Ifosfamide/carboplatin/etoposide (ICE) as front-line, topotecan/ cyclophosphamide as second-line and oral temozolomide as third-line treatment for advanced neuroblastoma over one year of age

Children affected by advanced neuroblastoma have a discouraging prognosis, but intensive induction chemotherapy may increase the complete response rate. The combination of ifosfamide, carboplatin and etoposide (ICE) was used for the first time as front-line regimen in patients with stage 4 neuroblastoma over the age of 1 y. Similarly, second-line treatment for children with relapsed neuroblastoma, particularly after high-dose chemotherapy, has been unsatisfactory. The combination of topotecan and cyclophosphamide was studied in resistant or relapsed solid tumors. Furthermore, there is a need for effective palliative treatment in patients failing therapy. Temozolomide, a new dacarbazine analog with optimal oral bioavailability, is being used in an ongoing phase II study as an alternative to oral etoposide. Seventeen patients with stage 4 neuroblastoma have entered the ICE study; 15/16 (94%) major responses after induction were observed and 6/16 (37%) evaluable patients are disease free after a median of 51 mo. Twenty-one patients with relapsed/refractory disease (of whom 13 neuroblastomas) entered the topotecan/cyclophosphamide study: 7/21 (33%) patients responded. Forty-one patients entered the temozolomide study (of whom 16 had neuroblastomas): stable disease and symptom relief were obtained in 15/30 (50%) evaluable patients. Intensive induction with ICE resulted in a faster response with high response rate; a larger study with longer follow-up is needed to confirm a survival advantage. Second-line treatment was effective in obtaining remissions, some of them long lasting. Third-line treatment did not elicit measurable responses in neuroblastoma, but achieved prolonged freedom from disease progression and excellent palliation in several patients.     

Topotecan and etoposide in the treatment of relapsed high-risk neuroblastoma: results of a phase 2 trial

We initiated a phase 2 trial with a combination of topotecan and etoposide (TE) in patients with relapse after intensive first line chemotherapy for neuroblastoma. TE chemotherapy consisted of topotecan (schedule A: 1.0 mg/m2/d 30-minute-infusion days 1 to 5, B: 0.7 mg/m2/d continuous infusion days 1 to 7, and C: 1.0 mg/m2/d continuous infusion days 1 to 7) followed by etoposide (100 mg/m2/d 1-hour-infusion days 8 to 10). TE was repeated every 28 days. The treatment was continued until severe nonhematopoietic toxicity or progression occurred or the treating physician chose alternative consolidation treatment after response to TE. Forty patients received 153 TE cycles. Grades 3 to 4 leukopenia was frequently observed in all schedules (A 51% of cycles, B 48%, and C 74%, P=0.141). Thrombocytopenia (A 69%, B 63%, and C 93%, P=0.004) and neutropenic fever (A 12%, B 29%, and C 37%, P=0.048) occurred more frequently in schedule C. No treatment-related fatal toxicity was observed. Among 36 patients evaluable for response, 4 patients achieved complete and 13 patients achieved partial remission (47%). We conclude that the combination of TE is effective and tolerable in the treatment of relapsed high-risk neuroblastoma.     

Oral topotecan for refractory and relapsed neuroblastoma: a retrospective analysis

PURPOSE: Among patients with multiply relapsed neuroblastoma refractory to conventional chemotherapy, oral topotecan has often been used for palliation. Although toxicity was generally thought to be mild, the efficacy of such an approach remains unproven. METHODS: The authors retrospectively analyzed patients with multiply relapsed or refractory neuroblastoma who were treated with oral topotecan for palliation. Each course was generally 1 mg/m2/d in two divided doses, for 21 consecutive days, repeated after a 1-week rest in patients without symptoms of progressive disease. Disease status was assessed by radiographic studies, urine catecholamine levels, and multiple bone marrow aspirations and biopsies. RESULTS: Twenty patients between the ages of 3 and 34 (median 13 years) received 1 (n = 7), 2 (n = 3), 3 (n = 4), 4 (n = 2), 6 (n = 2), and 12 courses (n = 2). Prior treatments included multiple cycles of high-dose alkylator-based chemotherapy (n = 20), high-dose intravenous topotecan (n = 8), myeloablative chemotherapy or radioimmunotherapy (n = 10), or experimental biologic agents (n = 16). Anti-neuroblastoma effects were seen in five patients lasting 6 to 12 months; two additional patients remained stable for 4 months. Thirteen patients had progressive disease (11 after one or two cycles). Toxicity included diarrhea (n = 12) requiring a dose adjustment in three patients and discontinuation of the drug in a fourth, and myelosuppression (n = 11) requiring transfusion and/or granulocyte-colony stimulating factor support.CONCLUSIONS: Oral topotecan therapy has antitumor activity in a small percentage of patients with relapsed or refractory neuroblastoma. Toxicities, including diarrhea and myelosuppression, may necessitate a dose adjustment in this patient population. Low-dose oral topotecan may have utility in the treatment of neuroblastoma.     

