median age 4, in Boston (2007-2011) and 38 patients, median age 3, in Cairo (2009-2011). Renal toxicity; creatinine was significantly higher in CEM than Bu/Mel: 57% (median day+90) vs. 29% (median>day+100), p = 0.004. One CEM patient died from renal dialysis at day+19. Hepatic toxicity was significantly higher in CEM than Bu/Mel: 80% (median day+26) vs. 58% (median day+60), p = 0.04. In infectious complications with CEM 14%, bacteremia (n = 4) and fungemia (n = 1), 3 had culture-negative sepsis requiring vasopressors. With Bu/Mel 18%, bacteremia (n = 7), none required pressors, p = 0.4. Bu/Mel was associated with less acute hepatic and renal toxicity and thus may be preferable for preserving organ functions.

Topics: Adolescent; Antineoplastic Agents; Boston; Brain Neoplasms; Busulfan; Carboplatin; Child; Child, Preschool; Egypt; Etoposide; Humans; Infant; Infant, Newborn; Melphalan; Neuroblastoma; Retrospective Studies; Transplantation Conditioning; Treatment Outcome

High-dose chemotherapy with autologous stem cell rescue (ASCR) is a key component of high-risk neuroblastoma therapy. Resources required to support patients treated with ASCR conditioning regimens [carboplatin/etoposide/melphalan (CEM) and busulfan/melphalan (BuMel)] have not been directly compared.. An administrative database was used to analyze resource utilization and outcomes in a cohort of high-risk neuroblastoma patients. Patients were followed for 60 days from start of conditioning or until death. Length of hospitalization, length of intensive care unit (ICU) level of care, incidence of sepsis and sinusoidal obstruction syndrome (SOS), and duration of use of specific supportive care resources were analyzed.. Six of 171 CEM patients and zero of 59 BuMel patients died during the study period (P = 0.34). Duration of hospitalization was longer following BuMel (median 35 vs. 31 days; P = 0.01); however, there was no difference in duration of ICU-level care. Antibiotic use was longer following CEM (median 19 vs. 15 days; P = 0.01), as was antihypertensive use (median 5 vs. 1.6 days; P = 0.0024). Duration of opiate and nonnarcotic analgesic use was longer following CEM early in the study period. Resources consistent with a diagnosis of SOS were used in a higher proportion of BuMel patients. A higher proportion of BuMel treated patients required mechanical ventilation (17% vs. 6%; P = 0.03).. We used administrative billing data to compare resources associated with ASCR conditioning regimens. CEM patients required more extended use of analgesics, antibiotics, and antihypertensives, while duration of hospitalization was longer, and SOS and the use of mechanical ventilation were more frequent following BuMel.

Topics: Adolescent; Antineoplastic Combined Chemotherapy Protocols; Autografts; Busulfan; Carboplatin; Child; Child, Preschool; Critical Care; Databases, Factual; Etoposide; Female; Follow-Up Studies; Humans; Incidence; Infant; Length of Stay; Male; Melphalan; Neuroblastoma; Peripheral Blood Stem Cell Transplantation; Sepsis; Stem Cells; Transplantation Conditioning; United States

High-dose chemotherapy (HDC) was investigated in high-risk neuroblastoma (HR-NBL) to reduce the risk of relapse. We report the results of the 30-year experience of a cohort of patients with HR-NBL treated with high-dose (HD) busulfan (Bu)-containing regimens. From 1980 to 2009, 215 patients aged >1 year with stage 4 NBL were treated with HD Bu-containing regimens at Gustave Roussy. These data were prospectively recorded in the Pediatric Transplantation Database. The median age at diagnosis was 40 months (12-218 months). All patients had a stage 4 neuroblastoma. NMYC amplification was displayed in 24% of the tumors. The hematopoietic support consisted of bone marrow or PBSCs in 46% and 49% of patients, respectively. The 5-year event-free survival and overall survival rates of the whole cohort were 35.1% and 40%, respectively. Age at diagnosis, bone marrow involvement and tumor response after induction chemotherapy were significant prognostic factors. Toxicity was manageable and decreased over time, owing to both PBSC administration and better supportive care. Based on this experience, HD Bu-melphalan (Mel) has been implemented in Europe and compared with Carboplatin-Etoposide-Mel in the European SIOP Neuroblastoma (SIOPEN)/HR-NBL randomized protocol. It has now become the standard HDC in the SIOPEN HR strategy.

Topics: Adolescent; Bone Marrow Transplantation; Busulfan; Child; Child, Preschool; Cohort Studies; Combined Modality Therapy; Female; Humans; Infant; Male; Melphalan; Neuroblastoma; Peripheral Blood Stem Cell Transplantation; Retrospective Studies; Risk Factors; Survival Analysis

Topics: Adolescent; Adult; Busulfan; Child; Child, Preschool; Female; Hematopoietic Stem Cell Transplantation; Humans; Infant; Infant, Newborn; Male; Melphalan; Neuroblastoma; Sarcoma, Ewing; Transplantation, Autologous; Young Adult

The optimal autologous stem cell rescue (HDC-SCR) regimen for children with high-risk neuroblastoma (HR-NBL) is not defined. Carboplatin/etoposide/melphalan (CEM) is the current US standard; however, European data suggest busulfan/melphalan (Bu/Mel) may have less toxicity. Published data regarding toxicities associated with CEM and Bu/Mel are limited. We conducted a single-institution retrospective cohort study of children with HR-NBL who received CEM or Bu/Mel preparative regimens. Toxicity data were analyzed using χ(2) or Fisher's exact, Wilcoxon two-sample or log-rank tests. Sinusoidal obstruction syndrome (SOS) was observed in 7/44 CEM (15.9%) and 5/21 (24%) Bu/Mel patients (P=0.50). Median time to SOS was longer following Bu/Mel than CEM (20 versus 9 days, P=0.02). Pulmonary hypertension (PHTN) was observed in ~20% of children after Bu/Mel and none after CEM (P=0.01). CEM patients had more nephrotoxicity (P=0.001), packed red blood cell (P=0.02) and platelet transfusions (P=0.008), and days on maximum pain support (P=0.0007). Time to engraftment, length of stay, documented infection rates and HDC-SCR-related mortality were similar. Nephrotoxicity and resource utilization associated with cytopenias and mucositis were greater after CEM. Pulmonary toxicities were more severe after Bu/Mel, and increased vigilance for PHTN may be warranted, particularly in children with hypoxemia out of proportion to respiratory distress.

Topics: Adolescent; Antineoplastic Combined Chemotherapy Protocols; Busulfan; Carboplatin; Child; Child, Preschool; Cohort Studies; Etoposide; Female; Hepatic Veno-Occlusive Disease; Humans; Hypertension, Pulmonary; Infant; Kidney Diseases; Male; Melphalan; Mucositis; Myeloablative Agonists; Neuroblastoma; Pancytopenia; Retrospective Studies; Stem Cell Transplantation; Transplantation Conditioning; Young Adult

An increasing number of children with advanced malignancies have recently received high-dose chemotherapy (HDC) with hematopoietic stem cell transplantation (HSCT), followed by surgery. In this study, we reviewed our experience with surgery after HDC and autologous (auto) or allogeneic (allo) HSCT to elucidate the problems associated with this treatment and establish the optimum surgical management strategy.. We retrospectively reviewed the cases of 24 children with advanced malignancy treated with HDC and HSCT before tumor resection at our institution. The tumors included 18 neuroblastomas, 5 soft tissue sarcomas, 2 hepatoblastomas, and 1 Wilms tumor. The source of hematopoietic stem cells was auto-HSCT in 19 patients and allo-HSCT in 5 patients. To be able to undergo surgery, it was necessary that the patient's general condition, including hemostasis, should be fairly good and that the results of hematological examinations should include a white blood cell (WBC) count of>1,000/µL, hemoglobin level of>10 g/dL and platelet count of>5 × 10(4)/µL.. The mean duration before WBC recovery after HSCT was 14.5 ± 1.4 days after auto-HSCT and 23.8 ± 1.2 days after allo-HSCT, respectively (p<0.01). The mean duration before platelet recovery after HSCT was 46.5 ± 5.2 days for auto-HSCT and 48.6 ± 5.5 days for allo-HSCT (not significant [n.s.]). The mean interval between allo-HSCT and surgery was significantly longer (92.8 ± 6.2 days) than that between auto-HSCT and surgery (57.0 ± 3.9 days) (p<0.01), likely because of the use of steroids and immunosuppressants after HSCT. The tumors were completely resected in all cases without severe complications. All the patients treated with allo-HSCT had an acute graft versus host (aGVH) reaction at 2 to 3 weeks after HSCT, and specifically required the administration of steroids and immunosuppressants to prevent aGVH. The postoperative complications included paralytic ileus in two cases and a tacrolimus-associated encephalopathy in one case involving allo-HSCT. In half of the patients, the WBC count was not elevated after surgery, whereas the postoperative serum C-reactive protein (CRP) level was elevated in all cases.. Our data indicate that surgical treatment can be safely performed even after HDC with HSCT if attention is paid to myelosuppression and the adverse effects of both chemotherapeutic agents and immunosuppressants.

Topics: Adolescent; Antineoplastic Agents; Antineoplastic Combined Chemotherapy Protocols; Chemotherapy, Adjuvant; Child; Child, Preschool; Drug Administration Schedule; Female; Hematopoietic Stem Cell Transplantation; Hepatoblastoma; Humans; Infant; Kidney Neoplasms; Liver Neoplasms; Male; Melphalan; Neoadjuvant Therapy; Neoplasms, Complex and Mixed; Neuroblastoma; Perioperative Care; Retrospective Studies; Sarcoma; Thiotepa; Transplantation, Autologous; Transplantation, Homologous; Treatment Outcome; Wilms Tumor

Bu-Mel as preparative therapy prior to autologous stem cell rescue was recently shown to be superior to the conventional CEM regimen for HR NBL in Europe. There are no data available on the feasibility and toxicity of Bu-Mel as consolidation therapy following the COG-type induction regimens used in North America. We report early complications and outcomes of patients with HR NBL who received Bu-Mel for consolidation following COG-based induction. Retrospective analysis of all patients who had received Bu-Mel as preparative regimen prior to stem cell rescue for HR NBL was carried out. Toxicity, outcomes, and any delays to receiving radiation or anti-GD2 antibody therapy were analyzed. Six patients undergoing PBSCT had received Bu-Mel. The treatment was well tolerated. Mucositis was the main toxicity; three patients had developed neutropenia fever and none developed pulmonary toxicity. One patient had developed moderate SOS that responded to conservative management. All patients were able to receive and tolerate post-transplant local radiotherapy and ch.14.18 anti-GD2 antibody therapy without any delays. All patients are alive with no disease recurrence. The Bu-Mel regimen is well tolerated and is feasible post-COG-type induction platform.

Topics: Busulfan; Child; Child, Preschool; Consolidation Chemotherapy; Female; Humans; Infusions, Intravenous; Male; Melphalan; Neuroblastoma; Peripheral Blood Stem Cell Transplantation; Recurrence; Retrospective Studies; Stomatitis; Treatment Outcome

MIBG is an effective component in treatment of neuroblastoma. Furthermore, MIBG scintigraphy is an imaging modality in primary assessments. None of the previous studies have evaluated the role of pretransplant MIBG scintigraphy in decision making for neuroblastoma treatment. We selected therapeutic regimen based on pretransplant (131) I-MIBG scintigraphy. Twenty high-risk patients were enrolled. On day -30, patients underwent diagnostic MIBG scintigraphy. Patients were then subdivided into two groups (10 cases in each arm). MIBG-avid subgroup received MIBG (12 mCi/kg), etoposide (1200 mg/m2), carboplatin (1500 mg/m2), and melphalan (210 mg/m2). Non-MIBG-avid subgroup received etoposide (600 mg/m2), carboplatin (1200 mg/m2), and melphalan (150 mg/m2). Patients received CRA after ASCT. Mean age at diagnosis was 42.5 months (range, 17-65) in MIBG-avid and 38.9 months (range, 18-65) in non-MIBG-avid patients. Mean age at diagnosis and transplantation did not reveal significant difference between two subgroups. In MIBG-avid patients, the three-yr OS was 66 ± 21%. In MIBG-non-avid subgroup, the three-yr OS was 53 ± 20%. In MIBG-avid and non-MIBG-avid subgroups, the three-yr EFS were 66 ± 21% and 47 ± 19%, respectively. These findings may suggest an effective role in selecting the therapeutic strategy for pre-ASCT MIBG scintigraphy in high-risk neuroblastoma. MIBG-avid subset may benefit from the combination of therapeutic MIBG and high dose of chemotherapy.

Topics: 3-Iodobenzylguanidine; Carboplatin; Child; Child, Preschool; Disease-Free Survival; Etoposide; Female; Humans; Infant; Male; Melphalan; Neoplasm Recurrence, Local; Neuroblastoma; Pilot Projects; Prognosis; Prospective Studies; Radionuclide Imaging; Stem Cell Transplantation; Transplantation Conditioning; Transplantation, Autologous; Treatment Outcome

The poor prognosis of children with high-grade glioma (HGG) and high-risk neuroblastoma, despite multidisciplinary therapeutic approaches, demands new treatments for these indications. F14512 is a topoisomerase II inhibitor containing a spermine moiety that facilitates selective uptake by tumor cells via the Polyamine Transport System (PTS) and increases topoisomerase II poisoning. Here, F14512 was evaluated in pediatric HGG and neuroblastoma cell lines. PTS activity and specificity were evaluated using a fluorescent spermine-coupled probe. The cytotoxicity of F14512, alone or in combination with ionizing radiation and chemotherapeutic agents, was investigated in vitro. The antitumor activity of F14512 was assessed in vivo using a liver-metastatic model of neuroblastoma. An active PTS was evidenced in all tested cell lines, providing a specific and rapid transfer of spermine-coupled compounds into cell nuclei. Competition experiments confirmed the essential role of PTS in the cell uptake and cytotoxicity of F14512. This cytotoxicity appeared greater in neuroblastoma cells compared with HGG cells but appeared independent of PTS activity levels. In vivo evaluation confirmed a marked and prolonged antitumoral effect in neuroblastoma cells. The combinations of F14512 with cisplatin and carboplatin were often found to be synergistic, and we demonstrated the significant radiosensitizing potential of F14512 in the MYCN-amplified Kelly cell line. Thus, F14512 appears more effective than etoposide in pediatric tumor cell lines, with greater efficacy in neuroblastoma cells compared with HGG cells. The synergistic effects observed with platinum compounds and the radiosensitizing effect could lead to a clinical development of the drug in pediatric oncology.

Topics: Animals; Antineoplastic Agents; Carboplatin; Cell Line, Tumor; Cell Survival; Cisplatin; Etoposide; Female; Glioma; Humans; Liver Neoplasms; Melphalan; Mice, Inbred BALB C; Neuroblastoma; Podophyllotoxin; Radiation, Ionizing; Spermine

Drug resistance is a major cause of treatment failure in cancer. Here, we have evaluated the role of STAT3 in environment-mediated drug resistance (EMDR) in human neuroblastoma. We determined that STAT3 was not constitutively active in most neuroblastoma cell lines but was rapidly activated upon treatment with interleukin (IL)-6 alone and in combination with the soluble IL-6 receptor (sIL-6R). Treatment of neuroblastoma cells with IL-6 protected them from drug-induced apoptosis in a STAT3-dependent manner because the protective effect of IL-6 was abrogated in the presence of a STAT3 inhibitor and upon STAT3 knockdown. STAT3 was necessary for the upregulation of several survival factors such as survivin (BIRC5) and Bcl-xL (BCL2L1) when cells were exposed to IL-6. Importantly, IL-6-mediated STAT3 activation was enhanced by sIL-6R produced by human monocytes, pointing to an important function of monocytes in promoting IL-6-mediated EMDR. Our data also point to the presence of reciprocal activation of STAT3 between tumor cells and bone marrow stromal cells including not only monocytes but also regulatory T cells (Treg) and nonmyeloid stromal cells. Thus, the data identify an IL-6/sIL-6R/STAT3 interactive pathway between neuroblastoma cells and their microenvironment that contributes to drug resistance.

