Highly effective induction therapy for stage 4 neuroblastoma in children over 1 year of age.

1994 ◽  
Vol 12 (12) ◽  
pp. 2607-2613 ◽  
Author(s):  
B H Kushner ◽  
M P LaQuaglia ◽  
M A Bonilla ◽  
K Lindsley ◽  
N Rosenfield ◽  
...  
Keyword(s):  
Primary Tumor ◽  
Residual Disease ◽  
Poor Response ◽  
High Dose Chemotherapy ◽  
Unknown Primary ◽  
High Dose ◽  
Intravenous Infusions ◽  
Stage 4 ◽  
Biologic Response ◽  
Iodine 131

PURPOSE To test the efficacy of a protocol for poor-risk neuroblastoma that builds on the following: (1) our favorable previously reported results with dose-intensive use of cyclophosphamide; (2) our retrospective analysis of neuroblastoma chemotherapy reports, which supported the value of high-dose cisplatin and etoposide (VP-16); and (3) the Goldie-Coldman hypothesis that rapid cytoreduction plus the use of non-cross-resistant chemotherapy combinations will decrease the risk of drug resistance. PATIENTS AND METHODS The N6 protocol included seven courses of high-dose chemotherapy plus surgical resection of bulk disease. Courses 1, 2, 4, and 6 consisted of 6-hour intravenous infusions of cyclophosphamide 70 mg/kg/d on days 1 and 2 (ie, 140 mg/kg per course), a 72-hour intravenous infusion of doxorubicin 75 mg/m2 and vincristine 0.1 mg/kg beginning day 1, and vincristine 1.5 mg/m2 intravenous bolus on day 9. Courses 3, 5, and 7 consisted of 2-hour intravenous infusions of VP-16 200 mg/m2/d on days 1 to 3 (ie, 600 mg/m2 per course), and 1-hour intravenous infusions of cisplatin 50 mg/m2/d on days 1 to 4 (ie, 200 mg/m2 per course). Courses were to start after neutrophil counts reached 500/microL and platelet counts reached 100,000/microL. Response was defined by international criteria. RESULTS Among 24 consecutive previously untreated patients diagnosed with stage 4 neuroblastoma at more than 1 year of age, 21 patients achieved a complete or very good partial remission; one patient had no evidence of disease except by iodine-131-metaiodobenzylguanidine (MIBG) scan, which was markedly improved; and one patient had resolution of extensive metastatic disease, but still had an incompletely resected primary tumor. The sole patient to have a poor response had clinical features at diagnosis that are atypical for neuroblastoma, namely, 8 years of age and an unknown primary tumor. Severe toxicities included myelosuppression, mucositis, and hearing deficits. CONCLUSION The N6 approach reliably achieves significant cytoreduction against stage 4 neuroblastoma. This may eventuate in an improved cure rate, since consolidative treatments using myeloablative therapy, immunotherapy, or biologic response modifiers such as cis-retinoic acid are most likely to be effective against minimal residual disease.

Oral Etoposide for Refractory and Relapsed Neuroblastoma

1999 ◽  
Vol 17 (10) ◽  
pp. 3221-3225 ◽  
Author(s):  
Brian H. Kushner ◽  
Kim Kramer ◽  
Nai-Kong V. Cheung
Keyword(s):  
Residual Disease ◽  
Alkylating Agents ◽  
High Dose Chemotherapy ◽  
Treatment Programs ◽  
Induction Treatment ◽  
High Dose ◽  
Oral Etoposide ◽  
Disease Markers ◽  
Stage 4 ◽  
Dose Oral