Phase II trial of etoposide and cisplatin in patients with refractory and relapsed non-Hodgkin's lymphoma: Cancer and leukemia group B study 8351

A phase-II study was conducted by the Cancer and Leukemia Group B (CALGB) in patients with refractory and relapsed non-Hodgkin's lymphoma (NHL) to assess the activity of the combination of etoposide and cisplatin. Sixty-five patients were entered on study, and 51 patients were evaluated for this report. The treatment regimen consisted of etoposide, 80 mg/m² IV daily times 5 and cisplatin 20 mg/m² IV daily times 5, repeated every 21 days. All patients had failed 1–3 prior chemotherapeutic regimens, had measurable disease, and had a performance status of 0–2. In the 51 evaluable patients, there were 4 complete responses (8%) and 12 partial responses (23%), for an overall response rate of 31% (95% Cl: 19%, 46%). In addition, 15 patients (29%) had some improvement in disease and 6 (12%) had stable disease. Failure-free survival for the 51 eligible patients was 40% at 3 months, 23% at 6 months, and 15% at 1 year. Significant toxicity was observed with this regimen. Severe neutropenia occurred in 20 patients (39%), severe anemia in 8 patients (16%), and severe thrombocytopenia in 18 patients (35%). One patient died of infection. Severe neurotoxicity (1) and hemorrhage (3) were also seen. The etoposide, cisplatin combination is active in NHL; however, in this dose and schedule their combined activity is only minimally better than published reports of etoposide alone. Further studies of related combinations are under evaluation by the CALGB. © 1993 Wiley-Liss, Inc.     

Phase II trial of etoposide and cis-diaminodichloro-platinum in patients with refractory and relapsed Hodgkin's disease: Cancer and Leukemia Group B (CALGB) Study 8353

A phase II study was conducted by the Cancer and Leukemia Group B (CALGB) in patients with refractory and relapsed Hodgkin's disease (HD) to assess the activity of the combination of etoposide and cis-platin. Twenty-seven patients were entered; 22 were evaluated for this report. Treatment consisted of etoposide (VP-16), 80 mg/m2 IV over 1 hour and cis-platin, 20 mg/m2 IV over 1/2-1 hour; both agents were given daily for 5 days and repeated every 21 days. All patients had received at least 2 prior chemotherapy regimens, had measurable disease, and most (86%) had a performance status of 0-1. In the 22 evaluable patients, there were 4 complete responses (18%) and 4 partial responses, for an overall response rate of 36% (95% Cl: 17.2%, 59.3%). Response duration was from 2.1 to 31 months. Significant toxicity was observed with this regimen. Ten patients (45%) had leukopenia less than 1,000/microliters, and 11 patients (50%) had thrombocytopenia less than 25,000/microliters. Serum creatinine levels reached greater than 2.0 in 14% of patients. Seven patients (32%) had severe nausea and vomiting. VP-16, cis-platin appears to be an active combination in HD; however, their combined activity is only marginally better than reported single-agent activity for VP-16 in the doses and schedule used. Further studies of related combinations in HD are currently under evaluation by the CALGB.     