Topics: Antineoplastic Agents, Phytogenic; Apoptosis; Bone Neoplasms; Cell Line, Tumor; Cell Survival; Coculture Techniques; Drug Resistance, Neoplasm; Etoposide; Gene Expression Regulation, Neoplastic; Humans; Interleukin-6; Melphalan; Membrane Potential, Mitochondrial; Mesenchymal Stem Cells; Monocytes; Neuroblastoma; Receptors, Interleukin-6; STAT3 Transcription Factor; Up-Regulation

(131) I-metaiodobenzylguanidine (MIBG) produces a 37% response rate in relapsed/refractory neuroblastoma, and could be used to improve remission status prior to myeloablative chemotherapy with autologous stem cell transplant (ASCT). The purpose of our report was to evaluate safety and response with MIBG therapy followed by myeloablative busulfan and melphalan (BuMel) with ASCT in patients with refractory neuroblastoma.. Retrospective chart review was done on patients treated with MIBG (18 mCi/kg) on Day 1 and ASCT on day 14. Six to eight weeks after MIBG, patients without progressive disease received IV busulfan on days -6 to -2 (target Css 700-900), melphalan (140 mg/m2 IV) on day -1, and ASCT on Day 0. Response and toxicity were evaluated after MIBG and again after myeloablative therapy.. Eight patients completed MIBG/ASCT followed by BuMel/ASCT. MIBG was well tolerated, with grade 3 or 4 non-hematologic toxicity limited to one patient with sepsis. Grade 3 mucositis occurred in six patients after BuMel/ASCT. One patient developed sinusoidal obstructive syndrome (SOS) and died 50 days post-ASCT following myeloablative conditioning. All patients engrafted neutrophils (median 16.5 days) and platelets (median 32 days) after BuMel, excluding the patient with SOS. After all therapy, there were three complete, two partial, and one minor response in seven evaluable patients.. MIBG at doses up to 18 mCi/kg can be safely administered 6 weeks prior to a BuMel consolidative regimen for refractory neuroblastoma. Preceding MIBG did not impair engraftment following BuMel. This regimen is being further evaluated in a Children's Oncology Group (COG) trial.

Topics: 3-Iodobenzylguanidine; Antineoplastic Agents; Antineoplastic Combined Chemotherapy Protocols; Busulfan; Child; Child, Preschool; Combined Modality Therapy; Female; Humans; Male; Melphalan; Neuroblastoma; Radiopharmaceuticals; Retrospective Studies; Stem Cell Transplantation; Transplantation, Autologous

High-risk neuroblastoma (NB) has a poor prognosis. Even with intensive myeloablative chemotherapy, relapse is common and almost uniformly fatal, and new treatments are needed. Translocator protein 18kDa (TSPO) ligands have been studied as potential new therapeutic agents in many cancers, but not in NB. We studied the effects of TSPO ligands on cell proliferation, cell cycle progression and apoptosis using paired cell lines derived from the same patient at the time of initial surgery and again after development of progressive disease or relapse post-chemotherapy. We found that TSPO expression was significantly increased 2- to 10-fold in post-relapse cell lines compared with pre-treatment lines derived from the same individual. Subsequently, these cell lines were treated with the specific TSPO ligand 1-(2-chlorophenyl-N-methylpropyl)-3-isoquinolinecarboxamide (PK11195) (0-160µM) as a single agent, with cytotoxic chemotherapy agents alone (carboplatin, etoposide or melphalan), or with combinations of PK11195 and chemotherapy drugs. We found that PK11195 inhibited proliferation in a dose-dependent manner, induced apoptosis and caused G 1/S cell cycle arrest in all tested NB cell lines at micromolar concentrations. In addition, PK11195 significantly decreased mRNA expression of the chemotherapy resistance efflux pumps ABCA3, ABCB1 and ABCC1 in two post-relapse NB cell lines. We also found that pre-treatment with PK11195 sensitized these cell lines to treatment with cytotoxic chemotherapy agents. These results suggest that PK11195 alone or in combination with standard chemotherapeutic drugs warrants further study for the treatment of neuroblastoma.

Topics: Antineoplastic Combined Chemotherapy Protocols; Apoptosis; ATP-Binding Cassette Transporters; Carboplatin; Cell Cycle Checkpoints; Cell Line, Tumor; Cell Proliferation; Etoposide; Humans; Isoquinolines; Ligands; Melphalan; Neuroblastoma; Receptors, GABA; Recurrence; RNA, Messenger

Outcome of high risk neuroblastoma (NBL) remains unsatisfactory in spite of intensive treatment efforts. Consolidation with high-dose (HD) chemotherapy and autologous stem cell transplantation (ASCT) has been intensified with tandem and triple cycles with promising results. Our purpose was to improve the outcome with two or three HD-consolidations.. Thirty six children with high risk NBL, diagnosed 1995-2010, had intensive induction and surgery, and were stratified to single, tandem or triple HD-therapy and ASCT, followed by local irradiation and cis-retinoic acid. In inoperable patients surgery was facilitated by preoperative HD-melphalan. Long-term outcome of our old cohort from 1987-1994 was updated.. Ten year event-free survival (EFS) from diagnosis was 0.44+/-0.10 of the old and 0.43+/-0.085 of the new cohort. EFS from the last ASCT was 0.53 +/-0.12 and 0.48+/-0.091, respectively. Preoperative HD-melphalan rendered 73% of bulky primaries operable in the new cohort. The 5-yr EFS from ASCT was 0.46+/-0.15 for single and 0.73+/-0.15 for tandem ASCT (P = 0.19). All triple ASCT patients, selected by poor/slow response, relapsed or died.. Thiotepa- and melphalan based HD regimens, with or without total body irradiation (TBI), appeared to give an outcome comparable to major NBL study groups with acceptable toxicity. Tandem HD therapy gave a 5-year EFS of 73%, whereas a third HD consolidation did not offer any additional advantage for ultra high risk patients with slow response. Pediatr Blood Cancer 2012; 59: 1190-1197. © 2012 Wiley Periodicals, Inc.

Topics: Antineoplastic Combined Chemotherapy Protocols; Child; Child, Preschool; Combined Modality Therapy; Disease-Free Survival; Female; Humans; Infant; Male; Melphalan; Neuroblastoma; Peripheral Blood Stem Cell Transplantation; Remission Induction; Survival Rate; Thiotepa; Transplantation, Autologous; Whole-Body Irradiation

Topotecan is an active drug in relapsed neuroblastoma. We investigated the efficacy and toxicity of a topotecan-based induction regimen in newly diagnosed neuroblastoma.. Patients older than 1 year with either metastatic or localised stage 2-3 MYCN-amplified neuroblastoma received 2 courses of high-dose topotecan (HD-TPT) 6mg/m(2) and high-dose cyclophosphamide (HD-CPM) 140 mg/kg, followed by 2 courses of ifosfamide, carboplatin and etoposide (ICE) every 28 days. After surgery on primary tumour, a fifth course with vincristine, doxorubicin and CPM was given, followed by high-dose chemotherapy with stem cell support. Response was assessed in accordance with the International Neuroblastoma Response Criteria.. Of 35 consecutive patients, 33 had metastatic disease. The median length of induction phase was 133 days (range 91-207) and time to high-dose chemotherapy was 208 days (range 156-285). The median tumour volume reduction was 55% after two HD-TPT/HD-CPM courses and 80% after four courses. Radical surgery was performed in 16/27 patients after chemotherapy. After the fifth course, 29/34 patients (85%) had achieved a partial remission (12) or a CR/very good partial remission (17). CR of metastases was achieved in 13/32 (41%) and bone marrow was in complete remission in 16/24 patients (67%). Grade 4 neutropenia and/or thrombocytopenia occurred in 100% of HD-TPT/HD-CPM and in 95% of ICE courses, while non-haematological toxicities were manageable.. These data indicate that our induction regimen is feasible and well tolerated. A major response rate of 85% with 41% complete metastatic response confirms this regimen as effective induction in high-risk neuroblastoma.

Topics: Abdominal Neoplasms; Adolescent; Antineoplastic Combined Chemotherapy Protocols; Carboplatin; Child; Child, Preschool; Etoposide; Female; Humans; Ifosfamide; Infant; Kaplan-Meier Estimate; Lomustine; Male; Melphalan; Mesna; Neuroblastoma; Pilot Projects; Risk Factors; Thoracic Neoplasms; Topotecan; Treatment Outcome

Three pediatric patients with infratentorial metastatic non-epithelial malignant brain tumors were successfully treated by radical surgical resection followed by aggressive radiochemotherapy. One patient with neuroblastoma and two with rhabdomyosarcoma were successfully treated by first line multimodal treatments, but developed infratentorial metastasis after several months of remission. All patients revealed intracranial metastases manifesting as rapidly progressing neurological symptoms caused by mass effect in the posterior fossa. Radical surgical resection was performed without morbidity. The patients were then treated by adjuvant radiochemotherapy with or without autologous peripheral blood stem cell transplantation, resulting in complete remission. Two patients developed extracranial recurrences 4 months after the treatments for intracranial metastases. One patient was treated by second high-dose chemotherapy with allogeneic cord blood transplantation, again resulting in complete remission. Another patient was treated by second chemotherapy and maintaining stable disease. The other patient maintained complete remission. All three patients were alive without neurological deficit for 8, 11, and 12 months after diagnosis of brain metastasis. Patients with infratentorial brain metastases of highly malignant pediatric non-epithelial tumors are in a severe clinical state, but still can have longer and useful lives with aggressive multimodal treatments combined with radical surgical resection.

Topics: Antineoplastic Agents; Antineoplastic Combined Chemotherapy Protocols; Brain Neoplasms; Camptothecin; Carboplatin; Chemotherapy, Adjuvant; Child; Child, Preschool; Cisplatin; Combined Modality Therapy; Dactinomycin; Doxorubicin; Etoposide; Humans; Ifosfamide; Infant; Infratentorial Neoplasms; Irinotecan; Melphalan; Neoplasm Metastasis; Neuroblastoma; Rhabdomyosarcoma; Thiotepa; Topotecan; Vincristine

The aim of this retrospective study was to analyze the outcome and identify risk factors associated with progression-free survival (PFS) in 36 children with high-risk neuroblastoma who underwent autologous peripheral blood progenitor cell (PBPC) transplantation between 1994 and 2010. The conditioning regimen used in all cases consisted of high-dose of busulfan and melphalan. Median age at transplantation was 3 years (range: 0.7-14 years). The median times to neutrophil and platelet engraftment were 11 days (range: 9.16 days) and 13 days (range: 9.33), respectively. Twenty-one patients developed nonhematologic toxicity: 15 patients had mucositis, 4 patients developed an engraftment syndrome, and there were 2 cases of liver toxicity. No toxic deaths were observed. There were 15 patients who relapsed. The median time to relapse was 6 months after the transplant (range: 3-13 months). With a median follow-up of 55 months (range: 4-180 months), the PFS was 57% ± 8.5% for the whole group. In multivariate analysis, age below 3 years (P < .005), complete remission (CR) pretransplantation (P < .07) and 1p germline status (P < .01) were variables associated with better outcomes. Patients who were or achieved early CR following transplantation (3 months posttransplantation) had a probability of PFS of 91% ± 6% as compared to patients who did not (PFS 9% ± 8%) (P < .0001). This retrospective study shows that high dose of busulfan and melphalan as conditioning regimen in children with high-risk neuroblastoma is associated with very low morbidity and no mortality in the authors' hands. Younger patients with no 1p deletions and in first CR at transplantation had the better outcome.

Topics: Adolescent; Antineoplastic Agents, Alkylating; Bone Marrow Neoplasms; Bone Neoplasms; Busulfan; Child; Child, Preschool; Combined Modality Therapy; Female; Follow-Up Studies; Hematopoietic Stem Cell Mobilization; Humans; Infant; Liver Neoplasms; Male; Melphalan; Neoplasm Staging; Neuroblastoma; Peripheral Blood Stem Cell Transplantation; Remission Induction; Risk Factors; Survival Rate; Transplantation Conditioning; Transplantation, Autologous; Treatment Outcome

The local control of neuroblastoma is a very important treatment consideration. We describe a patient who received high-dose rate 60Co remote after loading system treatment for local control of recurrent neuroblastoma and discuss the efficacy of high-dose rate 60Co remote after loading system treatment.

Topics: Abdominal Neoplasms; Antineoplastic Combined Chemotherapy Protocols; Brachytherapy; Busulfan; Carboplatin; Cisplatin; Cobalt Radioisotopes; Combined Modality Therapy; Cord Blood Stem Cell Transplantation; Cyclophosphamide; Cytarabine; Doxorubicin; Etoposide; Humans; Ifosfamide; Infant; Male; Melphalan; Neoadjuvant Therapy; Neoplasm Recurrence, Local; Neuroblastoma; Peripheral Blood Stem Cell Transplantation; Radiotherapy Dosage; Radiotherapy, Adjuvant; Remission Induction; Vidarabine; Vincristine

Topics: Acute Kidney Injury; Antineoplastic Combined Chemotherapy Protocols; Carboplatin; Child; Combined Modality Therapy; Etoposide; Granulocyte Colony-Stimulating Factor; Hematopoietic Stem Cell Mobilization; Humans; Male; Melphalan; Neuroblastoma; Peripheral Blood Stem Cell Transplantation; Transplantation, Autologous; Treatment Outcome; Tumor Lysis Syndrome

13-cis-Retinoic acid (13-cis-RA) is given at completion of cytotoxic therapy to control minimal residual disease in neuroblastoma. We investigated the effect of combining 13-cis-RA with cytotoxic agents employed in neuroblastoma therapy using a panel of 6 neuroblastoma cell lines. The effect of 13-cis-RA on the mitochondrial apoptotic pathway was studied by flow cytometry, cytotoxicity by DIMSCAN, and protein expression by immunoblotting. Pretreatment and direct combination of 13-cis-RA with etoposide, topotecan, cisplatin, melphalan, or doxorubicin markedly antagonized the cytotoxicity of those agents in 4 out of 6 tested neuroblastoma cell lines, increasing fractional cell survival by 1 to 3 logs. The inhibitory concentration of drugs (IC(99)) increased from clinically achievable levels to nonachievable levels, greater than 5-fold (cisplatin) to greater than 7-fold (etoposide). In SMS-KNCR neuroblastoma cells, 13-cis-RA upregulated expression of Bcl-2 and Bcl-xL RNA and protein, and this was associated with protection from etoposide-mediated apoptosis at the mitochondrial level. A small molecule inhibitor of the Bcl-2 family of proteins (ABT-737) restored mitochondrial membrane potential loss and apoptosis in response to cytotoxic agents in 13-cis-RA treated cells. Prior selection for resistance to RA did not diminish the response to cytotoxic treatment. Thus, combining 13-cis-RA with cytotoxic chemotherapy significantly reduced the cytotoxicity for neuroblastoma in vitro, mediated at least in part via the antiapoptotic Bcl-2 family of proteins.

Topics: Alkylating Agents; Apoptosis; Biphenyl Compounds; Cell Line, Tumor; Cisplatin; Cytochromes c; Cytoprotection; Doxorubicin; Drug Resistance, Neoplasm; Drug Screening Assays, Antitumor; Etoposide; Gene Expression Regulation, Neoplastic; Humans; Isotretinoin; Melphalan; Membrane Potential, Mitochondrial; Mitochondria; Neuroblastoma; Nitrophenols; Piperazines; Protective Agents; Proto-Oncogene Proteins c-bcl-2; RNA, Messenger; Signal Transduction; Sulfonamides; Topoisomerase Inhibitors; Tumor Suppressor Protein p53

Focal nodular hyperplasia (FNH) is a benign, poorly understood hepatic tumor that is rare in children. Although there is no evidence for malignant degeneration, FNH can occur adjacent to a malignancy. Here, the case of a 4-year-old boy with a hepatic mass and history of stage IV neuroblastoma is presented. Initial imaging and core-needle biopsy were consistent with FNH. However, after left lateral segmentectomy, pathologic examination revealed a malignant tumor most consistent with small cell undifferentiated hepatoblastoma as well as 3 foci of FNH in the surrounding parenchyma.

