High-dose carmustine, thiotepa and etoposide followed by autologous bone marrow rescue for the treatment of high risk central nervous system tumors

Abstract

Summary:Forty-two patients (29 newly diagnosed) with high grade gliomas (n = 37), medulloblastoma (n = 2) or nonbiopsied tumors (n = 3) with supratentorial (n = 24), brain stem (n = 11), posterior fossa (n = 5) or spinal (n = 2) location were eligible for this study with adequate organ function and no bone marrow tumor infiltration. Median patient age was 12.2 years (range, 0.7-46.8). A total of 600 mg/m 2 BCNU, 900 mg/m 2 thiotepa and 1500 or 750 mg/m 2 etoposide (VP-16) was administered followed by autologous bone marrow reinfusion (ABMR). Twenty-one newly diagnosed patients received local irradiation (RT) post ABMR. Nine early deaths were observed (21%), as well as one secondary graft failure. Half of the patients aged 18 years or older experienced toxic deaths, whereas only 15% of patients younger than 18 years experienced toxic death (P = 0.05). Of 25 evaluable newly diagnosed patients, 20% achieved complete remission (CR) and 4% partial remission (PR), while 28% remained in continuing complete remission (CCR) and 44% remained with stable disease prior to RT. Of eight evaluable patients with recurrent disease, one achieved CR and two PR, while one remained in CCR and four with stable disease for 1 to 110.2 months. Overall survival was 36%, 24% and 17% at 1, 2 and 3 years following ABMR, with three newly diagnosed patients and one patient treated for recurrent disease being alive, without disease progression 64.4, 67.0, 86.3 and 110.2 months after ABMR, respectively. The combination of high-dose BCNU/ thiotepa/VP-16 has substantial toxicity but definite activity for high risk CNS tumors. Similar protocols with lower toxicity merit further evaluation in both

Phase I study of temozolomide in combination with thiotepa and carboplatin with autologous hematopoietic cell rescue in patients with malignant brain tumors with minimal residual disease

“…24 Previously successful myeloablative regimes often involved combinations of thiotepa, etoposide, carboplatin, carmustine and topotecan. 4,5,15,20,23,25 Thiotepa is an important component of high-dose chemotherapy owing to its steep dose-response and evidence that thiotepa is non-cross resistant with other alkylating agents such as cyclophosphamide and melphelan. 26,27 In the past, combinations of a number of these agents have resulted in high levels of toxicity including mucositis, microvascular damage and acute neurological dysfunction.…”

Transplante de medula óssea e transplante de sangue de cordão umbilical em pediatria

“…Tal qual com o transplante alogênico, as discussões a respeito das indicações são constantes. Atualmente há evidências de que o TMO autogênico seja eficaz no tratamento das seguintes doenças: -Linfoma de Hodgkin em 2 a remissão 39 ; -Linfoma não Hodgkin em 2 a remissão 40 ; -Neuroblastoma avançado (IV), sendo que nesta doença o transplante associado ao uso de ácido retinóico teve um impacto positivo no prognóstico 41 ; -Sarcoma de Ewing em segunda remissão, onde tenha havido uma ressecção completa do tumor 42 ; -LMA; mesmo sendo uma doença onde a medula óssea é comprometida, a realização de um transplante autogê-nico após a remissão teve um impacto positivo em alguns estudos 33 ; -Tumor de Wilms em 2 a remissão 43 ; -Tumor de células germinativas em 2 a remissão 44 ; -Meduloblastoma de alto risco ou em 2 a remissão 45 .…”

“…Todos os pacientes que receberam células progenitoras hematopoéticas alogênicas provenientes da medula óssea, do sangue periférico ou do sangue de cordão umbilical estão sujeitos a desenvolver a doença enxerto contra o hospedeiro (DECH) 22,32,[34][35][36][37][38][39][40][41][42][43][44][45][46][47] .…”

High-Dose Chemotherapy in Childhood Brain Tumors

“…There was some success in medulloblastoma [37][38][39], but not in malignant glioma or diffuse intrinsic pontine gliomas [37]. Thiotepa (500-800 mg/m 2 ) was combined with BCNU (carmustine, 450-600 mg/m 2 ) and etoposide (750-1,500 mg/m 2 ) in numerous phase I [41] and phase II studies [25,26,39,[41][42][43]. Unquestionable tumor efficacy was seen [25,29,41] but a high early death rate (20% [43]) and the long-term pulmonary toxicity lead to discontinuation of this regimen in most transplant centers [42].…”