Feasibility study of IL-11 and granulocyte colony-stimulating factor after myelosuppressive chemotherapy to mobilize peripheral blood stem cells from heavily pretreated patients

PURPOSE: Pediatric patients with solid tumors treated with prolonged dose-intensive chemoradiotherapy are poor mobilizers of peripheral blood stem cells (PBSC). We have conducted a pilot study to mobilize PBSC in eight pediatric patients with relapsed solid tumors using ifosfamide, carboplatin, and etoposide (ICE) followed-up by IL-11 plus granulocyte colony-stimulating factor (G-CSF). PATIENTS AND METHODS: Patients received ifosfamide 1.8 g/m2 per day for 5 days, carboplatin 400 mg/m2 per day for 2 days, and etoposide 100 mg/m2 per day for 5 days. After completion of ICE chemotherapy, patients received daily subcutaneous injections of G-CSF (5 microg/kg per day) and IL-11 (50-100 microg/kg per day) until peripheral stem cell apheresis. RESULTS: The median age was 11 years. Diagnosis included three relapsed Hodgkin disease, three relapsed central nervous system tumors, one relapsed Wilms tumor, and one relapsed rhabdomyosarcoma. The median number of apheresis procedures required to obtain 5 x 10(6) CD34+ cells/kg was one. The mean +/- standard error of mean (SEM) total CD34+ cells collected was 14.0+/-2.7 x 10(6)/kg. The mean +/- SEM total CD34+/CD41+ cells collected was 4.6+/-1.9 x 10(6)/kg. Seven of the eight patients have subsequently undergone myeloablative chemotherapy with autologous PBSC transplantation and have reconstituted hematopoiesis with a median time to neutrophil recovery of 10 days and platelet recovery of 15.5 days. CONCLUSIONS: We conclude that the regimen of ICE/IL-11 plus G-CSF is successful in mobilizing large numbers of CD34+ PBSC cells with a limited number (one) of apheresis collections in patients that have previously been heavily pretreated with chemotherapy/radiotherapy.     

Similar chromosomal patterns and lack of N-myc gene amplification in localized and IV-S stage neuroblastomas in infants

Chromosome analysis was performed on 33 neuroblastomas in infants. Near triploid chromosome abnormalities (range, 60 to 77) were found in 29 patients with localized and IV-S stage neuroblastoma, and hyperdiploidy (range, 50 to 56) in 3 patients with localized neuroblastoma. No marker chromosome 1, homogeneously staining region (HSR), or double minutes (DMS) was observed in these patients, all of which have been previously reported in advanced neuroblastomas. N-myc gene amplification was not detected in any of these patients. All the patients were completely free of disease 4-45 months after diagnosis. Only one patient with stage IV neuroblastoma had a marker chromosome 1 (mode 46) and N-myc gene amplification and relapsed. Five patients with IV-S neuroblastoma lacking N-myc gene amplification had near triploid chromosomal abnormalities similar to those seen in localized neuroblastoma in infants. We consider that, cytogenetically, localized and IV-S neuroblastoma may be within the same disease category and different from advanced neuroblastoma.     

Treatment of Hodgkin's disease stages I and II with chemotherapy alone

Ten previously untreated patients with stages I and II Hodgkin's disease were treated with MOPP chemotherapy alone. Eight of nine evaluable patients went into complete remission (CR). Six remained in CR on the average 82.7 months after induction. Two patients relapsed early and died more than 5 years after entering the study. The patient in whom CR was not achieved died as well. The estimated 10-year survival rate is 51%. This experience adds to the very small number of reports that have appeared describing the results of treatment of patients with early stage Hodgkin's disease with MOPP alone.     

RT-PCR检测神经母细胞瘤患儿化疗后骨髓PGP9.5mRNA表达在预后判断中的意义

目的：该研究试图阐明诱导化疗后在转录水平清除骨髓肿瘤细胞能否取得好的疗效。方法：应用以PGP9.5为靶基因的逆转录聚合酶链式反应(RT-PCR)技术,其敏感性为106个细胞,测定32例发病时组织学存在骨髓转移的神经母细胞瘤患者,测定初诊及诱导治疗结束后骨髓肿瘤细胞水平。入选病例须在诱导治疗后用免疫组织化学法测定骨髓瘤细胞阴性。结果：32例患者诊断时骨髓PGP9.5mRNA均阳性,诱导结束后16例仍阳性,自体骨髓移植后随访3.4±0.9年11例复发,无病生存率31%;16例阴转,骨髓移植后随诊3.2±0.7年仅有5例复发,无病生存率69%,两组无病生存率有显著性差异(P=0.018)。结论：诱导治疗在转录水平清除骨髓神经母细胞瘤后行自体骨髓移植可以取得较好疗效。     

A phase 2 trial of all-trans-retinoic acid in combination with interferon-alpha2a in children with recurrent neuroblastoma or Wilms tumor: A Pediatric Oncology Branch, NCI and Children's Oncology Group Study