Topics: Adrenal Gland Neoplasms; Antibodies, Monoclonal; Antibodies, Monoclonal, Murine-Derived; Antineoplastic Combined Chemotherapy Protocols; Bone Marrow Transplantation; Carboplatin; Child, Preschool; Cisplatin; Combined Modality Therapy; Cyclophosphamide; Etoposide; Fluorouracil; Focal Nodular Hyperplasia; Granulocyte Colony-Stimulating Factor; Hepatectomy; Hepatoblastoma; Humans; Ifosfamide; Immunoglobulin G; Incidental Findings; Liver Neoplasms; Male; Melphalan; Mesna; Neoplasms, Radiation-Induced; Neoplasms, Second Primary; Neuroblastoma; Radiotherapy, Adjuvant; Tomography, X-Ray Computed; Vincristine

Glutamine is an essential amino acid for the synthesis of glutathione (GSH), the major endogenous antioxidant which protects cells from oxidative injury. To evaluate the effects of glutamine concentrations, cell growth, GSH levels, oxidative stress, and chemosensitivity were evaluated in neuroblastoma cell lines.. Three human neuroblastoma cell lines (SMS-KCNR, SMS-KANR, SMS-LHN) were cultured with different concentrations of glutamine (2, 0.2 and 0 mM) under hypoxic (5% O(2)) or normoxic (20% O(2)) condition. Cell proliferation and chemosensitivity were determined by MTT assay, and the levels of intracellular GSH were measured by DTNB-GSSG reductase method. Cellular reactive oxidative species (ROS) were quantified by flow cytometry.. There was a significant decrease of cell growth in low glutamine (0.2 and 0 mM) compared with control (2 mM) in all three cell lines (P < 0.01), while adding GSH partially restored the reduced cell proliferation by low glutamine. The levels of GSH in neuroblastoma cells decreased significantly in low glutamine compared with the levels of control cells cultured in 2 mM glutamine (P < 0.05), and the accumulation of cellular ROS was significantly higher in 0 mM glutamine compared to the control. Moreover, glutamine deprivation significantly enhanced cytotoxicity of L-PAM in all three cell lines, which was abolished after addition of GSH.. Glutamine deprivation decreased cell proliferation and enhances cell chemosensitivity in neuroblastoma, which is presumably associated with GSH depletion.

Topics: Antineoplastic Agents, Alkylating; Cell Hypoxia; Cell Line, Tumor; Cell Proliferation; Flow Cytometry; Glutamine; Glutathione; Humans; Melphalan; Neuroblastoma; Oxidation-Reduction; Reactive Oxygen Species

Topics: Antineoplastic Agents, Alkylating; Combined Modality Therapy; Hematopoietic Stem Cell Transplantation; Hodgkin Disease; Humans; Leukemia, Myeloid; Lymphoma, Non-Hodgkin; Melphalan; Multiple Myeloma; Myeloablative Agonists; Neoplasms; Neoplasms, Germ Cell and Embryonal; Neuroblastoma; Precursor Cell Lymphoblastic Leukemia-Lymphoma

The murine monoclonal antibody 3F8 mediates lysis of neuroblastoma (NB) by complement and leukocytes (including neutrophils) but is neutralized if human anti-mouse antibody (HAMA) forms. We assessed the impact on rapid HAMA formation of prior chemotherapy in NB patients.. For the 153 patients treated with 3F8 after conventional therapy (Group 1), the analysis included time from chemotherapy to the start of 3F8. For the 103 patients treated with 3F8 after myeloablative alkylator-based therapy (MAT) (Group 2), the analysis included both chemotherapy administered before stem-cell collection and time from MAT to the start of 3F8.. In Group 1, the incidence of HAMA-positivity was significantly lower if patients received high-dose cyclophosphamide (HD-Cy, > or = 4,000 mg/m2) before 3F8 treatment (P < 0.001). In addition, HAMA-positivity was least likely if 3F8 treatment was initiated <90 days post-HD-Cy (2/76 compared to 3/19 first treated at 90-120 days, and 17/27 first treated at >120 days, P < 0.001). In Group 2 patients who were transplanted with stem cells collected after HD-Cy, HAMA-positivity occurred in 1/60 patients treated <90 days post-MAT versus 13/23 treated >90 days post-MAT (P < 0.001). Among Group 2 patients transplanted with stem cells collected after no prior HD-Cy, the incidence of HAMA-positivity was significantly higher (15/19, P < 0.001), including 5/7 whose 3F8 treatment began <90 days post-MAT.. HD-Cy reliably blocks humoral responses to a murine antibody. This capacity to prevent host rejection of foreign or not fully humanized proteins raises the possibility of a broad role for HD-Cy in immunotherapeutic strategies.

Topics: Adolescent; Adult; Animals; Antibodies, Anti-Idiotypic; Antibodies, Monoclonal; Antibodies, Monoclonal, Murine-Derived; Antibody Formation; Antineoplastic Agents, Alkylating; Antineoplastic Combined Chemotherapy Protocols; Carboplatin; Child; Child, Preschool; Combined Modality Therapy; Cyclophosphamide; Doxorubicin; Etoposide; Female; Hematopoietic Stem Cell Transplantation; Humans; Immunoglobulin G; Immunosuppressive Agents; Immunotherapy; Infant; Male; Melphalan; Mice; Neuroblastoma; Retrospective Studies; Thiotepa; Topotecan; Transplantation Conditioning; Transplantation, Autologous; Treatment Outcome; Vincristine; Whole-Body Irradiation

To develop a population pharmacokinetic model for melphalan in children with malignant diseases and to evaluate limited sampling strategies for melphalan.. Melphalan concentration data following a single intravenous dose were collected from 59 children with malignant diseases aged between 0.3 and 18 years. The data were split into two sets: the model development dataset (39 children, 571 concentration observations) and the model validation dataset (20 children, 277 concentration observations). Population pharmacokinetic modelling was performed with the NONMEM software. Stepwise multiple linear regression was used to develop a limited sampling model for melphalan.. A two-compartment model was fitted to the concentration-vs.-time data. The following covariate population pharmacokinetic models were obtained: (i) Clearance (l h(-1)) = 0.34.WT - 3.17.CPT + 0.0377.GFR, where WT = weight (kg), CPT = prior carboplatin therapy (0 = no, 1 = yes), and GFR = glomerular filtration rate (ml min(-1) 1.73 m(-2)); (ii) Volume of distribution (l) = 1.12 + 0.178.WT. Interpatient variability (coefficient of variation) was 27.3% for clearance and 33.8% for volume of distribution. There was insignificant bias and imprecision between observed and model-predicted melphalan concentrations in the validation dataset. A three-sample limited sampling model was developed which adequately predicted the area under the concentration-time curve (AUC) in the development and validation datasets.. A population pharmacokinetic model for melphalan has been developed and validated and may now be used in conjunction with pharmacodynamic data to develop safe and effective dosing guidelines in children with malignant diseases.

Topics: Adolescent; Antineoplastic Agents, Alkylating; Bone Marrow Transplantation; Child; Child, Preschool; Dose-Response Relationship, Drug; Female; Humans; Infant; Infant, Newborn; Male; Melphalan; Models, Statistical; Myosarcoma; Neuroblastoma

Cytotoxicity assays in 96-well tissue culture plates allow rapid sample handling for multicondition experiments but have a limited dynamic range. Using DIMSCAN, a fluorescence digital image system for quantifying relative cell numbers in tissue culture plates, we have developed a 96-well cytotoxicity assay with a >4-log dynamic range.. To overcome background fluorescence that limits detection of viable cells with fluorescein diacetate, we used 2'4'5'6'-tetrabromofluorescein (eosin Y) to quench background fluorescence in the medium and in nonviable cells to enhance the reduction of background fluorescence achieved with digital image thresholding. The sensitivity and linearity of the new assay were tested with serial dilutions of neuroblastoma and leukemia cell lines. DIMSCAN was compared with other in vitro cytotoxicity assays: 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide, colony formation, and trypan blue dye exclusion.. Without background fluorescence reduction, scans produced a nearly flat curve across various cell concentrations from 100 to 10(6) cells per well. Either digital image thresholding or eosin Y dramatically reduced background fluorescence, and combining them achieved a linear correlation (r > 0.9) of relative fluorescence to viable cell number over >4 logs of dynamic range, even in the presence of 4 x 10(4) nonviable cells per well. Cytotoxicity of deferoxamine for neuroblastoma cell lines measured by the DIMSCAN assay achieved dose-response curves similar to data obtained by manual trypan blue counts or colony formation in soft agar but with a wider dynamic range. Long-term cultures documented the clonogenic ability of viable cells detected by DIMSCAN over the entire dynamic range. The cytotoxicity of two drug combinations (buthionine sulfoximine + melphalan or fenretinide + safingol) was tested using both DIMSCAN and 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT) assays, and the wider dynamic range of DIMSCAN facilitated detection of synergistic interactions.. DIMSCAN offers the ability to rapidly and efficiently conduct cytotoxicity assays in 96-well plates with a dynamic range of >4 logs. This assay enables rapid testing of anticancer drug combinations in microplates.

Topics: Antineoplastic Combined Chemotherapy Protocols; Buthionine Sulfoximine; Cell Proliferation; Drug Screening Assays, Antitumor; Drug Synergism; Enzyme Inhibitors; Eosine Yellowish-(YS); Fenretinide; Fluorescent Dyes; Humans; Leukemia; Melphalan; Microscopy, Fluorescence; Neuroblastoma; Protein Kinase C; Sphingosine; Tumor Cells, Cultured; Tumor Stem Cell Assay

Neuroblastoma is the most common extracranial solid tumor of childhood. The activity of J1 (l-melphalanyl-p-l-fluorophenylalanine ethyl ester), an enzymatically activated melphalan prodrug, was evaluated in neuroblastoma models in vitro and in vivo. Seven neuroblastoma cell lines with various levels of drug resistance were screened for cytotoxicity of J1 alone or in combination with standard cytotoxic drugs, using a fluorometric cytotoxicity assay. J1 displayed high cytotoxic activity in vitro against all neuroblastoma cell lines, with IC(50) values in the submicromolar range, significantly more potent than melphalan. The cytotoxicity of J1, but not melphalan, could be significantly inhibited by the aminopeptidase inhibitor bestatin. J1 induced caspase-3 cleavage and apoptotic morphology, had additive effects in combination with doxorubicin, cyclophosphamide, carboplatin, and vincristine, and synergistically killed otherwise drug-resistant cells when combined with etoposide. Athymic rats and mice carrying neuroblastoma xenografts [SH-SY5Y, SK-N-BE(2)] were treated with equimolar doses of melphalan, J1, or no drug, and effects on tumor growth and tissue morphology were analyzed. Tumor growth in vivo was significantly inhibited by J1 compared with untreated controls. Compared with melphalan, J1 more effectively inhibited the growth of mice with SH-SY5Y xenografts, was associated with higher caspase-3 activation, fewer proliferating tumor cells, and significantly decreased mean vascular density. In conclusion, the melphalan prodrug J1 is highly active in models of neuroblastoma in vitro and in vivo, encouraging further clinical development in this patient group.

Topics: Animals; Antineoplastic Combined Chemotherapy Protocols; Apoptosis; Carboplatin; Cell Line, Tumor; Cell Survival; Dipeptides; Dose-Response Relationship, Drug; Doxorubicin; Drug Screening Assays, Antitumor; Etoposide; Female; Humans; Immunoenzyme Techniques; Male; Melphalan; Mice; Molecular Structure; Neovascularization, Pathologic; Neuroblastoma; Prodrugs; Rats; Rats, Nude; Tumor Cells, Cultured; Vincristine

The F7-26 monoclonal antibody (Mab) has been reported to be specific for single-strand DNA damage (ssDNA) and to also identify cells in apoptosis. We carriedout studies to determine if F7-26 binding measured by flow cytometry was able to specifically identify exogenous ssDNA as opposed to DNA damage from apoptosis. Neuroblastoma cells were treated with melphalan (L-PAM), fenretinide, 4-hydroperoxycyclophosphamide (4-HC)+/-pan-caspase inhibitor BOC-d-fmk, topotecan or with 10Gy gamma radiation+/-hydrogen peroxide (H2O2) and fixed immediately postradiation. Cytotoxicity was measured by DIMSCAN digital imaging fluorescence assay. The degree of ssDNA damage was analyzed by flow cytometry using Mab F7-26, with DNA visualized by propidium iodide counterstaining. Flow cytometry was used to measure apoptosis detected by terminal deoxynucleotidyltransferase (TUNEL) assay and reactive oxygen species (ROS) by carboxy-dichlorofluorescein diacetate. Irradiated and immediately fixed neuroblastoma cells showed increased ssDNA, but not apoptosis by TUNEL (TUNEL-negative). 4-HC or L-PAM+/-BOC-d-fmk increased ssDNA (F7-26-positive), but BOC-d-fmk prevented TUNEL staining. Fenretinide increased apoptosis by TUNEL but not ssDNA damage detected with F7-26. Enhanced ssDNA in neuroblastoma cells treated with radiation+H2O2 was associated with increased ROS. Topotecan increased both ssDNA and cytotoxicity in 4-HC-treated cells. These data demonstrate that Mab F7-26 recognized ssDNA due to exogenous DNA damage, rather than apoptosis. This assay should be useful to characterize the mechanism of action of antineoplastic drugs.

Topics: Antibodies, Monoclonal; Antineoplastic Agents; Apoptosis; Benzyl Compounds; Cell Line, Tumor; Child; DNA Damage; DNA, Single-Stranded; Enzyme Inhibitors; Fenretinide; Flow Cytometry; Gamma Rays; Humans; Hydrocarbons, Fluorinated; Hydrogen Peroxide; In Situ Nick-End Labeling; Melphalan; Neuroblastoma; Oxidants; Reactive Oxygen Species; Topotecan

We have previously reported the selection of a radioresistant human neuroblastoma cell line, Clone F, from IMR32 cells. We have shown that clonogenic radioresistance in these cells is accompanied by a reduced level of radiation-induced apoptosis [Cancer Res 55 (1995) 4915]. Here, we measured the response of these lines to several cytotoxic agents, in terms of clonogenicity and apoptosis. In the clonogenic assay, the radioresistant line was also resistant to cisplatin, melphalan and doxorubicin, but not to perillyl alcohol. However, all these agents produced less apoptosis in the Clone F cells, except cisplatin, which failed to induce any apoptosis in either cell line. Reduced apoptosis cannot be the cause of the Clone F cells' resistance to cisplatin. By extension, the Clone F cells' resistance to radiation and other agents cannot be due to diminished apoptosis either. Based on these results, apoptosis may not be a useful surrogate for clonogenic outcome.

Topics: Antineoplastic Agents; Apoptosis; Blotting, Western; Cell Line, Tumor; Cell Survival; Cisplatin; Dose-Response Relationship, Drug; Dose-Response Relationship, Radiation; Doxorubicin; Drug Resistance, Neoplasm; Genes, bcl-2; Humans; Melphalan; Monoterpenes; Neuroblastoma; Radiation Tolerance; Tumor Stem Cell Assay

Green fluorescent protein (GFP) is employed as a selection marker for gene transduction and to track tumor cells. Transduction of enhanced GFP (eGFP) into human neuroblastoma cell lines via a lentiviral vector significantly sensitized CHLA-20 (wild-type and functional TP53), and to a lesser extent CHLA-90 cells (multidrug-resistant, mutant, and nonfunctional TP53) to carboplatin, doxorubicin, etoposide, or melphalan, relative to cells transduced using the cell surface antigen CD80 as a selection marker. Total glutathione (GSH) was significantly up-regulated (1.8- to 2.8-fold) after eGFP (but not CD80) transduction in cell lines with, but not in those lacking, functional p53. Cytotoxicity of GSH depletion by buthionine sulfoximine in CHLA-20 (but not in CHLA-20-eGFP) was diminished by hypoxia (2% O(2)). Thus, oxidative stress produced by GFP selects for cells with up-regulated GSH in a p53-dependent manner, and also enhanced the cytotoxicity of anticancer drugs in neuroblastoma cell lines. Our data suggest caution when employing GFP-transduced cells to assess drug sensitivity and that using a cell surface antigen as a selection marker for gene transduction may perturb cells less than GFP.