PURPOSE: To describe the efficacy of oral etoposide against resistant stage 4 neuroblastoma. PATIENTS AND METHODS: Patients with refractory or recurrent stage 4 neuroblastoma were treated with etoposide 50 mg/m2 taken orally each day, in two or three divided doses, for 21 consecutive days. Treatment could be repeated after a 1-week period. Extent-of-disease studies included imaging with 131-iodine-metaiodobenzylguanidine and extensive bone marrow (BM) sampling. RESULTS: Oral etoposide was used in 20 children between the ages of 2 and 11 years (median, 6 years). Prior treatment included high doses of alkylating agents and a median of 4.5 cycles of etoposide-containing chemotherapy, with cumulative etoposide doses of 1,800 mg/m2 to 3,935 mg/m2 (median, 2,300 mg/m2). Oral etoposide produced antineuroblastoma effects in four of four children with disease refractory to intensive induction treatment; sampling variability could account for resolution (n = 3) or reduction (n = 1) of BM involvement, but improvement in other markers also occurred. Antineuroblastoma effects were also evident in five of five children with asymptomatic relapses after a long chemotherapy-free interval: BM disease resolved and all other disease markers significantly improved in two patients, and disease markers improved or stabilized in three patients on treatment for more than 6 months. In these nine patients, extramedullary toxicity was absent, neutropenia did not occur, transfusional support was not needed, and preliminary data suggested little immunosuppression (phytohemagglutinin responses). Oral etoposide was ineffective in all (11 of 11) patients with rapidly growing tumor masses. CONCLUSION: Given the absence of toxicity to major organs, the minimal myelosuppression or immunosuppression, and the antineoplastic activity in patients with low tumor burdens after high-dose chemotherapy, limited use of low-dose oral etoposide should be considered for inclusion in postinduction consolidative treatment programs aimed at eradicating minimal residual disease.

scholarly journals Influence of Surgical Excision on the Survival of Patients With Stage 4 High-Risk Neuroblastoma: A Report From the HR-NBL1/SIOPEN Study

2020 ◽  
Vol 38 (25) ◽  
pp. 2902-2915 ◽  
Author(s):  
Keith Holmes ◽  
Ulrike Pötschger ◽  
Andrew D. J. Pearson ◽  
Sabine Sarnacki ◽  
Giovanni Cecchetto ◽  
...  
Keyword(s):  
High Risk ◽  
Primary Tumor ◽  
Tumor Resection ◽  
Observation Time ◽  
Mycn Amplification ◽  
High Dose ◽  
Local Progression ◽  
Stage 4 ◽  
Operative Complications ◽  
The Impact

PURPOSE To evaluate the impact of surgeon-assessed extent of primary tumor resection on local progression and survival in patients in the International Society of Pediatric Oncology Europe Neuroblastoma Group High-Risk Neuroblastoma 1 trial. PATIENTS AND METHODS Patients recruited between 2002 and 2015 with stage 4 disease > 1 year or stage 4/4S with MYCN amplification < 1 year who had completed induction without progression, achieved response criteria for high-dose therapy (HDT), and had no resection before induction were included. Data were collected on the extent of primary tumor excision, severe operative complications, and outcome. RESULTS A total of 1,531 patients were included (median observation time, 6.1 years). Surgeon-assessed extent of resection included complete macroscopic excision (CME) in 1,172 patients (77%) and incomplete macroscopic resection (IME) in 359 (23%). Surgical mortality was 7 (0.46%) of 1,531. Severe operative complications occurred in 142 patients (9.7%), and nephrectomy was performed in 124 (8.8%). Five-year event-free survival (EFS) ± SE (0.40 ± 0.01) and overall survival (OS; 0.45 ± 0.02) were significantly higher with CME compared with IME (5-year EFS, 0.33 ± 0.03; 5-year OS, 0.37 ± 0.03; P < .001 and P = .004). The cumulative incidence of local progression (CILP) was significantly lower after CME (0.17 ± 0.01) compared with IME (0.30 ± 0.02; P < .001). With immunotherapy, outcomes were still superior with CME versus IME (5-year EFS, 0.47 ± 0.02 v 0.39 ± 0.04; P = .038); CILP was 0.14 ± 0.01 after CME and 0.27 ± 0.03 after IME ( P < .002). A hazard ratio of 1.3 for EFS associated with IME compared with CME was observed before and after the introduction of immunotherapy ( P = .030 and P = .038). CONCLUSION In patients with stage 4 high-risk neuroblastoma who have responded to induction therapy, CME of the primary tumor is associated with improved survival and local control after HDT, local radiotherapy (21 Gy), and immunotherapy.

Prior Rituximab Reduces Relapse and Improves Survival Following High Dose Chemotherapy and Stem Cell Transplantation for Relapsed Composite Low and Intermediate Grade (Including Transformed) Lymphoma.