BACKGROUND: The combination of the antiproliferative and differentiation-inducing effects of retinoids together with the antiproliferative, immunostimulatory, and differentiation-potentiating effects of interferon-alpha (IFN-alpha) were the basis for the development of this combination in pediatric patients with refractory neuroblastoma or Wilms tumor. PROCEDURE: A phase 2 trial of all-trans-retinoic acid (ATRA), administered orally at a dose of 90 mg/m(2)/day in three divided doses for 3 consecutive days per week, and IFN-alpha2a, administered subcutaneously daily at a dose of 3 x 10(6) U/m(2)/day for 5 consecutive days per week, in 4 week cycles was performed. A two-stage design was used for each disease stratum. RESULTS: Seventeen patients (16 evaluable) with neuroblastoma, median age 9 years, and 15 patients (14 evaluable) with Wilms tumor, median age 6 years, were enrolled. Overall, the combination was well tolerated, with headache being the most common toxicity observed. There were no complete or partial responses. The median number of cycles administered was 1 (range 1-9). Four patients with neuroblastoma had stable disease for 12 or more weeks. CONCLUSIONS: The combination of ATRA and IFN-alpha2a was inactive in children with relapsed or refractory neuroblastoma and Wilms tumor. The lack of activity with this combination in children with refractory neuroblastoma is similar to the disappointing phase 2 results of single agent 13-cis-retinoic-acid (13cRA) and does not support further development of ATRA for children with relapsed neuroblastoma.     

Does consolidation with autologous stem cell transplantation improve the outcome of children with metastatic or relapsed Ewing sarcoma?

OBJECTIVE: To evaluate the role of high-dose chemotherapy (HDC) and autologous stem cell transplantation (ASCT) as consolidation therapy for children with high-risk Ewing sarcoma (ES) treated at The Hospital for Sick Children (SickKids), Toronto. PATIENTS AND METHODS: The charts of children treated for high-risk ES (defined as metastatic at diagnosis or relapsed) between 1990 and 2005 at SickKids were reviewed. Forty-five children were identified. Twenty patients received ASCT after induction with vincristine, doxorubicin, ifosfamide, cyclophosphamide, and etoposide. Patients with resectable tumor or lung metastases underwent surgery and those with non-resectable tumors were treated with irradiation. Twenty-five patients were treated with conventional chemotherapy (CC). Primary metastatic patients were treated with either a local protocol or as per POG 9354. At relapse, patients were treated with topotecan, cyclophosphamide, then ifosfamide, carboplatin, and etoposide (ICE). Local control was attained with surgery and/or irradiation. RESULTS: Ten of the 20 patients treated with ASCT are alive (median follow-up 6 years), with 8/10 being in remission more than 5 years from diagnosis. The 3-year overall survival (OS) for ASCT was 59%, (95% CI: 36%, 81%) compared to 34% (14%, 53%) for patients treated with CC (P-value = 0.06). The 3-year event-free survival (EFS) for the ASCT was 39% (17%, 60%) compared to 32% (13%, 50%) in the CC group (P = 0.08). CONCLUSION: ASCT appears to add some benefit to conventional multimodality therapy for children with high-risk ES. Randomized controlled trials are warranted.     

Haploidentical stem cell transplantation in patients with pediatric solid tumors: preliminary results of a pilot study and analysis of graft versus tumor effects

Pediatric patients with relapsed metastatic tumors have a poor prognosis and new treatment strategies are warranted. We present preliminary results of a pilot study, evaluating the feasibility and toxicity of transplantation of haploidentical T and B cell depleted grafts with high numbers of NK cells. 6 patients with relapsed metastatic neuroblastomas (n = 4), rhabdomyosarcoma (n = 1) or Ewing's sarcoma (n = 1) after previous autologous transplantation received CD3/CD19 depleted grafts from mismatched family donors with a median number of 16 x 10 (6)/kg stem cells, 167 x 10 (6)/kg Natural Killer cells and only 5.4 x 10 (4)/kg residual T cells. A melphalan-based, reduced intensity conditioning was used. Despite pretransplant chemotherapy, patients entered transplantation with significant tumor burden. Primary engraftment occurred in 6/6 patients. One patient had secondary graft failure. Hematopoietic recovery was rapid (ANC > 0.5 x 10 (9)/L: 11 days (9-12); independence from platelet substitution: 8 days (7-11)). Four patients had acute GvHD grade II, limited chronic GvHD was observed in 2 patients. No transplant-related mortality and only low toxicity occurred. Four patients died from progression, two patients are alive. Overall median survival time is 6 months (2-11) to date. Analysis of posttransplant NK cell function revealed stable cytotoxic activity against K562 targets, whereas activity against neuroblastoma targets was low. Stimulation with cytokines and use of appropriate antibodies clearly enhanced specific lysis in vitro. In summary, these preliminary results indicate the feasibility and low toxicity even in intensively pre-treated patients with neuroblastomas/sarcomas. This approach may form the basis for posttransplant immunomodulation and other therapeutic strategies. Further experience is warranted to evaluate the method.     