Topics: Antineoplastic Agents; Apoptosis; B7-1 Antigen; Buthionine Sulfoximine; Carboplatin; Doxorubicin; Drug Resistance, Multiple; Drug Resistance, Neoplasm; Etoposide; Glutathione; Green Fluorescent Proteins; Humans; Lentivirus; Luminescent Proteins; Melphalan; Mutation; Neuroblastoma; Oxidative Stress; Transduction, Genetic; Tumor Cells, Cultured; Tumor Suppressor Protein p53

Patients with high-risk neuroblastoma (NB) initially respond to aggressive, alkylator-based therapy only to die from recurrent disease that is refractory to chemotherapy, including alkylating agents. We examined the ability of buthionine sulfoximine (BSO)-mediated glutathione (GSH) depletion to modulate melphalan (L-PAM) resistance in five NB cell lines established after progressive disease following myeloablative therapy (high-dose melphalan, carboplatin, etoposide and total body irradiation) supported by autologous hematopoietic stem cell transplant (AHSCT), and in 15 NB cell lines established at diagnosis or after non-myeloablative therapy (pre-AHSCT). Four of five post-AHSCT NB cell lines and 10 of 15 pre-AHSCT NB cell lines were sensitive to single agent BSO (LC(90) <300 microM BSO), while two of five post-AHSCT lines and one of 15 pre-AHSCT lines showed high-level resistance to L-PAM (LC(90)>30 microM). Fixed ratio analysis demonstrated BSO/L-PAM synergy (combination index <1) for all five post-AHSCT and for all 15 pre-AHSCT cell lines tested. Multi-log cytotoxicity (often exceeding four logs of cell kill) was observed in post-AHSCT L-PAM-resistant cell lines (including p53 non-functional lines) only when clinically achievable concentrations of BSO were combined with myeloablative concentrations of L-PAM. We conclude that most neuroblastoma cell lines, including post-AHSCT NB cell lines that are highly resistant to myeloablative levels of L-PAM and lack p53 function, are sensitive to clinically achievable concentrations of L-PAM and BSO. However, some L-PAM-resistant NB cell lines (especially those lacking p53 function) require dose escalation of L-PAM to myeloablative concentrations in order to demonstrate significant synergistic cytotoxicity. Thus, optimal clinical application of BSO/L-PAM may require AHSCT.

Topics: Antineoplastic Combined Chemotherapy Protocols; Buthionine Sulfoximine; Cell Survival; Dose-Response Relationship, Drug; Drug Resistance, Neoplasm; Drug Synergism; Glutathione; Humans; Melphalan; Myeloablative Agonists; Neuroblastoma; Recurrence; Tumor Cells, Cultured

Eight children developed osteochondroma (OS) at a mean of 88 months after hematopoietic stem cell transplantation (HSCT). The mean age at HSCT was 56 months (12-84). This represents a cumulative incidence of 20% among patients less than 18 years of age transplanted from 1981 to 1997. These eight patients underwent allogeneic (n = 2) or autologous (n = 6) transplantation for either acute leukemia (n = 6) or neuroblastoma (n = 2) after a conditioning regimen including TBI (n = 7) or a combination of Bu and CY. OS was multiple in seven patients and solitary in one. Eight lesions were resected and all were benign. Four children received growth hormone before diagnosis of OS, but there was no clinical, radiological or histological difference between those who did not. Univariate analysis showed an increased rate associated only with autologous HSCT, with a 31.7% probability of a new OS at 12 years after HSCT. Osteochondroma should be added to the other adverse effects of HSCT in children.

Topics: Actuarial Analysis; Acute Disease; Bone Neoplasms; Busulfan; Child; Child, Preschool; Cranial Irradiation; Cyclophosphamide; Female; Hematopoietic Stem Cell Transplantation; Humans; Infant; Leukemia, Myeloid; Male; Melphalan; Neoplasms, Radiation-Induced; Neoplasms, Second Primary; Neuroblastoma; Osteochondroma; Precursor Cell Lymphoblastic Leukemia-Lymphoma; Transplantation Conditioning; Whole-Body Irradiation

Neuroblastomas can acquire a sustained high-level drug resistance during chemotherapy and especially myeloablative chemoradiotherapy. p53 mutations are rare in primary neuroblastomas, but a loss of p53 function could play a role in multidrug resistance. We determined p53 function by measuring induction of p21 and/or MDM2 proteins in response to melphalan (L-PAM) in seven L-PAM-sensitive and 11 L-PAM-resistant neuroblastoma cell lines. p53 was functional in seven/seven drug-sensitive but in only 4/11 drug-resistant cell lines (P = 0.01). In four of the seven cell lines lacking p53 function, mutations of p53 were detected by the microarray GeneChip p53 Assay and automated sequencing, whereas six cell lines with functional p53 had no evidence of p53 mutations. All of the cell lines with wild-type (wt) p53 showed a strong transactivation of the p53-HBS/CAT reporter gene, whereas the four cell lines with mutant p53 failed to transactivate p53 HBS/CAT. Overexpression of MDM2 protein (relative to p53 functional lines) was seen in two p53-nonfunctional cell lines with wt p53; one showed genomic amplification of MDM2. Nonfunctional and mutated p53 was detected in a resistant cell line, whereas a sensitive cell line derived from the same patient before treatment had functional and wt p53. Loss of p53 function was selectively achieved by transduction of human papillomavirus 16 E6 (which degrades p53) into two drug-sensitive neuroblastoma cell lines with intact p53, causing high-level drug resistance to L-PAM, carboplatin, and etoposide. These data obtained with neuroblastoma cell lines suggest that the high-level drug resistance observed in some recurrent neuroblastomas is attributable to p53 mutations and/or a loss of p53 function acquired during chemotherapy. If confirmed in patient tumor samples, these data support development of p53-independent therapies for consolidation and/or salvage of recurrent neuroblastomas.

Topics: Antineoplastic Agents; Carboplatin; Cyclin-Dependent Kinase Inhibitor p21; Cyclins; Drug Resistance, Multiple; Etoposide; Gene Amplification; Humans; Melphalan; Mutation; Neuroblastoma; Nuclear Proteins; Oncogene Proteins, Viral; Proto-Oncogene Proteins; Proto-Oncogene Proteins c-mdm2; Repressor Proteins; Transcriptional Activation; Transduction, Genetic; Tumor Cells, Cultured; Tumor Suppressor Protein p53

In the hospitals of the Tohoku Neuroblastoma Study Group (TNBSG), treatment for children with advanced neuroblastoma (NB) was intensified in the mid-1990's with the introduction of myeloablative therapy (MT) with stem cell transplantation (SCT) including the use of autologous peripheral blood stem cells (PBSC) and bone marrow transplantation (BMT). In this report, we examined whether the intensified therapy improved the outcome of children with advanced NB (age> 12 months) who were diagnosed between 1991 and 1997. Patients were 36 children (23 boys and 13 girls) with an average age of 3.4 years (range; 1 to 14 years). Six of them had stage III disease, and the other 30 had stage IV. They were treated initially with induction chemotherapy, surgery, and post-operative chemoradiotherapy, after which 17 of them continued further chemotherapy and the other 19 received MT/SCT (18 with PBSCT and 1 with BMT). Progression-free survival (PFS) rate at seven years from diagnosis was 43.5% for all patients, 66.7% for stage III patients and 38.2% for stage IV patients. The difference between stage III and IV patients was not significant. Among the 30 patients with stage IV disease, PFS at seven years was significantly higher in the 19 patients who received MT/SCT (55.6%) than in the 11 patients who did not receive it (12.5%). There was no difference in clinical and biological risk factors between these two groups, except for the proportion of patients with favorable response to initial therapy (36% and 80% for patients without and with MT/SCT, respectively). Furthermore, the proportion of patients with N-myc amplification was significantly higher in patients with progressive disease (PD) after MT/SCT than in those in CR after MT/SCT. The results of this retrospective study of children with advanced NB suggest that therapy intensification involving MT/SCT might result in lengthened survival time for patients with stage IV disease, and that post-transplant PD remains a risk for patients with high levels of N-myc amplification.

Topics: Antineoplastic Agents; Antineoplastic Combined Chemotherapy Protocols; Carboplatin; Child; Child, Preschool; Combined Modality Therapy; Doxorubicin; Etoposide; Hematopoietic Stem Cell Transplantation; Humans; Infant; Japan; Melphalan; Myeloablative Agonists; Neuroblastoma; Retrospective Studies; Risk Factors; Survival Rate; Transplantation Conditioning; Treatment Outcome; Universities

Alkylator resistance contributes to treatment failure in high-risk neuroblastoma. Buthionine sulfoximine (BSO) can deplete glutathione and synergistically enhance in vitro sensitivity to the alkylating agent melphalan (L-PAM) for many neuroblastoma cell lines, but optimal use of this combination needs to be defined because clinical responses have been less frequent and not durable.. The authors established and characterized a neuroblastoma cell line (CHLA-171) from a patient who died of progressive disease after treatment with BSO and low-dose L-PAM.. CHLA-171 lacks MYCN amplification, expresses PGP (P-glycoprotein) 9.5 RNA, and shows cell surface antigen expression (human leukocyte antigen class I weakly positive, but HSAN 1.2 (hybridoma, SAN 1.2) and anti-GD2 (anti-ganglioside GD2 antibody) strongly positive) characteristic of neuroblastoma cell lines. Twenty-four hours of BSO treatment (0-1,000 micromol/L) maximally depleted CHLA-171 glutathione to 36% of baseline. The cytotoxic response of CHLA-171 to BSO and L-PAM, alone and in combination, was measured by digital image microscopy (DIMSCAN) over a range of drug concentrations and compared with drug levels obtained in the patient during BSO/L-PAM therapy. As single agents, CHLA-171 was highly resistant to L-PAM (LD90 = 42 micromol/L; peak plasma concentration in the patient equals 3.9 micromol/L) and moderately resistant to BSO (LD90 = 509 micromol/L; steady-state concentration in the patient equals 397 micromol/L). Treatment with a 10:1 (BSO:L-PAM) fixed ratio combination synergistically overcame resistance (3-4 logs of cell kill, combination index <1) at clinically achievable levels of BSO (100-400 micromol/L) and levels of L-PAM (10-40 micromol/L) clinically achievable only with hematopoietic stem cell support.. The in vitro results obtained for CHLA-171 suggest that BSO/L-PAM therapy may be optimally effective for drug-resistant neuroblastoma using myeloablative doses of L-PAM.

Topics: Antimetabolites, Antineoplastic; Antineoplastic Agents, Alkylating; Apoptosis; Buthionine Sulfoximine; Cell Survival; Child; Dose-Response Relationship, Drug; Drug Resistance, Neoplasm; Drug Therapy, Combination; Female; Glutathione; Humans; Melphalan; Neuroblastoma; Polymerase Chain Reaction; Reverse Transcriptase Polymerase Chain Reaction; Tumor Cells, Cultured

Although infants with stage 4 neuroblastoma (NB) usually have a good prognosis, metastatic relapses after 1 year of age and amplification of the N-myc oncogene are established poor prognostic factors. In order to improve the survival of patients with such high-risk factors, we performed consolidation with a busulfan (600 mg/m2)-melphalan (140 mg/m2)-containing regimen followed by autologous stem cell transplantation (SCT). From 1986 to 1998, 12 patients were treated according to this strategy. Their median age at diagnosis was 9 months (1-11). Consolidation was performed after a metastatic relapse in five children, because of persistent bone metastases in one and as first-line consolidation in six patients whose tumor exhibited N-myc amplification. The 5-year EFS rate is 64. 5% (36-85%) with a median follow-up of 92 months (20-126). One toxicity-related death occurred in a very heavily pretreated patient. Hepatic veno-occlusive disease was the major side-effect that occurred in nine of 12 children. This busulfan-melphalan combination appears to dramatically improve the prognosis of these high-risk infants with metastatic NB. Given its high toxicity, indications for this consolidation must be restricted to high-risk infants and a lower dose of busulfan (480 mg/m2) is recommended in children weighing less than 10 kg. Bone Marrow Transplantation (2000) 25, 937-942.

Topics: Antineoplastic Combined Chemotherapy Protocols; Body Weight; Brain Neoplasms; Busulfan; Combined Modality Therapy; Hematopoietic Stem Cell Transplantation; Humans; Immunosuppressive Agents; Infant; Melphalan; Neuroblastoma; Prognosis; Survival Analysis; Transplantation, Autologous

Despite intensive-alkylator based regimens, >50% of patients with high-risk neuroblastoma (NB) die from recurrent disease that is probably due, in part, to acquired alkylator resistance.. Using buthionine sulfoximine (BSO)-mediated, glutathione (GSH) depletion to modulate melphalan (L-PAM) resistance, we examined six NB cell lines established after progressive disease following either standard chemotherapy, BSO/L-PAM therapy, or myeloablative therapy and autologous hematopoietic stem cell transplant (AHSCT).. Four of the six cell lines (three p53-nonfunctional and one p53-functional) showed high-level L-PAM resistance.. Fixed ratio analysis demonstrated BSO/L-PAM synergy (combination index >1) for all cell lines tested. In L-PAM-resistant cell lines, the minimal cytotoxicity observed for BSO combined with nonmyeloablative concentrations of L-PAM was markedly enhanced (>4 logs total cell kill) when BSO was combined with myeloablative concentrations of L-PAM. In alkylator-resistant NB, the optimal use of BSO may require dose escalation of L-PAM to levels requiring AHSCT.

Topics: Antimetabolites, Antineoplastic; Antineoplastic Agents, Alkylating; Buthionine Sulfoximine; Child; Disease Progression; Drug Screening Assays, Antitumor; Drug Synergism; Humans; Melphalan; Neuroblastoma; Tumor Cells, Cultured

The purpose of this paper is to study prognostic factors in neuroblastoma patients treated with high-dose chemotherapy and hematopoietic stem cell transplantation. Two hundred and eighteen children over 1 year of age and treated for stage 4 neuroblastoma were enrolled in this study. The median age at diagnosis was 39 months, the sex ratio 1.5 and 84% of patients had an abdominal primary tumor. Skeletal disease was detected in 79% of cases and bone marrow involvement in 93%. N-myc oncogene amplification was present in 27% of the patients studied. The probability of event-free survival at 5 years post-diagnosis was 29% in this series. Three major favorable prognostic factors were significant and independent in the multivariate analysis: age under 2 years at diagnosis (P<0.01), absence of bone marrow metastases at diagnosis (P<0.04) and the high-dose conditioning regimen containing busulfanmelphalan combination (P = 0.001). The quality of response to conventional primary chemotherapy was close to significance (P = 0.053). We conclude that factors related to the patient (age) and extent of disease are predictive of outcome in patients with neuroblastoma treated with conventional chemotherapy followed by surgical excision of the primary and consolidation with high-dose chemotherapy. They should be taken into account in future prospective studies. Moreover, the type of conditioning regimen appears to be the most important prognostic factor. This should encourage new investigations into innovative drug combinations.