Blood ◽  
2006 ◽  
Vol 108 (11) ◽  
pp. 3662-3662
Author(s):  
Khaled M. Ramadan ◽  
Joseph M. Connors ◽  
Abdulwahab J. Al-Tourah ◽  
Randy D. Gascoyne ◽  
Kevin Song ◽  
...  
Keyword(s):  
Stem Cell ◽  
Stem Cell Transplantation ◽  
Cell Transplantation ◽  
Residual Disease ◽  
Chronic Gvhd ◽  
High Dose Chemotherapy ◽  
Clinicopathological Characteristics ◽  
High Dose ◽  
Intermediate Grade ◽  
Non Hodgkin Lymphoma

Abstract The effect of prior exposure to rituximab (ritux) on relapse (REL) and survival following stem cell transplantation (SCT) in patients (pts) with REL composite low and intermediate grade non-Hodgkin lymphoma (L/I-NHL) is unknown. Fifty-four pts with REL L/I-NHL underwent high-dose chemotherapy (CT) and SCT Jan ’89 to June ’05. Follow-up is complete to April ’6 with a median of 32 mo. Ritux was added to CT regimens since 2001 and given at 375 mg/m2. Eighteen pts received ritux at initial diagnosis of NHL or after REL with salvage CT prior to SCT. Pts proceeded to high dose CT with allogeneic (allo) (n=12) or autologous (auto) SCT (n=6). This group was compared with a group of pts not receiving ritux pre-SCT (n=36)(Table 1). Eleven pts (61%) are alive in the ritux group compared with 11 pts (31%) in the non-ritux group. The 2 and 4-y OS for pts who received ritux were 52% and 52%, vs 36% and 24% (p=.12, RR=.52) for pts who did not receive ritux. The EFS were significantly different with 2 and 4-y EFS for the ritux group 56% and 56% vs 24% and 18% (P=.038, RR=.42) for the non-ritux group (figure 1). No effect was seen on TRM. The risk of REL post SCT was significantly lower in the ritux group (p=.017)(figure 2). Two of 18 pts (11%) had NHL REL in the ritux vs 18 of 36 (50%) in the non-ritux group. The hazard rate of REL in pts who received ritux was 20% that of pts in the non-ritux group. Significance maintained in multivariate analysis (p=.016). No impact was seen on graft-versus-host disease (GVHD). Fifty percent and 61% of pts developed acute GVHD grades 2–4 and 50% and 64% of pts developed chronic GVHD in the ritux and non-ritux groups respectively. In conclusion, prior treatment with ritux in pts with relapsed composite L/I-NHL undergoing SCT was associated with reduced risk of REL and improved survival without associated increase in toxicity. Further analysis is underway to clarify the nature of this important finding. Table 1: Clinicopathological characteristics of ritux and non-ritux groups Parameter$ Rituximab group, n=18 (%) Non-rituximab group, n=36 (%) $ all p values are >0.1. *at diagnosis Median age at SCT 48 y 44 y M:F 2.6:1 1.6:1 Allo-SCT 12(67) 28(78) BM involvement* 10(56) 22(61) B symptoms* 7(39) 10(28) Prior purine analogue therapy 8(44) 11(31) Residual disease prior to SCT 9(50) 14(39) TBI in conditioning 13(72) 30(83) Figure Figure Figure Figure

Idiotype Vaccination in Human Myeloma: Generation of Tumor-Specific Immune Responses After High-Dose Chemotherapy

Blood ◽  
1999 ◽  
Vol 94 (2) ◽  
pp. 673-683 ◽  
Author(s):  
Massimo Massaia ◽  
Paolo Borrione ◽  
Silvano Battaglio ◽  
Sara Mariani ◽  
Eloise Beggiato ◽  
...  
Keyword(s):  
Immune Responses ◽  
Residual Disease ◽  
Interleukin 2 ◽  
Keyhole Limpet Hemocyanin ◽  
High Dose Chemotherapy ◽  
Outpatient Setting ◽  
Delayed Type Hypersensitivity ◽  
High Dose ◽  
Gm Csf ◽  
Macrophage Colony