Second-line treatment of pediatric patients with relapsed rhabdomyosarcoma adapted to initial risk stratification: Data of the European Soft Tissue Sarcoma Registry (SoTiSaR)

Background

Outcome of relapsed disease of localized rhabdomyosarcoma remains poor. An individual treatment approach considering the initial systemic treatment and risk group was included in the Cooperative Weichteilsarkom Studiengruppe (CWS) Guidance.

Methods

Second-line chemotherapy (sCHT) ACCTTIVE based on anthracyclines (adriamycin, carboplatin, cyclophosphamide, topotecan, vincristine, etoposide) was recommended for patients with initial low- (LR), standard- (SR), and high-risk (HR) group after initial treatment without anthracyclines. TECC (topotecan, etoposide, carboplatin, cyclophosphamide) was recommended after initial anthracycline-based regimen in the very high-risk (VHR) group. Data of patients with relapse (n = 68) registered in the European Soft Tissue Sarcoma Registry SoTiSaR (2009–2018) were retrospectively analyzed.

Results

Patients of initial LR (n = 2), SR (n = 16), HR (n = 41), and VHR (n = 9) group relapsed. sCHT consisted of ACCTTIVE (n = 36), TECC (n = 12), or other (n = 15). Resection was performed in 40/68 (59%) patients and/or radiotherapy in 47/68 (69%). Initial risk stratification, pattern/time to relapse, and achievement of second complete remission were significant prognostic factors. Microscopically incomplete resection with additional radiotherapy was not inferior to microscopically complete resection (p = .17). The 5-year event-free survival (EFS) and overall survival (OS) were 26% (±12%) and 31% (±14%). The 5-year OS of patients with relapse of SR, HR, and VHR groups was 80% (±21%), 20% (±16%), and 13% (±23%, p = .008), respectively.

Conclusion

Adapted systemic treatment of relapsed disease considering the initial risk group and initial treatment is reasonable. New treatment options are needed for patients of initial HR and VHR groups.     

A phase 1 study of nifurtimox in patients with relapsed/refractory neuroblastoma

The primary aim of this phase 1 study was to determine the maximum tolerated dose (MTD) and evaluate the safety of nifurtimox alone and in combination with cyclophosphamide and topotecan in multiple relapsed/refractory neuroblastoma pediatric patients. The secondary aim was to evaluate the pharmacokinetics of nifurtimox and the treatment response. To these ends, we performed a phase 1 dose escalation trial of daily oral nifurtimox with toxicity monitoring to determine the MTD, followed by 3 cycles of nifurtimox in combination with cyclophosphamide and topotecan. Samples were collected to determine the pharmacokinetic parameters maximum concentration, time at which maximum concentration is reached, and area under the curve between 0 and 8 hours. Treatment response was evaluated by radiographic and radionuclide (I-metaiodobenzylguanidine) imaging, measurement of urinary catecholamines, and clearance of bone marrow disease. We determined the MTD of nifurtimox to be 30 mg/kg/d. The non-dose-limiting toxicities were mainly nausea and neuropathy. The dose-limiting toxicities of 2 patients at 40 mg/kg/d were a grade 3 pulmonary hemorrhage and a grade 3 neuropathy (reversible). Overall, nifurtimox was well tolerated by pediatric patients at a dose of 30 mg/kg/d, and tumor responses were seen both as a single agent and in combination with chemotherapy. A Phase 2 study to determine the antitumor efficacy of nifurtimox is currently underway.     