Topics: Adolescent; Adult; Antineoplastic Combined Chemotherapy Protocols; Busulfan; Child; Child, Preschool; Combined Modality Therapy; Female; Hematopoietic Stem Cell Transplantation; Humans; Infant; Male; Melphalan; Multivariate Analysis; Neuroblastoma; Prognosis

Impaired growth after TBI prior to BMT has been a constant finding in children with leukemia. The growth of poor-risk neuroblastoma (NBL) survivors treated with myeloablative preparative regimens and ABMT at the Hospital for Children and Adolescents, University of Helsinki, since 1982 is reported. Two separate groups were analyzed: (1) The TBI- patients (n = 15) were conditioned with high-dose chemotherapy only. They had been treated at the age of 1.0-6.3 (mean 3.0) years and the post-ABMT follow-up time was 1.5-14.5 (mean 7.7) years. (2) The TBI+ patients (n = 16) had received TBI in addition to high-dose chemotherapy. They had been treated at the age of 1.3-4. 8 (mean 3.0) years, and the post-ABMT follow-up time was 1.5-8.0 (mean 4.7) years. The height standard deviation score (SDS) was similar for the two groups at the time of diagnosis, -0.3 +/- 1.2 (mean +/- s.d.), and at the time of ABMT, -0.7 +/- 1.1. After transplantation, the height SDS continued to decrease in the TBI+ group, the mean being -2.0 SDS at 5 years after ABMT. In the TBI-group, the mean height SDS remained within -0.7 to -0.9 to the 10 years of follow-up. Five patients received growth hormone (GH) therapy starting 2-6 years after ABMT. They all had low GH secretion in provocative tests. All showed some response to GH therapy. The mean height SDS increased 0.4 SDS during the 3 years following the start of GH therapy, while in the untreated patients a decrease of 0. 8 SDS during the corresponding time (P = 0.009) was observed. We conclude that NBL patients grow poorly following ABMT when TBI is included in the conditioning regimen, but close to normally when treated without TBI. The need for GH therapy should be evaluated early to avoid an unnecessary decrease in final height.

Topics: Antineoplastic Agents, Alkylating; Antineoplastic Combined Chemotherapy Protocols; Body Height; Bone Marrow Transplantation; Brain Neoplasms; Child; Child, Preschool; Cisplatin; Combined Modality Therapy; Etoposide; Growth; Human Growth Hormone; Humans; Infant; Melphalan; Neuroblastoma; Retrospective Studies; Risk Factors; Thyroxine; Transplantation, Autologous; Whole-Body Irradiation

To determine if neuroblastoma acquires a sustained drug-resistant phenotype from patient exposure to therapy, we studied neuroblastoma cell lines established at different points of therapy: at diagnosis prior to therapy, at progressive disease after induction therapy and at relapse after intensive chemoradiotherapy and bone marrow transplantation (post-BMT). Melphalan, cisplatin, carboplatin, doxorubicin, and etoposide cytotoxicities were determined by DIMSCAN assay. Drug resistance progressively increased with therapy and 3/5 post-BMT lines showed high resistance to most drugs. IC 90s 37, 78, 719 and 256 times higher than clinically achievable drug levels were obtained in post-BMT cell lines for melphalan, cisplatin, doxorubicin and etoposide, respectively. Resistance correlated with the therapies patients received: considerable etoposide and doxorubicin resistance (> 1000-fold resistance) was seen in cell lines obtained from patients treated with these drugs. These cell lines indicate that neuroblastoma acquires resistance to cytotoxic drugs that is probably due to stable genetic alterations occurring during therapy.

Topics: Antineoplastic Agents; Carboplatin; Cisplatin; Disease Progression; Doxorubicin; Drug Resistance, Neoplasm; Drug Screening Assays, Antitumor; Etoposide; Humans; Melphalan; Neuroblastoma; Tumor Cells, Cultured

Buthionine sulphoximine (BSO) selectively inhibits glutathione (GSH) synthesis and may enhance the antineuroblastoma activity of melphalan (L-PAM). We determined the cytotoxicity of BSO (dose range 0-1000 microM) alone and in combination with L-PAM (dose range 0-0 microM) in a panel of 18 human neuroblastoma cell lines. BSO alone was highly cytotoxic with 16/18 neuroblastoma cell lines having IC90 values (range 2.1- > 1000 microM) below the clinically achievable steady-state plasma level of 500 microM BSO. Maximal cell killing correlated with GSH levels decreased to less than 10% baseline, and was partially reversed by the addition of exogenous anti-oxidants (GSH, vitamin E and ascorbate). Fluorocytometric analysis of DNA fragments by the Tunnel method detected 92% of a BSO sensitive cell line in apoptosis after a 48 h exposure to 500 microM BSO. The combination of L-PAM and BSO synergistically enhanced the cell killing of L-PAM alone by > 1-3 logs (combination index < 1). We conclude that BSO has significant single-agent cytotoxicity against neuroblastoma and enhances cell killing when combined with L-PAM.

Topics: Antineoplastic Agents; Antioxidants; Apoptosis; Buthionine Sulfoximine; Drug Screening Assays, Antitumor; Drug Synergism; Glutathione; Humans; Melphalan; Neuroblastoma; Tumor Cells, Cultured

In an attempt to improve the poor prognosis of poor responders with stage IV neuroblastoma, a new combined high-dose chemotherapy conditioning regimen was tested. Event-free and overall survival, as well as the incidence of complications, were analysed. Twenty-five children aged 12-146 months at diagnosis entered this study. All were in complete remission (CR) at the time of high-dose chemotherapy. Two or three different protocols had been necessary for them to achieve a CR. High-dose chemotherapy consisted of a combination of busulfan (600 mg/m2), cyclophosphamide (4400 mg/m2) and melphalan (140 mg/m2). It was followed by autologous bone marrow transplantation (ABMT). The bone marrow graft was purged in vitro with mafosfamide. The probability of event-free survival (EFS) at 5 years post-ABMT was 34%, compared to < 8% in a historical series. Toxicity was severe but manageable and 2 complication-related deaths were observed. Veno-occlusive disease was the most frequent extrahaematopoietic complication encountered, but its outcome was always favourable. By using a very intensive conditioning regimen consisting of a combination of three alkylating agents, the EFS of poor responders with metastatic neuroblastoma was improved and similar to that of good responders. When compared with a previously published similar series of patients, the improvement in survival appears probably related to intensification of the conditioning regimen.

Topics: Antineoplastic Combined Chemotherapy Protocols; Bone Marrow Purging; Busulfan; Child; Child, Preschool; Combined Modality Therapy; Cyclophosphamide; Disease-Free Survival; Female; Follow-Up Studies; Humans; Infant; Male; Melphalan; Neoplasm Metastasis; Neuroblastoma; Remission Induction; Treatment Outcome

This study reports a large cooperative experience in myeloablative therapy and bone marrow rescue undertaken to define better the outcome of children with disseminated neuroblastoma after megatherapy. Between 1984 and 1993, 135 children underwent myeloablative therapy with bone marrow transplantation (BMT) in nine Italian Centres. One hundred and seventeen children received unpurged autologous BMT, five allogeneic BMT and 13 peripheral blood progenitor cells as rescue. Of these 135 children, 57 were in 1st CR, 11 in 2nd or subsequent CR, 42 in 1st PR, and 25 had more advanced disease. Twelve children (9%) died of toxicity, 86 relapsed or progressed at 1-68 months (median 7 months) and 80 of these subsequently died of progressive disease. Forty-three children are still alive with 37 in continuous remission at a median of 65 months (30-123 months) after BMT. Overall and disease-free survival at 8 years are 28.5% (s.e. 4.3) and 26% (s.e. 4), respectively. Disease-free survival is 34.6% (s.e. 6.7) for the patients grafted in 1st complete remission, 23.6% (s.e. 6.6) for patients grafted in 1st partial remission, 36.4% (s.e. 14.5) for patients grafted in 2nd or subsequent CR, and 8% (5.4) for patients with advanced disease. We conclude these data confirm that early toxicity of myeloablative therapy is manageable and that myeloablative therapy with bone marrow rescue may contribute to an improved long-term survival of children with disseminated neuroblastoma but the objective of cure of all patients remains distant.

Topics: Antineoplastic Combined Chemotherapy Protocols; Bone Marrow Transplantation; Chemical and Drug Induced Liver Injury; Child; Child, Preschool; Combined Modality Therapy; Disease-Free Survival; Female; Humans; Infant; Infant, Newborn; Infections; Italy; Liver Diseases; Male; Melphalan; Neuroblastoma; Registries; Survival Analysis; Survival Rate; Transplantation Conditioning; Treatment Outcome; Vincristine; Whole-Body Irradiation

Carboplatin and melphalan are two drugs whose toxicity profile makes them suitable for use in high doses followed by stem cell rescue. We report the use of high-dose carboplatin, with the dose based on glomerular filtration rate (GFR), combined with melphalan followed by autologous stem cell rescue in children with advanced stage or chemoresistant solid tumours. Thirty children were treated. After multiagent induction chemotherapy before BMT, 13 were in CR, five in VGPR, 11 in PR and one had progressive disease. They received melphalan, 180 mg/m2 and carboplatin, followed by autologous stem cell rescue. The dose of carboplatin was varied by GFR rather than fixed by surface area. The dose given ranged from 0.7 to 2.6 g/m2. Haematological and gastrointestinal toxicities were severe. Life-threatening or fatal toxicity was attributable to opportunistic infection in two cases and regimen-related in two cases. Of the 30 patients, 15 are alive and 13 disease-free at 4-36 months post-BMT. This simple two-drug combination has been used as consolidation of initial remission for patients with high-risk tumours. The toxicity is severe but tolerable. Use of a carboplatin dose based on GFR should optimise effectiveness in patients with good renal function and avoid excessive toxicity where renal function is impaired.

Topics: Adolescent; Antineoplastic Combined Chemotherapy Protocols; Bone Marrow Diseases; Carboplatin; Child; Child, Preschool; Disease-Free Survival; Female; Glomerular Filtration Rate; Hematopoietic Stem Cell Transplantation; Humans; Infant; Infections; Kidney Diseases; Male; Melphalan; Neoplasms; Neuroblastoma; Treatment Outcome

Disseminated neuroblastoma after infancy has a dismal prognosis; long-term survival with conventional therapy occurs in approximately 10% of cases.. Between 1985 and 1992, we followed a strategy aimed to achieve remission with an induction combination of intensive chemotherapy, primary resection, and tumor-bed radiotherapy (TBRT). Patients who achieved remission proceeded to myeloablative chemoradiotherapy and unpurged autologous bone marrow transplant (ABMT). Twenty-eight patients older than 1 year presented with stage IV disease during the study period; six died of progressive disease and three died of complications of therapy. Nineteen patients achieved remission, two of whom did not receive ABMT. Seventeen patients proceeded to ABMT. Conditioning was with teniposide 130 mg/m2, doxorubicin 30 mg/m2, melphalan 120 mg/m2, cisplatin 80 mg/m2, and total-body irradiation 12 Gy in six fractions (modified VAMP-TBI).. Principal nonhematologic toxicities were mucositis and diarrhea. There were no ABMT-related deaths. Two patients relapsed at 8 and 26 months post-ABMT, respectively. Fifteen patients remain in complete remission (CR) at 24 to 102 months (median, 71) from ABMT and 30 to 114 months (median, 78) from diagnosis. Survival rates of all 28 patients are 61% and 50% at 2 and 5 years, respectively, and the disease-free survival (DFS) of the ABMT group is 94% and 87% at 2 and 5 years, respectively.. Modified VAMP-TBI appears to be an effective conditioning regimen, with 15 of 17 patients remaining disease-free, with no toxic deaths. This result compares favorably with that of other groups. Larger numbers of patients need to be treated to confirm the efficacy of this therapy.

Topics: Adrenal Gland Neoplasms; Antineoplastic Combined Chemotherapy Protocols; Bone Marrow Transplantation; Child; Child, Preschool; Cisplatin; Combined Modality Therapy; Disease-Free Survival; Doxorubicin; Female; Humans; Infant; Male; Melphalan; Neuroblastoma; Remission Induction; Teniposide; Transplantation, Autologous; Whole-Body Irradiation

Topics: Antineoplastic Combined Chemotherapy Protocols; Child; Cisplatin; Cyclophosphamide; Disease-Free Survival; Drug Resistance; Humans; Melphalan; Neuroblastoma; Prognosis; Teniposide; Vincristine

New therapeutic approaches are needed for advanced neuroblastoma as few patients are currently curable. We describe an innovative strategy combining [131I]meta-iodobenzylguanidine ([131I]mIBG) therapy with high dose chemotherapy and total body irradiation. The aim of combining these treatments is to overcome the specific limitations of each when used alone to maximise killing of neuroblastoma cells. Five children received combined therapy with [131I]mIBG followed by high dose melphalan and fractionated total body irradiation. Autologous bone marrow transplantation was undertaken in 3 patients and allogeneic in 2 patients. One patient received additional localised radiotherapy to residual bulk disease. One patient is alive without relapse 32 months after treatment. 4 patients relapsed after remissions of 9, 10, 14 and 21 months. These results indicate that this combined modality approach is feasible and safe, but further evaluation is necessary to establish whether it has advantages over conventional megatherapy using melphalan alone.

Topics: 3-Iodobenzylguanidine; Bone Marrow Transplantation; Child; Child, Preschool; Combined Modality Therapy; Feasibility Studies; Female; Humans; Iodine Radioisotopes; Iodobenzenes; Male; Melphalan; Neuroblastoma; Pilot Projects; Remission Induction; Whole-Body Irradiation

We report the data of CD34+ cell immunoselection from peripheral blood after G-CSF-alone mobilization (10 micrograms/kg/d s.c.) in nine children with neuroblastoma (median age 4-5 years (2-8), median body weight 16 kg (10-20). Leukaphereses were carried out on a Cobe Spectra separator and two consecutive harvests (4 blood volumes processed) were used for immunoselection on a Ceprate column. The yield of CD34+ cells in the purified fraction was 50% (23-80), with a median number of 2.8 x 10(6) CD34+ cells/kg (1-9.4). All patients were reinfused with selected CD34+ cells after busulfan 600 mg/m2 +melphalan 180 mg/m2 and achieved successful haemopoietic recovery.

Topics: Antigens, CD34; Body Weight; Busulfan; Child; Child, Preschool; Granulocyte Colony-Stimulating Factor; Hematopoietic Stem Cell Transplantation; Hematopoietic Stem Cells; Humans; Leukapheresis; Melphalan; Neuroblastoma

Clinical strategies which modulate the human anti-mouse antibody response (HAMA) in patients may have a profound influence on the idiotype network inducible by murine monoclonal antibodies (MoAb). Prior to myeloablative chemotherapy (ABMT), 9 patients with Stage IV neuroblastoma were imaged with 131I-3F8, a MoAb specific for the ganglioside GD2. Their serum HAMA, anti-idiotypic, anti-GD2, and anti-anti-idiotypic antibodies were assayed by enzyme-linked immunosorbent assay prior to, and at 3 and 6 months postimaging. HAMA and anti-idiotypic levels remained low, in contrast to the high levels in 10 patients imaged with 131I-3F8 without ABMT. Five of the 9 patients are long-term survivors; all had elevated anti-GD2 and anti-anti-idiotypic levels, significantly higher than those who died of disease. Although 131I-3F8 imaging prior to ABMT detected abnormal sites in 4 of 9 patients, 3 of the 4 patients have continued in remission for 24-63 months after ABMT, and all 3 mounted anti-GD2 and anti-anti-idiotypic antibody responses. We conclude that myeloablative therapy strongly suppressed the HAMA/anti-idiotypic response to murine MoAb and that the prognostic significance of host immune response to ganglioside GD2 MoAb deserves further investigation.