Abstract Igs contain unique portions, collectively termed idiotypes (Id), that can be recognized by the immune system. Id expressed by tumor cells in B-cell malignancies can be regarded as tumor-specific antigens and a target for vaccine immunotherapy. We have started a vaccination trial in multiple myeloma (MM) using Id-specific proteins conjugated to keyhole limpet hemocyanin (KLH) as immunogens and low doses of subcutaneous granulocyte-macrophage colony-stimulating factor (GM-CSF) or interleukin-2 (IL-2) as immunoadjuvants. Twelve patients who had previously been treated with high-dose chemotherapy followed by peripheral blood progenitor cell (PBPC) transplantation entered this study from August 1995 to January 1998. All patients were in first remission at the time of vaccination. They received subcutaneous injections of Id vaccines and immunoadjuvants in an outpatient setting. The generation of Id-specific T-cell proliferative responses was documented in 2 patients, whereas a positive Id-specific delayed-type hypersensitivity (DTH) reaction was observed in 8 of the 10 patients studied. DTH specificity was confirmed in 1 patient by investigating the reactivity to synthetic peptides derived from the VDJ sequence of the tumor-specific Ig heavy chain. None of the patients generated soluble immune responses to Id, whereas the generation of soluble and cellular immune responses to KLH was observed in 100% and 80%, respectively. Eleven patients completed the treatment, whereas 1 patient failed to finish owing to progression of disease. Freedom from disease progression (FFDP), measured from the date of first Id/KLH injection to the date of first treatment after vaccination or last follow-up, ranged from 9 to 36 months. These data indicate that the immune competence status of MM patients is still susceptible to specific immunization after high-dose chemotherapy and PBPC transplantation. It remains to be determined whether generation of Id-specific immune responses can reduce the relapse rate of patients with minimal residual disease.

Prolonged CD4 depletion after sequential autologous peripheral blood progenitor cell infusions in children and young adults

Blood ◽  
2000 ◽  
Vol 96 (2) ◽  
pp. 754-762 ◽  
Author(s):  
Crystal L. Mackall ◽  
Dagmar Stein ◽  
Thomas A. Fleisher ◽  
Margaret R. Brown ◽  
Frances T. Hakim ◽  
...  
Keyword(s):  
T Cells ◽  
T Cell ◽  
Peripheral Blood ◽  
Immune Reconstitution ◽  
Residual Disease ◽  
High Dose Chemotherapy ◽  
High Dose ◽  
Cell Dose ◽  
Age Related ◽  
Large Numbers

Administration of mobilized peripheral blood progenitor cells (PBPCs) after high-dose chemotherapy rapidly restores multilineage hematopoiesis, but the ability of such products to restore lymphocyte populations remains unclear. In this report, we evaluated immune reconstitution in a series of patients treated with sequential cycles of high-dose chemotherapy, followed by autologous PBPC infusions (median CD34+ cell dose 7.2 × 106 cells/kg [range 2-29.3]). Although patients experienced rapid reconstitution of B cells and CD8+ T cells, we observed CD4 depletion and diminished immune responsiveness in all patients for several months after completion of therapy. Mature CD4+ T cells contained within the grafts did not appear to contribute substantially to immune reconstitution because CD4 counts did not differ between recipients of unmanipulated T-cell replete infusions versus CD34 selected, T-cell–depleted infusions. Rather, at 12 months after therapy, total CD4 count was inversely proportional to age (ρ = −0.78,P = .04), but showed no relationship to CD34 cell dose (ρ = −0.42, P = .26), suggesting that age-related changes within the host are largely responsible for the limited immune reconstitution observed. These results demonstrate that in the autologous setting, the infusion of large numbers of PBPCs is not sufficient to restore T-cell immune competence and emphasize that specific approaches to enhance immune reconstitution are necessary if immune-based therapy is to be used to eradicate minimal residual disease after autologous PBPC transplantation.

scholarly journals ATRT-30. RETROSPECTIVE ANALYSIS OF CHILDREN WITH ATYPICAL TERATOID RHABDOID TUMOR TREATED ACCORDING TO ACNS0333