替莫唑胺联合托泊替康治疗儿童难治性/复发神经母细胞瘤6例临床分析

目的观察替莫唑胺(TMZ)联合托泊替康(TOPO)即TOTEM方案治疗儿童难治性/复发神经母细胞瘤(NB)的疗效。方法 6例难治性/复发NB患儿,分别给予替莫唑胺150 mg/(m~2·d),d1-5,口服;托泊替康0.75 mg/(m~2·d),d1-5,静脉点滴,每3周为一个化疗周期,每个患儿共接受8~10个周期的化疗。治疗中监测血常规、肝功、肾功、心脏功能等;每2个化疗周期行CT或MRI等影像学检查,同时结合骨髓受累病例中微小残留检测结果,进行疗效估。结果 6例NB患儿接受共53个周期TOTEM方案化疗,3例患儿临床达到完全缓解,2例患儿为部分缓解,1例患儿因疾病进展,放弃治疗,本组病人平均随诊时间为15个月,随访1年时4例存活。化疗期间不良反应主要表现为:5例出现Ⅲ°~Ⅳ°骨髓抑制,3例出现Ⅱ°~Ⅲ°恶心、呕吐、厌食,但整个治疗中无化疗相关性死亡病例发生。结论难治性/复发NB患儿对TOTEM方案表现较理想的治疗反应和顺应性,但远期疗效尚待进一步观察,可作为目前治疗儿童难治性/复发NB的选择之一。     

Long-term survival following a phase I/II trial with VETOPEC for solid tumors in childhood

The objective of this study was to evaluate long-term survival after treatment during a phase I/II trial with a specific regimen of vincristine, etoposide, and escalating cyclophosphamide (VETOPEC). Fifty-six children with poor-prognosis solid tumors were enrolled on study between May 1991 and May 1994. All had tumors that had relapsed on, or were refractory to, conventional treatment, or for whom existing treatment options were considered ineffective. The records of all surviving patients were reviewed to ascertain their disease and health status. Of the 56 patients, 10 patients (18%) remain alive with no further disease progression at a median follow-up of 11 years (range 7-13 years). Eight patients (14%) remain completely free of disease. None of the patients show long-term side effects directly attributable to the VETOPEC regimen, apart from one patient with ovarian failure. The VETOPEC regimen can offer not only good tumor responses but also the chance of cure for a surprisingly large number of children with very-poor-prognosis solid tumors. This regimen warrants continuing development and consideration for use in future trials.     

Long‐term survivor of relapsed stage IV malignant rhabdoid tumor of the kidney

The prognosis for metastatic malignant rhabdoid tumor (MRT) is poor, and metastatic (stage IV) MRT was resistant to conventional treatment, with less than 20% of cure rate. Moreover, there have been no reports of patients who have survived relapsed stage IV MRT. Here we report a long‐term survivor of relapsed MRT with lung metastasis at diagnosis. He was diagnosed as MRT of the kidney at 5‐month‐old. After resection of the renal tumor, he was treated with ICE (ifosfamide, carboplatin, and etoposide), total abdominal irradiation 10.8Gy and high‐dose chemotherapy using thiotepa and melphalan. Six months after initial treatment, a relapse in the lung was detected, and he received chemotherapy including doxorubicin/pirarubicin for 78 weeks. He is alive at five years of follow up, without any evidence of disease. Our report suggests the important role of anthracycline in treatment of MRT.     

Feasibility and effectiveness of treatment strategy of tandem high‐dose chemotherapy and autologous stem cell transplantation in combination with 131I‐MIBG therapy for high‐risk neuroblastoma