Topics: Animals; Antibodies, Anti-Idiotypic; Antibodies, Monoclonal; Antibody Formation; Antineoplastic Combined Chemotherapy Protocols; Bone Marrow Transplantation; Carmustine; Cisplatin; Enzyme-Linked Immunosorbent Assay; Etoposide; Gangliosides; Humans; Melphalan; Mice; Neoplasm Staging; Neuroblastoma; Prognosis; Radiotherapy Dosage; Survival Analysis; Survival Rate; Thiotepa

Topics: Antineoplastic Combined Chemotherapy Protocols; Bone Marrow Transplantation; Child; Child, Preschool; Cisplatin; Combined Modality Therapy; Doxorubicin; Female; Humans; Infant; Male; Melphalan; Neuroblastoma; Prognosis; Teniposide; Transplantation, Autologous; Whole-Body Irradiation

Previously, we reported that 26 children with stage III or IV neuroblastoma (NBL) treated with BMT grew poorly post-BMT and significantly worse than a comparison group of hematologic BMT patients. Furthermore, unlike the hematologic patients, there was no apparent catch-up growth. Six of these previously reported long-term (> 2 years) NBL patients surviving BMT were evaluated with growth hormone (GH) provocative testing, frequent (every 20 min) overnight GH sampling and IGF-1 determinations. Three of 6 patients were GH deficient based on subnormal responses to provocative stimuli and subnormal pooled 12 h GH values. Only one child had completely normal GH testing and his growth was normal. Four patients were tested with recombinant GH for a period of 12-21 months. Three patients demonstrated an improvement in their growth velocity on therapy. However, the overall response to GH treatment was significantly less than the growth response in children who are GH-deficient due to causes other than BMT. In summary, GH deficiency may be a frequent complication of BMT treatment of NBL. It also appears that the BMT treatment protocol employing total body irradiation and high-dose melphalan may induce GH resistance.

Topics: Antineoplastic Combined Chemotherapy Protocols; Bone Marrow Purging; Bone Marrow Transplantation; Child; Child, Preschool; Cohort Studies; Combined Modality Therapy; Cranial Irradiation; Drug Resistance; Female; Growth Disorders; Growth Hormone; Humans; Insulin-Like Growth Factor I; Male; Melphalan; Neuroblastoma; Radiation Injuries; Recombinant Proteins; Survivors; Whole-Body Irradiation

The aim of this paper was to present the results of bone marrow harvest followed by cryopreservation in 22 children with various malignant diseases, and the clinical course of autologous bone marrow transplantation (ABMT) performed in 10 children (three with acute lymphoblastic leukemia (ALL), three with acute myeloblastic leukemia (AML) and four neuroblastoma stage IV (NB)). In 20/22 children the harvested bone marrow contained a sufficient number of granulocyte-macrophage-colonyforming units (GM-CFU) for later marrow reinfusion. Hematological reconstitution was obtained in all 10 children who underwent ABMT. No child died of toxicity. The median time to neutrophil count > 0.5 x 10(9)/l, thrombocyte count > 50 x 10(9)/l and to discharge from hospital were 34, 49 and 29 days respectively. Five children are alive with no evidence of active disease 11-21 months after ABMT. Five children have suffered relapse and have died. It was concluded that sufficient amounts of precursor bone marrow cells may be harvested in children during a pause in cystostatic therapy. The acute toxicity of ABMT in children with malignant diseases was only moderate.

Topics: Adolescent; Bone Marrow Purging; Bone Marrow Transplantation; Busulfan; Child; Cryopreservation; Cyclophosphamide; Female; Humans; Immunosuppressive Agents; Leukemia, Myeloid, Acute; Male; Melphalan; Neuroblastoma; Precursor Cell Lymphoblastic Leukemia-Lymphoma; Transplantation, Autologous

Topics: Antineoplastic Combined Chemotherapy Protocols; Bone Marrow Purging; Bone Marrow Transplantation; Child; Child, Preschool; Combined Modality Therapy; Female; Glycine max; Granulocyte-Macrophage Colony-Stimulating Factor; Humans; Lectins; Male; Melphalan; Neuroblastoma; Plant Lectins; Radiotherapy Dosage; Soybean Proteins; Transplantation, Autologous; Vincristine

Seven children with advanced neuroblastoma and non-Hodgkin's lymphoma were treated with myeloablative chemoradiotherapy (180 mg/m2 melphalan plus 12 Gy fractionated total body irradiation), followed by autotransplantation of peripheral blood stem cells (PBSC). Sufficient PBSC to restore bone marrow function were collected by a small number of leukaphereses during haematopoietic recovery after chemotherapy and recombinant human granulocyte colony-stimulating factor (rhG-CSF). Furthermore, rapid recovery of neutrophils was found in all patients by the administration of rhG-CSF following transplantation: median 10 d (range 8-12) to attain more than 0.5 x 10(9)/l neutrophils, and 27 d (range 14-73) to attain more than 50 x 10(9)/l platelets, respectively. Haematopoietic reconstitution has been maintained throughout the follow-up period (median 15 months; range, 6-22). Peripheral blood stem cells mobilized by chemotherapy and rhG-CSF can induce complete haematopoietic reconstitution after myeloablative chemoradiotherapy.

Topics: Adolescent; Antineoplastic Combined Chemotherapy Protocols; Blood Transfusion, Autologous; Child; Child, Preschool; Combined Modality Therapy; Female; Granulocyte Colony-Stimulating Factor; Hematopoietic Stem Cell Transplantation; Humans; Leukocyte Count; Lymphoma, Non-Hodgkin; Male; Melphalan; Neuroblastoma; Neutrophils; Recombinant Proteins; Whole-Body Irradiation

Topics: Antineoplastic Combined Chemotherapy Protocols; Carboplatin; Etoposide; Humans; Infant; Melphalan; Neuroblastoma; Survival Rate; Vincristine

16 unselected patients with advanced neuroblastoma were given high-dose consolidation chemotherapy with vincristine, melphalan, etoposide and carboplatin over 5 h followed by autologous bone marrow rescue. 3 patients died from treatment-related toxicity, 2 from disease, 1 is alive with disease and 10 are alive and disease-free a median of 12.5 months (range 2-38 months) after bone marrow rescue. All had bone marrow toxicity, most mucositis and 6 had seizures. Renal failure was unexpectedly severe. In the last 3 patients, administration of carboplatin was delayed by 18 h in an attempt to reduce renal damage. The results show that this regimen produces significant morbidity and has a high mortality. Although the overall outcome is encouraging, too few patients have been studied to gauge its efficacy. Whether such aggressive consolidation is necessary in heavily pretreated children with neuroblastoma remains unknown.

Topics: Adolescent; Adrenal Gland Neoplasms; Antineoplastic Combined Chemotherapy Protocols; Bone Marrow; Bone Marrow Transplantation; Carboplatin; Child; Child, Preschool; Combined Modality Therapy; Drug Administration Schedule; Etoposide; Humans; Infant; Kidney; Melphalan; Neuroblastoma; Transplantation, Autologous; Vincristine

The efficacy and toxicity of a high-dose multiagent consolidation regimen, OMEC (vincristine, melphalan, etoposide and carboplatin), with autologous bone marrow rescue was studied in patients with poor-prognosis neuroblastoma, 20 patients were treated with OMEC, 18 after induction chemotherapy and 2 following relapse. All patients received, per m2, vincristine 4 mg, etoposide 1 g, carboplatin 1.0-1.75 g and melphalan 180 mg followed by bone marrow rescue. 4 patients (20%) died of treatment-related complications. Severe gastrointestinal toxicity occurred in all of these patients, and in 75% of patients overall. 1 of 5 patients with evaluable disease achieved complete remission. 13 patients (65%) have relapsed a median of 10 months (range 3-26) after receiving OMEC. Thus, OMEC was not more effective, yet more toxic, than high-dose melphalan given alone, and the use of similar multiagent regimens with overlapping toxicities in advanced neuroblastoma appears inadvisable.

Topics: Antineoplastic Combined Chemotherapy Protocols; Bone Marrow Transplantation; Carboplatin; Child; Child, Preschool; Combined Modality Therapy; Drug Administration Schedule; Etoposide; Female; Gastrointestinal Diseases; Humans; Infant; Male; Melphalan; Neuroblastoma; Pilot Projects; Transplantation, Autologous; Vincristine

Myeloablative treatment intensification in 25 patients diagnosed when older than 12 months of age with stage IV neuroblastoma included sequential delivery of cisplatin 120 mg/m2 x 1, hyperfractionated radiation (2,100 cGy) to the primary site and adjacent lymph nodes, carmustine (BCNU) 200 mg/m2 x 1, melphalan 60 mg/m2/d x 3 (n = 13) or thiotepa 300 mg/m2/d x 3. (n = 12), and etoposide (VP 16) 300 mg/m2/d x 3. Seventy-two hours after the last dose of VP 16, histologically tumor-free and 4-hydroperoxycyclophosphamide (4-HC; 100 mumol/L)-purged autologous bone marrow (ABMT) was infused. Acute toxicities included grade 3 to 4 oral mucositis, grade 1 to 2 diarrhea, and fevers. No patient required infusion of unpurged reserve autografts. At ABMT, 16 patients (group I) were progression-free 6.5 months to 14 months (median, 9 months) from diagnosis: seven remain progression-free 20 months to 46 months (median, 39 months) off therapy, six relapsed 4 months to 17 months post-ABMT, and three died of toxicity (candidiasis, metabolic derangement, and venoocclusive disease [VOD]). The event-free survival of group I patients is 44% at 24 months post-ABMT. Nine patients (group II) were in second remission at ABMT, including three who had relapsed after other transplant procedures: two are progression-free 24 months and 41 months off therapy, four relapsed 3 months to 12 months post-ABMT, and three died of toxicity (aspergillosis, hemorrhagic cystitis, VOD). Only one of 10 relapses involved a primary site, suggesting a beneficial effect of local radiation. In terms of survival or toxicity, an advantage for melphalan or thiotepa was not evident. Regimens such as this may prolong the survival of selected patients with poor-risk neuroblastoma, but concerns over late relapses and toxicity mandate continuing efforts to devise alternative, less risky, and more clearly beneficial approaches for definitive ablation of neuroblastoma.

Topics: Adrenal Gland Neoplasms; Antineoplastic Combined Chemotherapy Protocols; Bone Marrow Transplantation; Carmustine; Child; Child, Preschool; Cisplatin; Combined Modality Therapy; Cyclophosphamide; Doxorubicin; Etoposide; Female; Humans; Infant; Male; Melphalan; Neuroblastoma; Pelvic Neoplasms; Radiotherapy Dosage; Retroperitoneal Neoplasms; Survival Rate; Thiotepa; Whole-Body Irradiation

Long-term results are presented of 28 patients who were diagnosed with neuroblastoma at more than 12 months of age and who received melphalan 180 mg/m2 (n = 6) or 240 mg/m2 (n = 22) to consolidate remissions of Stage IV disease or to control refractory disease. Twenty-four patients also received dianhydrogalactitol 180 to 240 mg/m2, and 11 received total body irradiation 450 to 600 cGy. Autologous bone marrow transplantation (ABMT) was performed with marrow that was unpurged (n = 2) or purged ex vivo (n = 26) with 6-hydroxydopamine (6-OHDA) 20 micrograms/ml plus ascorbate 200 micrograms/ml. The median time to an absolute neutrophil count of 500/microliters was 21 days and to self-sustaining platelet counts more than 20,000/microliters, 28 days. One patient required infusion of unpurged reserve marrow. Two groups of patients underwent ABMT: (1) 17 patients (Group I) who were in first remission a median of 7 months after diagnosis; and (2) 11 patients (Group II) who had refractory disease or were in second remission. For Group I, event-free survival was 29% at 12 months and 6% at 24 months post-ABMT. All Group II patients died of disease or ABMT-related toxicity. Overall, of the 28 patients, one is a long-term relapse-free survivor; five died of ABMT-related toxicity; ten patients with tumors present at ABMT had progressive disease within 6 months of ABMT; and 12 patients with no measurable disease at ABMT relapsed 4 to 32 months (median, 12) post-ABMT. Among the latter, six relapses involved the primary site, and six were restricted to distant sites. These results--in accord with the long-term outcome in other series--suggest that for neuroblastoma high-dose melphalan cannot be relied on to ablate residual disease or to salvage patients with refractory tumors. In addition, the pattern of relapse in several patients could be explained by infusion of incompletely purged autografts; this would support recent laboratory evidence that 6-OHDA/ascorbate is a suboptimal purging method.

Topics: Adolescent; Adult; Antineoplastic Combined Chemotherapy Protocols; Ascorbic Acid; Bone Marrow Transplantation; Child; Child, Preschool; Combined Modality Therapy; Cyclophosphamide; Cytarabine; Dianhydrogalactitol; Doxorubicin; Female; Fluorouracil; Humans; Hydroxydopamines; Hydroxyurea; Infant; Male; Melphalan; Neoplasm Staging; Neuroblastoma; Oxidopamine; Prognosis; Radiotherapy Dosage; Remission Induction; Survival Rate; Vincristine; Whole-Body Irradiation

The objectives of this study were to determine (1) the role of selection before bone marrow transplantation (BMT), (2) the role of vincristine, melphalan, and total body irradiation (TBI) as consolidation of induction therapy for stage IV over 12 months at diagnosis, and (3) the role of immunomagnetic purging in metastatic neuroblastoma. Among 72 consecutive unselected patients, 10 were not grafted (four died at induction: two in complete remission [CR], two in partial remission [PR]); three had bone marrow progression before harvest; one had uncontrolled progression; and two had parental refusal). Sixty-two patients were grafted (23 in CR/very good PR [VGPR] and 39 in PR). Among the 62, 33 were consolidated with at least 90% excision of their initial tumor excised (53.2%), 15 with catecholamine secretions (24.2%), 22 with minor bone marrow involvement (35.5%), and 31 with positive bone scan (50%). Median observation time is 59 months. Progression-free survival (PFS) for the 10 excluded patients was 20% at 2 years and 0% at 4 years. PFS for the grafted population (n = 62) is 40% at 2 years, 20% at 4 years, and 13% at 7 years. No difference was observed between patients grafted in CR/VGPR or in PR. However, a group of 19 children was grafted resulting in complete normalization of metastasis (regardless of primary-site tumor status). In this group, PFS at 59 months was 38% with no relapses up to 7 years post-BMT. A group of 31 patients with no bone involvement at BMT was also identified. PFS at 5 years is 30% compared with 12% for bone-positive patients at BMT. Moreover, the 11 children presenting at diagnosis with no bone involvement (Evans stage IVS or stage C Memphis) and consolidated with BMT had PFS at 5 years of 50% with no late relapses. A subgroup of stage IV neuroblastoma patients older than 1 year of age at diagnosis may be curable with this therapeutic approach, and the use of multivariate analyses to search for prognostic factors is warranted in currently existing international registries.

Topics: Age Factors; Antineoplastic Combined Chemotherapy Protocols; Bone Marrow Transplantation; Combined Modality Therapy; Female; Follow-Up Studies; Humans; Infant; Male; Melphalan; Neoplasm Staging; Neuroblastoma; Quality of Life; Remission Induction; Survival Rate; Vincristine; Whole-Body Irradiation

Intensive chemotherapy prior to harvesting autologous bone marrow may be advantageous for cancers that infiltrate the bone marrow. This approach, however, may deplete hemopoietic reserves or damage the hemopoietic microenvironment and thereby jeopardize posttransplant engraftment; in vitro treatment of bone marrow to ensure a tumor-free state may enhance the risk of nonengraftment. We addressed these concerns in a pilot study of patients with disseminated neuroblastoma. Bone marrow was harvested after initial intensive therapy that included 1) three to six courses of very high dose cyclophosphamide (CPM) (100-140 mg/kg in five patients, 140-160 mg/kg in nine patients), plus doxorubicin and vincristine, followed by 2) a median of three strongly myelosuppressive courses of cisplatin/VP16. The median interval between courses was 23 days. The marrow was treated in vitro with the CPM congener 4-hydroperoxycyclophosphamide (4-HC) and cryopreserved. It was infused after a massive cytoreduction regimen of melphalan 180 mg/m2 (n = 7) or thiotepa 900 mg/m2 (n = 7), plus cisplatin, BCNU, VP16, and local radiation. All 14 patients reconstituted hemopoiesis (median of 37 days to neutrophils greater than or equal to 500/microliter and of 63 days to platelets greater than 50,000/microliters). The number per kilogram body weight of hemopoietic progenitor cells (CFU-GM, BFU-E) in the autografts correlated significantly with the rate of hematologic recovery. Preharvest CPM dosage, however, did not. The use of thiotepa, as opposed to melphalan, was associated with a significantly slower posttransplant platelet recovery, suggesting a possible adverse effect of high-dose thiotepa on posttransplant hemopoiesis. In sum, while reinforcing evidence of a stem cell sparing effect of CPM, this pilot study more importantly delineates the degree to which high-dose alkylator therapy can be exploited to attain maximal dose intensity beginning at diagnosis. This aggressive treatment approach may have wide applicability, since CPM is among the most active agents against a spectrum of pediatric cancers.