2020 ◽  
Vol 22 (Supplement_3) ◽  
pp. iii281-iii282
Author(s):  
Lindsey Hoffman ◽  
Ashley Margol ◽  
Kelly Faulk ◽  
Sara Hutchins ◽  
Gregory Friedman ◽  
...  
Keyword(s):  
Residual Disease ◽  
Tumor Location ◽  
High Dose Chemotherapy ◽  
Rhabdoid Tumor ◽  
Published Data ◽  
High Dose ◽  
Primary Therapy ◽  
Central Nervous System Tumor ◽  
Atypical Teratoid Rhabdoid Tumor ◽  
Atypical Teratoid

Abstract Atypical teratoid rhabdoid tumor (ATRT) is a central nervous system tumor with poor outcome. ACNS0333, a Children’s Oncology Group phase 3 trial, enrolled 65 evaluable patients who received two cycles of induction chemotherapy, three cycles of consolidative high-dose chemotherapy (HDCT), and focal radiation therapy (RT) pre- or post-consolidation. Craniospinal irradiation (CSI) was left to clinician discretion. We retrospectively analyzed medical records of 27 children treated at our institutions according to ACNS0333. Median age at diagnosis was 14 months (range 4–165); 13 (48%) were male. M-stage was M0, M2, and M3 for 18 (66%), 5 (19%), and 4 (15%), respectively. Tumor location was supratentorial (n=14, 52%), infratentorial (n=12, 44%), or both (n=1, 4%). Complete resection was achieved for 17 (63%). All but one completed induction. Of 13 (51%) with residual disease at diagnosis, 5 (36%) and 7 (50%), respectively, exhibited complete and partial response to induction. Three patients progressed on therapy, and six progressed after completion of therapy at a median of 9.7 months. In all, 18 patients completed RT (16 focal/4 CSI and 6 pre-/12 post-consolidation). Three died of therapy-related toxicity (two in primary therapy and one in relapse therapy), and 8 died of disease. Sixteen patients (59%) are alive at a median follow up of 53 months (range 9–114). Of 17 with germline testing, eight (47%) had rhabdoid predisposition syndrome of whom three are alive. At the time of presentation, data for approximately 50 patients is expected, and we will compare outcomes to soon-to-be published data from ACNS0333.

scholarly journals High-Dose Chemotherapy Followed by Peripheral and/or Bone Marrow Stem Cell Transplant in Patients With Advanced Sarcoma: Experience of a Canadian Centre

Sarcoma ◽  
2004 ◽  
Vol 8 (2-3) ◽  
pp. 63-69 ◽  
Author(s):  
Sébastien J. Hotte ◽  
Anne M. Smith ◽  
Vivien H.C. Bramwell ◽  
Kang Howson-Jan
Keyword(s):  
Stem Cell ◽  
Ewing’S Sarcoma ◽  
Ewing's Sarcoma ◽  
Residual Disease ◽  
High Dose Chemotherapy ◽  
High Dose ◽  
Cell Transplant ◽  
Alive With Disease ◽  
Risk Patients ◽  
Time To Relapse

Purpose: Few reports have been published on the evaluation of stem cell auto transplantation for chemosensitive sarcomas. Some suggest benefit, others do not. We present results of 24 patients with sarcoma undergoing autotransplantation at a Canadian institution.Patients and Methods: Twenty-four patients were treated between 1988 and 1998: 23 were ≥18 years (median 27; range 12–56); genders were equal; 12 patients had Ewing's sarcoma. At diagnosis, 12 (50%) had metastatic disease. Prior to autotransplant, all had ≥1 chemotherapy regimen. Fourteen (58%) were in complete remission (CR) and seven (29%) had minimal residual disease. All received etoposide 60 mg/kg (Day –4), melphalan 140 mg/m2on (Day –3) and a stem cell reinfusion (Day 0).Results: Three patients (12.5%) were alive and disease-free with median follow-up of 92 months (80–142); one was alive with disease 32 months post-autotransplant. Twenty had died (disease, 17; transplant-related, 2; unknown, 1). Of the four alive, three had Ewing's sarcoma, one alveolar rhabdomyosarcoma, and all were in CR at transplant. Median time to relapse was 6 months (2–59). Sixteen of 18 (89%) relapsed within 1 year. Median overall survival was 10 months (0–137). A trend towards improved survival (P=0.07) was evident for patients in CR prior to autotransplant.Conclusions: Stem cell autotransplantation does not benefit most patients with sarcoma. A subgroup of high-risk patients in CR may fare better and warrant further study.

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