This study was performed to evaluate the safety and effectiveness of tandem HDCT/ASCT combined with targeted radiotherapy using ¹³¹I‐MIBG for high‐risk neuroblastoma. Patients with high‐risk neuroblastoma were treated with 8 to 10 cycles of induction chemotherapy before tandem HDCT/ASCT. Patients received ¹³¹I‐MIBG treatment before the second HDCT/ASCT. Local radiotherapy and maintenance therapy were performed after tandem HDCT/ASCT. Between 2012 and 2016, 19 patients were diagnosed with high‐risk neuroblastoma in our institution and 18 of them received tandem HDCT/ASCT combined with ¹³¹I‐MIBG therapy. For the first HDCT/ASCT regimen, 12 patients received busulfan/melphalan and six patients received melphalan/etoposide/carboplatin. The second HDCT included ThioCy. The median dose of ¹³¹I‐MIBG was 17.2 mCi/kg for the first eight patients, while 12 patients in the latter period of the study received reduced dose of 10.7 mCi/kg. The 5‐year OS and EFS rates were 79% and 61%, respectively, for all 19 patients with high‐risk neuroblastoma, and 83% and 64%, respectively, for 18 patients who completed tandem HDCT/ASCT combined with ¹³¹I‐MIBG therapy. Six patients experienced disease relapse and five patients died. Treatment‐related mortality was not observed. Among 15 evaluable patients, 11 patients (73%) developed hypothyroidism, six patients (40%) had CKD, and six patients (40%) had growth failure. Hypothyroidism and growth failure were less frequent in patients who received reduced doses of ¹³¹I‐MIBG therapy. Tandem HDCT/ASCT combined with HD ¹³¹I‐MIBG therapy could be feasible for patients with high‐risk neuroblastoma with acceptable toxicity profiles and favorable outcomes.     

Hematopoietic stem cell transplantation (HSCT) with a conditioning regimen of busulfan, cyclophosphamide, and etoposide for children with acute myelogenous leukemia (AML): a phase I study of the Pediatric Blood and Marrow Transplant Consortium

BACKGROUND: Hematopoietic stem cell transplantation (HSCT) is an important treatment modality for children with AML. The optimal conditioning regimen is unknown. The aim of this study was to determine the appropriate dosing of etoposide in combination with busulfan and cyclophosphamide in this setting. PROCEDURE: Twenty patients with a diagnosis of AML in first or second remission, or myelodysplasia scheduled for bone marrow transplantation, were included in this study. Patients received busulfan 640 mg/m(2) in 16 doses, cyclophosphamide 120 to 150 mg/kg in two doses, and etoposide from 40-60 mg/kg as a single dose. Extensive toxicity data was collected. RESULTS: Nineteen patients were evaluable for toxicity. Mucositis was seen in all patients. Four patients developed bacteremia and one patient died from overwhelming sepsis on day +3. Four patients developed moderate to severe skin toxicity. The major dose-limiting +3 toxicity was hepatic toxicity, which occurred in 14 of 19 patients. Eight patients developed clinical veno-occlusive disease, including three patients at dose level 4, two of whom had life-threatening disease. This hepatic toxicity defined the MTD of 640 mg/m(2) busulfan, 120 mg/kg of cyclophosphamide, and 60 mg/kg of etoposide. Overall, 9 of 20 patients enrolled in the study survive in remission, 8/14 allogeneic (median follow-up 44 months), and one of six autologous patients (follow-up, 54 months). CONCLUSIONS: We conclude that the combination of busulfan, cyclophosphamide, and etoposide at the doses defined above has activity in the treatment of children with high-risk AML/MDS undergoing allogeneic HSCT. Whether it offers an advantage over other conditioning regimens will require a randomized trial with a larger cohort of patients.     

Langerhans cell histiocytosis in childhood: Results from the Italian cooperative AIEOP-CNR-H.X '83 study

Ninety patients with biopsy-proven Langerhans cell histiocytosis (LCH) were enrolled from June, 1983, to December, 1988, in the multicenter AIEOP-CNR-H.X. '83 study. They were divided into two groups: poor prognosis (PP), comprising 11 children with organ dysfunction (OD), and good prognosis (GP), made up of 79 patients without OD. Eighty-four patients were evaluable for treatment results. Among GP patients, 16 with a single lesion received only local treatment, while 59 entered a clinical trial of immunotherapy and/or monochemotherapy with vinblastine (VBL). Nonresponders, sequentially received doxorubicin (ADM) and then etoposide (VP16). PP patients were treated with 4 week cycles of vincristine, ADM, cyclophosphamide, and prednisone for nine courses. The overall survival was 92.8% (100% for GP patients and 45.5% for PP patients) at 48 months. The complete response (CR) rates for immunotherapy, VBL, ADM, and VP16 were 10%, 62.9%, 42.8%, and 88.2%, respectively. Two of the 11 PP patients had a CR (18.2%), while six died and three are still alive with recurrent disease. The overall incidence of disease-related disabilities was 47.7%, while that of diabetes insipidus was 20%. Monochemotherapy is probably adequate in GP patients, while more effective treatments are needed for PP patients. © 1993 Wiley-Liss, Inc.