Topics: Adolescent; Antineoplastic Combined Chemotherapy Protocols; Blood Platelets; Bone Marrow; Bone Marrow Transplantation; Child, Preschool; Cisplatin; Cyclophosphamide; Doxorubicin; Etoposide; Hematopoiesis; Humans; Infant; Melphalan; Neuroblastoma; Neutrophils; Thiotepa; Vincristine

Stage I neuroblastoma in a seven-year-girl have had local recurrence with bone metastasis. Second surgery was performed after the aggressive chemotherapy including cisplatin, VP16, cyclophosphamide, vincristine and doxorubicin. She underwent allogeneic bone marrow transplantation from her HLA identical brother, following the preparative regimen consisting of high-dose melphalan and total body irradiation (12 Gy). Clinical course after the transplantation was uneventful. She is still alive with no evidence of disease for twenty-eight months after the transplantation. It is suggested that bone marrow transplantation is an effective way of therapy even in a patient with relapsed neuroblastoma.

Topics: Adrenal Gland Neoplasms; Antineoplastic Combined Chemotherapy Protocols; Bone Marrow Transplantation; Bone Neoplasms; Child; Combined Modality Therapy; Cyclophosphamide; Doxorubicin; Etoposide; Female; Humans; Melphalan; Neuroblastoma; Remission Induction; Whole-Body Irradiation

Neuroblastoma is the third most frequent malignant tumor in childhood. One-third of the patients over one year of age at the time of diagnosis suffer from the disseminated form (stage IV). Despite highly aggressive chemotherapy survival rates are poor. One hundred and eighty-seven patients with neuroblastoma stage IV have been treated according to the German protocol NB 85. The probability of disease free survival is only 15% after 70 months. Treatment strategy in our protocol includes autologous and allogeneic bone marrow transplantation (BMT) for patients with stage IV (and greater than 1 year old). Twenty-two patients were grafted (7 allogeneic and 15 autologous). The conditioning regimen consisted mainly of high-dose melphalan (180 mg/m2) and total body irradiation (TBI) (3.4 Gy). Survival rates are discussed in the context of the chemotherapy protocol. Our own experience with autologous BMT is poor, despite of different purging methods. For this reason we decided to focus on allogeneic BMT. We have grafted five patients within the last 3 years. Three of them are alive and well, on died from veno-occlusive disease 70 days after BMT, and the remaining patient, grafted from a syngeneic donor, died from relapsing tumor. The main problem in neuroblastoma stage IV is resistance to chemotherapy. Intensification of the conditioning regimen or double autografting leads to a rate of toxic deaths close to 20% (Zucker, EBMT 1987) which is not tolerable. New improvements in the conditioning regimen have to be found to increase the effect of BMT.

Topics: Bone Marrow Transplantation; Germany, West; Humans; Infant; Melphalan; Neuroblastoma; Survival Rate; Tumor Cells, Cultured; Whole-Body Irradiation

Circulating hematopoietic stem cells were collected by three consecutive leukaphereses during post-chemotherapy expansion of the stem cell pool in a 3-year-old boy with advanced and therapy-resistant neuroblastoma. The cells were fractionated by discontinuous Percoll gradient centrifugation, frozen in a programmed freezer and then stored in liquid nitrogen. Following high-dose chemotherapy, the cells were thawed rapidly and re-infused into the patient. Early evidence of marrow recovery was first noted at day 13 and the times required to achieve a granulocyte count of greater than 0.5 x 10(9)/L and a platelet count of greater than 50 x 10(9)/L were 21 days and 30 days, respectively. This new marrow-rescue operation may have potential in cancer therapy as an alternative to bone marrow transplantation and further clinical investigation is warranted.

Topics: Antineoplastic Combined Chemotherapy Protocols; Blood Preservation; Bone Neoplasms; Child, Preschool; Cisplatin; Freezing; Hematopoietic Stem Cell Transplantation; Humans; Leukapheresis; Male; Melphalan; Neuroblastoma; Podophyllotoxin; Transplantation, Autologous

These studies suggest that intensive chemoradiotherapy (eg., VAMP-TBI), if given relatively soon after diagnosis and before development of progressive disease, improves long-term survival for patients with advanced neuroblastoma. Although this particular therapy is not useful for those who already have developed progressive disease, other intensive regimens may warrant testing in this latter group of patients. Our current study is testing aggressive induction chemotherapy, ex vivo purging of autologous marrow, and VAMP-TBI followed by BMT. Because of the increasing risk of progressive disease with time after diagnosis, we recommend beginning the BMT phase by 20 weeks after diagnosis. This should result in 85% of newly diagnosed patients entering the BMT phase without progressive disease; and, with fewer toxic deaths, 90% should survive the BMT phase. Thus, approximately 70% of patients could be disease-free survivors 8-9 months after diagnosis. Because a significant number of patients still develop progressive disease during induction or after BMT, efforts are being made to improve induction and pretransplant therapies and to identify prognostic factors. If modifications of the current regimens do not decrease the rate of progressive disease, it may be necessary to develop additional or different therapy for patients identified to be at high risk. Hopefully, new strategies will further increase the percentage of patients with tumor-free survival.

Topics: Bone Marrow Transplantation; Cisplatin; Combined Modality Therapy; Drug Therapy, Combination; Humans; Melphalan; Neuroblastoma; Prognosis; Teniposide; Transplantation, Homologous

A new therapeutic approach was adopted for 13 consecutive patients with stage IV neuroblastoma over 1 year of age admitted to the Children's Hospital, University of Helsinki, between October 1981 and August 1985. Treatment was based on induction, with aggressive, repeated early surgery and a relatively short course of chemotherapy with cisplatinum and etoposide, and on consolidation, with 140-180 mg/m2 of melphalan followed by autologous unpurged bone marrow. Induction therapy failed in only 2 of the 13 patients. One of the two was never autografted. So a total of 12 children underwent autologous marrow transplantations, 10 in primary and 1 in secondary remission, and one with residual disease. One patient died in septicemia during postmelphalan pancytopenia, and four patients relapsed 0.3-2.9 years after transplantation. Seven of the original 13 patients (54%) are well and living in continuous remission 2.3-4.1 (median 2.8) years after diagnosis.

Topics: Antineoplastic Agents; Bone Marrow Transplantation; Child; Child, Preschool; Cisplatin; Combined Modality Therapy; Etoposide; Female; Follow-Up Studies; Humans; Infant; Male; Melphalan; Neoplasm Recurrence, Local; Neoplasm Staging; Neuroblastoma; Prognosis; Remission Induction; Retrospective Studies; Survival Rate; Transplantation, Autologous; Tumor Lysis Syndrome

Among 62 children over 1 year of age at diagnosis who were treated for stage IV neuroblastoma, 33 entered remission after conventional therapy. They received high-dose chemotherapy and in vitro purged bone marrow transplantation as consolidation therapy. Fifteen patients received one course and 18 two courses. At present, 16/33 grafted patients are alive in CR with a median follow-up of 28 months. Toxicity of this regimen was tolerable. Under this treatment, actuarial disease free survival is improved compared with that observed under conventional therapy.

Topics: Antineoplastic Combined Chemotherapy Protocols; Bone Marrow Transplantation; Carmustine; Child; Child, Preschool; Combined Modality Therapy; Female; Follow-Up Studies; Humans; Infant; Male; Melphalan; Neoplasm Staging; Neuroblastoma; Prognosis; Teniposide; Transplantation, Autologous

Among 62 children over 1 year of age at diagnosis, who were treated for stage IV neuroblastoma, 33 entered complete remission (CR) or good partial remission (GPR) after conventional therapy and received high-dose chemotherapy (HDC) with in vitro purged autologous bone marrow transplantation (ABMT) as consolidation therapy. The HDC was a combination of carmustine (BCNU), teniposide (VM-26), and melphalan. Thirty-three patients received one course of this regimen, and 18 received two courses. At present, 16 of the 33 grafted patients are alive in continuous CR, with a median follow-up of 28 months. Toxicity of this regimen was tolerable, principally marked by bone marrow depression and gastrointestinal (GI) tract complications. Four complication-related deaths were observed. Relapse post-ABMT occurred most often in the bone marrow. Under this treatment, actuarial disease-free survival is improved compared with that observed under conventional therapy.

Topics: Abdominal Neoplasms; Adolescent; Antineoplastic Combined Chemotherapy Protocols; Bone Marrow Diseases; Bone Marrow Transplantation; Carmustine; Child; Child, Preschool; Cisplatin; Combined Modality Therapy; Cyclophosphamide; Doxorubicin; Etoposide; Gastrointestinal Diseases; Humans; Infant; Infections; Melphalan; Neuroblastoma; Teniposide; Thoracic Neoplasms; Transplantation, Autologous; Vincristine

Seven children with neuroblastoma who had relapsed on or after conventional therapy (3 originally stage IV, 3 stage III, 1 stage II) were entered on a study of "massive therapy" with purged autologous bone marrow rescue. In 5 patients attempts were made to reinduce remission with alternative chemotherapy, and a partial or complete response was achieved in 3. The massive therapy regimen comprised melphalan, vincristine, and total-body irradiation. Of 6 patients with measurable disease, all showed objective response to high-dose therapy (5 partial, 1 complete remission), but the median duration of remission was only 5 months (range 1/2 to 10). One patient remains disease-free at 18 months post graft. This patient was the only one treated in second complete remission. These data confirm the high response rate achieved by high-dose melphalan, total-body irradiation regimens, but it appears unlikely that a single high-dose chemoradiotherapy procedure will cure patients after relapse, particularly if they are unresponsive to conventional salvage regimens. Such protocols may, however, have a role as consolidation in first remission. The use of double-autograft procedures is an alternative that warrants further investigation in patients with relapsed neuroblastoma.

Topics: Adolescent; Antineoplastic Combined Chemotherapy Protocols; Bone Marrow Transplantation; Child; Child, Preschool; Combined Modality Therapy; Female; Humans; Infant; Male; Melphalan; Neuroblastoma; Vincristine; Whole-Body Irradiation

Since January 1983, 56 consecutive children over 1 year of age with stage IV neuroblastoma entered an aggressive protocol, including chemotherapy, radiation therapy, and bone marrow transplantation. The induction protocol included platinum and epipodophyllotoxin (VM-26), alternating with cyclophosphamide, Adriamycin (Adria Laboratories, Columbus, OH), and vincristine (PE/CADO). Surgery was performed after 2 to 4 months, and consolidation with intensive chemoradiotherapy and bone marrow transplantation (BMT) was performed within 12 months of diagnosis. The combination of vincristine, melphalan and total body irradiation (TBI) was used before BMT, and no further treatment was administered before progression. With the exception of two allografts, autologous BMT (ABMT) was given in all cases and was purged using an immunomagnetic procedure (Kemshead technique) in 32 of 35 cases, and a chemical procedure in three of 35. Of the 56 patients, 45 were evaluable. Of those, 23 were grafted in partial remission (PR), and 14 were grafted in either complete remission (CR) or very good partial remission (VGPR). The acute toxic death rate was 19%, the relapse rate was 32%, and the progressive disease rate was 19%. The progression-free survival in the CR/VGPR group (ie, 44% at 32 months post-diagnosis) and in the PR group (13% at 32 months) was not significantly different (P greater than .05). At 24 months, the overall survival of the 56 unselected patients was 39% compared with 12% for comparable patients previously treated by our group (P less than .005).

Topics: Antineoplastic Combined Chemotherapy Protocols; Bone Marrow Transplantation; Child, Preschool; Combined Modality Therapy; Female; Humans; Infant; Male; Melphalan; Neuroblastoma; Vincristine; Whole-Body Irradiation

The Authors describe a reversed-phase HPLC method for the separation of the six peptides which constitute the antitumoral drug Peptichemio (PTC). They also present some preliminary investigations concerning the in vitro biopharmacokinetics of this drug. Differences in selectivity and kinetics of peptides uptake have been investigated using human peripheral blood lymphocytes (PBL) and a human neuroblastoma derived cell line (SK-N-SH). Results will be discussed along with their clinical and pharmacological research implications.

Topics: Cell Line; Chromatography, High Pressure Liquid; Erythrocytes; Humans; Kinetics; Lymphocytes; Melphalan; Neuroblastoma; Peptichemio; Peptides

The effects of eight different chemotherapeutic agents were studied on a human neuroblastoma xenograft, designated TNB9, according to the standard Battelle Columbus Laboratories protocol. Cytogenetically and molecular-cytogenetically, this xenograft is known to have a homogeneously staining region (HSR) on chromosome 20 and to exhibit 60- to 80-fold amplification of clone #8 (1.75 kb) and N-myc (2.1 kb) in the HSR. Our previous analyses of cytogenetic and phenotypic characteristics on nine human neuroblastoma xenografts demonstrated that TNB9 is one of the most malignant strains of neuroblastoma. The in vivo chemotherapeutic sensitivity assessment disclosed that cyclophosphamide, cis-platinum, nitrosourea (ACNU), melphalan, and dacarbazine (DTIC) are effective, while aclarubicin, vincristine, and cytosine arabinoside are quite ineffective against this neuroblastoma xenograft.

Topics: Adolescent; Animals; Cell Line; Cisplatin; Cyclophosphamide; Dacarbazine; Drug Evaluation, Preclinical; Gene Amplification; Humans; Male; Melphalan; Mice; Mice, Inbred BALB C; Mice, Nude; Neuroblastoma; Nimustine; Nitrosourea Compounds; Staining and Labeling

Topics: Bone Marrow Transplantation; Child; Child, Preschool; Combined Modality Therapy; Female; Humans; Male; Melphalan; Neoplasm Recurrence, Local; Neuroblastoma; Sarcoma, Ewing; Transplantation, Autologous; Wilms Tumor

The incidence of hyponatremia in 34 patients following administration of high-dose L-phenylalanine mustard (L-PAM) and dianhydrogalactitol (DAG) was determined. Two consecutive daily levels of 133 mEq/l or less were observed in 12 patients. These episodes coincided with the advent of diarrhea about 10-12 days after drug administration. The hyponatremia was not due to the syndrome of inappropriate antidiuretic hormone secretion.

Topics: Diagnosis, Differential; Dianhydrogalactitol; Diarrhea; Humans; Hyponatremia; Inappropriate ADH Syndrome; Melphalan; Nervous System Neoplasms; Neuroblastoma; Prospective Studies

Chemotherapeutic agents are used in increasingly high dosages to treat patients with refractory cancers. An in vitro clonogenic assay was used to investigate the effects of melphalan on cultures of human neuroblastoma, Ewing's sarcoma, and osteosarcoma cells, as well as on normal bone marrow cells. A 1-hr incubation with 10(-5) M melphalan significantly inhibited tumor colony growth of both fresh neuroblastoma and osteosarcoma cells (p less than 0.01) while Ewing's sarcoma cells and normal bone marrow appeared resistant to melphalan even at a 100-fold higher concentration. Incubation with melphalan for 8 hr did not significantly increase the sensitivity of neuroblastoma and osteosarcoma or the relative resistance of Ewing's sarcoma cells; however, normal bone marrow which had remained resistant to melphalan after 1 hr of incubation, showed significant inhibition of colony growth after an 8-hr incubation with the agent. Repeated exposure to melphalan increased the degree of inhibition of both tumor and normal marrow colonies. Fresh neuroblastoma cells were significantly more sensitive than long-term cultured neuroblastoma cells at all drug doses tested. HPLC studies demonstrated that the loss of melphalan followed first-order kinetics with a half-life of 69 min, and that in addition to the 2 known breakdown products, mono- and dihydroxy-melphalan, several other peaks were present which were not attributable to the tissue culture medium or the buffer solutions.

