Treatment of children with poor risk solid tumors by further escalation of the VETOPEC regimen including very high-dose cyclophosphamide and peripheral stem cell support: an Australian and New Zealand Children's Hematology and Oncology Group study.

BACKGROUND: Children with solid tumors deemed to be poor risk at diagnosis and those who fail to respond or recur after chemotherapy have adverse outcomes. We sought to increase the dosage of cyclophosphamide (CPA) in the VETOPEC regimen (vincristine, etoposide, and CPA) with a view to improving the response rate and survival. PROCEDURE: Patients underwent peripheral blood stem cell (PBSC) harvest after standard dose VETOPEC (CPA 40 mg/kg/day for 3 days) followed by filgrastim. Those with sufficient PBSC received up to four intensive cycles (ICs) of VETOPEC with CPA dosages of 60-90 mg/kg/day for 3 days (escalated by 5 mg/kg/day in cohorts of at least five patients) followed by PBSC and filgrastim. RESULTS: Of the 59 enrolled patients, 58 were treated with mobilization chemotherapy and 57 proceeded to PBSC harvest. From 1 to 4 VETOPEC ICs were administered to 51 patients. The maximum tolerated dosage of CPA was not reached. The best response rate during the ICs for patients with recurrent or refractory/progressive disease was 67%; overall survival was 28% at 5 years and 25% at 10 years. The response rate for patients with newly diagnosed high-risk tumors was 89%. CONCLUSIONS: The VETOPEC regimen with CPA dosages up to 90 mg/kg/day for 3 days followed by PBSC and filgrastim can be given in a timely manner with manageable toxicity. Outcomes were not improved when compared to prior VETOPEC studies. VETOPEC produces high response rates and warrants further evaluation in appropriate patients with newly diagnosed high-risk solid tumors.

Efficacy of vincristine and etoposide with escalating cyclophosphamide in poor-prognosis pediatric brain tumors.

The objective of this study was to assess the efficacy of the VETOPEC regimen, a regimen of vincristine and etoposide with escalating doses of cyclophosphamide (CPA), in pediatric patients with high-risk brain tumors. Three consecutive studies by the Australia and New Zealand Children's Cancer Study Group--VETOPEC I, Baby Brain 91, and VETOPEC II--have used a specific chemotherapy regimen of vincristine (VCR), etoposide (VP-16) and escalating CPA in patients with relapsed, refractory, or high-risk solid tumors. Patients in the VETOPEC II cohort were treated with very high dose CPA with peripheral blood stem cell (PBSC) rescue. We analyzed the subset of patients with high-risk brain tumors treated with these intensive VETOPEC-based protocols to assess the response, toxicity, and survival. We also assessed whether the use of very high dose chemotherapy with stem cell rescue improved the response rate or affected toxicity. Seventy-one brain tumor patients were treated with VETOPEC-based protocols. Of the 54 patients evaluable for tumor response, 17 had a complete response (CR) and 20 a partial response (PR) to treatment, which yielded an overall response rate of 69%. The CR + PR was 83% (19/23) for medulloblastomas, 56% (5/9) for primitive neuroectodermal tumors, 55% (6/11) for grade 3 and 4 astrocytomas, and 80% (6/8) for ependymomas. At a median follow-up of 36 months, overall survival for the entire cohort of 71 patients was 32%, with event-free survival of 13%. There were no toxic deaths within the PBSC-supported VETOPEC II cohort, despite higher CPA doses, compared with 7% among the non-PBSC patients. This regimen produces high response rates in a variety of very poor prognosis pediatric brain tumors. The maximum tolerated dose of CPA was not reached. Higher escalation in doses of CPA did not deliver a further improvement in response. With PBSC rescue in the VETOPEC II study, hematologic toxicity was no longer a limiting factor. The response rates observed support further development of this chemotherapy regimen.

Pegfilgrastim to support CHOP-14 in elderly patients with non-Hodgkin's lymphoma.

This study investigated whether pegfilgrastim support would enable on-schedule delivery of dose-dense cyclophosphamide, doxorubicin, vincristine and prednisone (CHOP-14) to elderly patients with non-Hodgkin's lymphoma (NHL). Thirty patients 60 years of age and older with aggressive NHL were evaluated after receiving up to six cycles of CHOP-14 supported with pegfilgrastim. The median age was 68 years (range 61 - 74). Forty-seven per cent of patients received full dose chemotherapy on schedule for all cycles (range 65 - 93). Chemotherapy was delayed in 10 patients and dose reduced in 15 patients. Hematological toxicity was the most common reason for delays and dose reduction. Six of nine patients (67%) achieved a peripheral blood CD34+ count of at least 20 cellsx106 L-1 on day 12 of cycle one. The delivery on schedule of dose-dense CHOP-14 to elderly patients with previously untreated aggressive NHL is safe and efficacious with once per cycle pegfilgrastim support.

Improved haematopoietic recovery following transplantation with ex vivo-expanded mobilized blood cells.

Infusions of ex vivo-expanded (EXE) mobilized blood cells have been explored to enhance haematopoietic recovery following high dose chemotherapy (HDT). However, prior studies have not consistently demonstrated improvements in trilineage haematopoietic recovery. Three cohorts of three patients with breast cancer received three cycles of repetitive HDT supported by either unmanipulated (UM) and/or EXE cells. Efficacy was assessed by an internal comparison of each patient's consecutive HDT cycles, and to 106 historical UM infusions. Twenty-one cycles were supported by EXE cells and six by UM cells alone. Infusions of EXE cells resulted in fewer days with an absolute neutrophil count (ANC) <0.1 x 10(9)/l (median 2 vs. 4 d, P = 0.002) and 3 d faster ANC recovery to >0.1 x 10(9)/l (median 5 vs. 8 d, P = 0.0002). This resulted in a major reduction in the incidence of febrile neutropenia compared with UM cycles (0% vs. 83%; P = 0.008) and in 66% of historical UM cycles (P = 0.01) and a marked reduction in hospital re-admission. There were also fewer platelet transfusions required (43% vs. 100%; P = 0.009). We conclude that EXE cells enhance both neutrophil and platelet recovery and reduce febrile neutropenia, platelet transfusion and hospital re-admission.