Topics: Bone Marrow; Cells, Cultured; Chromatography, High Pressure Liquid; Humans; Melphalan; Neoplasms; Neuroblastoma; Osteosarcoma; Sarcoma, Ewing; Tumor Stem Cell Assay

Fifteen children with advanced neuroblastoma according to Evans' classification (1 with stage III and 14 with stage IV) were treated with high-dose melphalan (HDM) followed by autologous bone marrow transplantation. Before HDM, all patients had been extensively treated with multimodality therapy for a median duration of 9 months. At the time of HDM, seven children were in partial remission (PR) with measurable residual tumor and 8 were in complete remission (CR) or good partial remission (GPR). No reduction in measurable tumor size was observed in any of the PR patients. However, when HDM was used as consolidation therapy (CR and GPR patients) survival appeared encouraging, since five of eight patients are alive with no evidence of disease at (NED) 29+ to 54+ months after HDM. Tolerance of this high-dose chemotherapy was satisfactory; gastrointestinal toxicity appeared to be the most important limiting factor. These results suggest that chemotherapy including high-dose melphalan is promising when used as consolidation therapy in patients who have already attained CR with conventional therapies.

Topics: Adolescent; Bone Marrow Transplantation; Child; Child, Preschool; Combined Modality Therapy; Female; Humans; Infant; Male; Melphalan; Neuroblastoma; Prognosis

The case of a 4 year 8 months old boy with neuroblastoma of unknown primary, metastatic to the bone and to the bone marrow is presented. After achieving a partial remission with six cycles of conventional chemotherapy, the patient was given supraconventional chemotherapy (melphalan 220 mg/m2 bolus i.v.) in an effort to eliminate residual disease. Prior to the administration of the drug, 560 cc of autologous bone marrow, morphologically free of tumor was harvested (total 110 X 10(8) nucleated cells) and concentrated to a mononuclear cell fraction with a total of 10 X 10(8) cells. After in vitro purging with the stable metabolite of 4-hydroperoxycyclophosphamide ASTA Z 7654 (40 micrograms/2 X 10(7) mononuclear cells/ml), the mononuclear cell suspension was retransfused 10 hours following the application of high dose melphalan. Hemopoietic reconstitution was delayed with a platelet count reaching 70,000/microliter only after seven months. At the time of this writing (20 months after diagnosis and 16 months after autologous bone marrow transplantation) there is no evidence for active disease according to the bone scan and multiple bone marrow biopsies. In view of the dismal prognosis of patients with neuroblastoma, stage IV it is recommended that further patients should be treated with a slightly modified protocol of the cooperative austrian neuroblastoma study.

Topics: Antineoplastic Combined Chemotherapy Protocols; Bone Marrow; Bone Marrow Transplantation; Bone Neoplasms; Child, Preschool; Cyclophosphamide; Humans; Male; Melphalan; Neoplasm Staging; Neoplasms, Unknown Primary; Neuroblastoma

Topics: Adolescent; Antineoplastic Combined Chemotherapy Protocols; Bone Marrow Transplantation; Carmustine; Child; Child, Preschool; Combined Modality Therapy; Dose-Response Relationship, Drug; Female; Hematologic Diseases; Humans; Infant; Male; Melphalan; Neuroblastoma; Teniposide

Topics: Adolescent; Antineoplastic Combined Chemotherapy Protocols; Bone Marrow Transplantation; Child; Child, Preschool; Female; Humans; Infant; Male; Melphalan; Neoplasm Staging; Neuroblastoma; Pilot Projects; Prognosis; Vincristine; Whole-Body Irradiation

Nine children with poor-prognosis malignancies--seven with advanced neuroblastoma and two with metastatic Ewing's sarcoma--were given high doses of melphalan (HDM), 150 mg/m2 (3 patients) and 180 mg/m2 (6 patients), as a 'late intensification' agent combined with noncryopreserved autologous bone marrow transplants. Melphalan levels in the plasma decreased biphasically, with mean half-lives of 6.6 min and 3.0 h. At the time of marrow reinfusion (12-21 h after HDM) the melphalan plasma level was generally below 0.1 microgram/ml. The renal contribution to melphalan clearance was low, a mean of 5.8% of the injected dose being found in patients' urine over the 12 h following HDM administration. No significant difference was seen in pharmacokinetic parameters between patients undergoing and not undergoing forced diuresis.

Topics: Child; Child, Preschool; Dose-Response Relationship, Drug; Half-Life; Humans; Infant; Kinetics; Male; Melphalan; Neoplasm Metastasis; Neuroblastoma; Sarcoma, Ewing

Neuroblastoma and Ewing's sarcoma are examples of pediatric cancers in which disseminated disease is often present at diagnosis or develops later in spite of combination therapy. The demonstration that marrow-ablative doses of chemotherapy can increase tumor cell kill, and that autologous bone marrow can be cryopreserved and reinfused into the patient to reverse such marrow ablation, has stimulated interest in this approach to refractory childhood cancers. We present results of treating eighteen patients with recurrent neuroblastoma and Ewing's sarcoma resistant to conventional therapy. We used supralethal doses of melphalan, supported by reinfusion of previously cryopreserved autologous bone marrow. Seven of 10 neuroblastoma and six of eight Ewing's sarcoma patients had complete or partial responses, lasting for a median of 6 months (neuroblastoma) and 3 months (Ewing's sarcoma). Prolonged hospitalization, pancytopenia complicated by sepsis, and reversible gastrointestinal toxicity were the major side effects. These results suggest this approach should be tested in therapeutic trials at an earlier disease stage in children who have cancers with a predictably bad prognosis.

Topics: Abdominal Neoplasms; Adolescent; Adult; Bone Marrow Transplantation; Bone Neoplasms; Child; Child, Preschool; Combined Modality Therapy; Gastrointestinal Diseases; Humans; Melphalan; Neoplasm Recurrence, Local; Neuroblastoma; Pancytopenia; Sarcoma, Ewing; Transplantation, Autologous

Topics: Antineoplastic Combined Chemotherapy Protocols; Bone Marrow Transplantation; Child; Child, Preschool; Combined Modality Therapy; Cyclophosphamide; Female; Humans; Infant; Male; Melphalan; Neuroblastoma; Transplantation, Autologous

Peptichemio (PTC), a multipeptidic complex of m-L-phenyl-alanine mustard, was administered to 39 children with neuroblastoma at relapse. The compound was given in two 5-day cycles at dosages varying from 1.0-1.5 mg/kg/day. We were able to evaluate 29 of the initial 39 children for PTC effect; 21 of them had received PTC as first therapy following diagnosis. Ten patients underwent other chemotherapy for relapse before PTC. Three patients were off therapy when relapse occurred. Subjective improvement was observed in 18 cases (62%). Eleven patients (38%) experienced an objective regression, which was scored as complete response in three cases, partial response in two, mixed response in six. In ten children no significant disease change was observed; the remaining eight had a progression of their disease while receiving PTC. The incidence of responses has been higher in patients off therapy at moment of relapse, and lower in those pretreated for their relapse. Previous administration of PTC did not reduce the chance of response at relapse. Major toxic effects were transient, mostly moderate myelodepression and phlebosclerosis. Allergic reactions, nausea, and vomiting, occurred in a few patients. These data indicate that PTC may exert objective antitumor activity in approximately one-third of neuroblastoma patients at relapse.

Topics: Child; Child, Preschool; Drug Evaluation; Female; Humans; Infant; Leukopenia; Male; Melphalan; Neuroblastoma; Peptichemio; Recurrence; Thrombocytopenia; Veins

Thirty-three adult and pediatric patients with refractory malignancies were treated with escalating doses of melphalan (120-225 mg/m2 IV over 3 days) followed by reinfusion of previously harvested and cryopreserved autologous marrow. The hematological and nonhematological toxicities and the therapeutic effects of this regimen were evaluated. Increasing doses of melphalan did not alter the rate of decline nor the recovery of peripheral blood counts. Granulocyte (greater than 500/microL) and platelet count (greater than 20,000/microL) recovery occurred in a median of 19 (range 12-54) and 24 (range: 12-54) days after bone marrow transplantation, respectively. Five patients experienced severe infection, three of which were fatal, and one patient died due to thrombocytopenic hemorrhage. Toxicity to the gastrointestinal system was dose limiting. The maximum tolerated dose of melphalan was 180 mg/m2; only three of 24 patients experienced severe stomatitis, esophagitis, and diarrhea at this level or less, while eight of nine patients at 225 mg/m2 were affected (p less than 0.005). Administration of cyclophosphamide (300 mg/m2 IV) 1 week before melphalan therapy did not reduce the incidence of severe gastrointestinal toxicity. Plasma melphalan concentration peaked 30-60 min after infusion (4.8-11.5 micrograms/mL) but declined rapidly. Cerebrospinal fluid concentration was 10% of the corresponding plasma concentration and was undetectable at 3 hours. Antitumor responses occurred in nine of 13 patients with malignant melanoma (five complete and four partial remissions), and ranged 2-12+ months with a median of 5 months. Four of six neuroblastomas demonstrated responses (three complete and one partial remission( lasting a median of 7.5 (range: 5-10) months. Other tumors in which this regimen had activity included breast cancer and Ewing's sarcoma. The overall response rate for the 33 patients was 30% complete remissions (10 patients) and 21% partial remissions (seven patients). High dose melphalan and autologous bone marrow transplantation is a promising therapy for patients with malignancies for which no effective treatment is known or for patients whose cancer is refractory to conventional therapeutic agents.

Topics: Adolescent; Adult; Aged; Bone Marrow Transplantation; Breast Neoplasms; Child; Child, Preschool; Combined Modality Therapy; Evaluation Studies as Topic; Female; Gastrointestinal Diseases; Humans; Male; Melanoma; Melphalan; Middle Aged; Neuroblastoma; Neutropenia; Sarcoma, Ewing; Thrombocytopenia; Time Factors

The pharmacokinetics of high-dose IV melphalan (140 or 220 mg m-2) were studied after 12 administrations in 10 children (aged 2.5-16 years) undergoing chemotherapy for either neuroblastoma or Ewing's tumour. To assess whether a simpler and less expensive nitrobenzylpyridine (NBP) spectrophotometric assay for alkylating activity was a satisfactory alternative to high-pressure liquid chromatography (HPLC), the plasma melphalan concentration was estimated by both methods in five cases. Analysis of the disposition of melphalan gave a mean half-life of 1.3 +/- 1.0 (SD) h, clearance 18.4 +/- 9.4 l X h-1 X m-2, and apparent volume of distribution 26.3 +/- 18.0 l X m-2. These pharmacokinetic parameters were similar to those found in adults: no correlation was found between any parameter and age or glomerular filtration rate. NBP alkylating activity determinations yielded consistent results and good correlation with plasma melphalan concentration. However, concordance analysis indicated a consistent bias, the NBP assay always giving lower estimates of plasma melphalan concentration: HPLC assay therefore remains the method of choice for determining plasma melphalan pharmacokinetics.

Topics: Adolescent; Child; Child, Preschool; Female; Half-Life; Humans; Injections, Intravenous; Kinetics; Male; Melphalan; Neuroblastoma; Sarcoma, Ewing

A group of 12 children with advanced neuroblastoma (7 Stage IV and 5 Stage III), selected by their initial response to chemotherapy with pulsed cyclophosphamide/vincristine/Adriamycin (CVA), were given consolidation therapy with high-dose melphalan (140 mg/m2) and then surgical removal of residual disease. Twenty-two high-dose melphalan procedures were combined with autologous marrow grafting to offset myelotoxicity and were well tolerated. In each of 2 additional children, procedures carried out without marrow autografting led to serious marrow and mucosal toxicity. There were no treatment-related deaths. In 7/11 patients with evaluable computerized tomographic (CT) scans there was a decrease in maximum diameter of the primary tumour after melphalan. Complete response was achieved in 6 patients, of whom 3 are well and have no evidence of disease at 35, 33 and 18 months from completion of all treatment; however, although survival (median 23 months) of all 12 autografted patients is longer than that of 28 comparable children treated between 1970-77 with conventional chemotherapy (median 14 months) the difference is not statistically significant. High-dose melphalan is a safe and tolerable treatment in children when combined with autologous marrow grafting, but further study is required to determine whether the procedure can improve prognosis for patients with advanced neuroblastoma.

Topics: Adolescent; Bone Marrow Transplantation; Child; Child, Preschool; Drug Administration Schedule; Humans; Melphalan; Neuroblastoma; Tomography, X-Ray Computed

PTC, a mixture of oligopeptides of m-L-sarcholysin, acting primarily as an alkylating agent, was utilized as initial therapy following diagnosis in 80 children with nonlocalized neuroblastoma. Of the 67 evaluable patients (21 Stage III, 41 Stage IV and five Stage IV-S), 51 had measurable lesions allowing to evaluate PTC activity; objective tumor responses to the drug were recorded in 45 of these 51 cases (88.2%); 5/5 Stage III, 37/41 Stage IV, 3/5 Stage IV-S. Complete responses were obtained in seven patients (13.7%), partial responses in 32 (62.7%), objective improvement in six (11.8%). Four patients (7.8%) had either no tumor change, or tumor progression. There have been two early drug-related deaths (3.9%). Stage III and IV patients responding to PTC were then treated by irradiation + VCR, followed by cycles of a combination of ADriamycin, vincristine, and cyclophosphamide. Stage IV-S patients received no further therapy. Thirteen of 21 Stage III (61.9%), five of 41 Stage IV (12.2%) and four of five Stage IV-S (80%) are presently alive from 19-48 months (median, 27 months). PTC is an effective agent in advanced neuroblastoma. However, the results of this report do not indicate that its addition to a "standard" treatment, at least in the schedule adopted in this protocol, has improved the final outcome of children with nonlocalized disease.

Topics: Adolescent; Child; Child, Preschool; Female; Humans; Infant; Male; Melphalan; Neuroblastoma; Peptichemio; Vincristine

Autologous non-cryopreserved bone marrow infused 8 hours after an intravenous injection of melphalan, 140 mg/m2, accelerates bone marrow recovery. This effect is most noticeable in the recovery of peripheral blood granulocytes. Twenty patients with disseminated malignant melanoma were treated with this regimen: there were 12 responses, two of them complete but the toxicity of the treatment was not sufficient to justify using this method of treatment routinely since survival was little influenced by treatment (4-11 months). In 8 patients with disseminated neuroblastoma, high dose melphalan/autograft was used in a program of combined modality treatment. Three of the patients are disease free at 16, 11 and 6 months and in one the disease is 'static', not having grown for 13 months. The treatment for this tumour deserves further exploration, and perhaps similar treatment ought to be explored for other tumours.

Topics: Bone Marrow Transplantation; Humans; Leukocyte Count; Melanoma; Melphalan; Neuroblastoma; Neutrophils

Topics: Child; Child, Preschool; Female; Humans; Male; Melphalan; Neoplasm Metastasis; Neuroblastoma

Topics: Aorta; Aorta, Abdominal; Bone Neoplasms; Carotid Arteries; Chemotherapy, Cancer, Regional Perfusion; Chondrosarcoma; Dactinomycin; Dogs; Fibrosarcoma; Iliac Artery; Iliac Vein; Leiomyosarcoma; Liposarcoma; Lymphoma, Non-Hodgkin; Melphalan; Mesothelioma; Neoplasms; Neuroblastoma; Osteosarcoma; Rhabdomyosarcoma; Sarcoma; Sarcoma, Kaposi; Subclavian Artery; Vena Cava, Inferior