Phase I study of high-dose thiotepa with busulfan, etoposide, and autologous stem cell support in children with disseminated solid tumors

Abstract

Background The aim of this phase I study was to define the maximum tolerated dose (MTD) of thiotepa (TT), administered with busulfan (BU) 480 mg/m2 and etoposide 2,400 mg/m2, followed by autologous bone marrow transplantation (ABMT) or peripheral blood stem cell transplantation (APBSCT) support in children with solid tumors either disseminated at diagnosis or after relapse. Procedure Nineteen patients, between 2 and 16 years of age, received a high‐dose chemotherapy regimen including escalating doses of TT starting from 150 mg/m2. Subsequent dose escalation was determined by a modified Fibonacci scheme. Whenever one patient at one dosage level showed a grade III or grade IV reversible toxicity, additional patients were admitted (one by one) up to a maximum number of 6. Upon observing grade III or IV reversible toxicity in two or more systems, in 3 of the 6 patients, no further escalation was performed, and the corresponding dosage was taken as the MTD. WHO criteria were adopted to assess grade of toxicity. Results All patients had hematological recovery; and neutrophils and platelet engraftment were observed after median times of 12 and 29 days from stem cell infusion, respectively. The MTD of TT was determined to be 750 mg/ m2. At this level, 3 of 6 patients experienced grade III mucositis and/or grade III gastrointestinal toxicity. No patient died of treatment‐related toxicity. Conclusions A dose of 750 mg/m2 TT is the MTD when it is associated with BU 480 mg/m2 and etoposide 2,400 mg/m2. This ablative regimen represents a feasible and tolerable combination for high‐dose chemotherapy followed by hematopoietic stem cell rescue (HSCR). Phase II studies in children with poor‐prognosis solid tumors are required to evaluate the effectiveness of this treatment. Med. Pediatr. Oncol. 33:450–454, 1999. © 1999 Wiley‐Liss, Inc.

HLA-Mismatched Hematopoietic Stem Cell Tranplantation for Pediatric Solid Tumors

“…The examples of NB 7 and ESFT 5,8 in this sense, are paradigmatic. Despite the development of new treatment options, the prognosis of high-risk neuroblastoma patients remains dismal; in more than half of patients the disease returns.…”

“…The median Follow-Up time has been 4 months. 3–7 The median time of take has been 10 days for polimorphonucleated cells 8–12 and 10 days for platelets respectively. 9–12 Complete donor chimerism has been obtained in all of the patients at day +30.…”

High-dose chemotherapy with autologous stem cell rescue in children with retinoblastoma

“…Neutrophil counts of 40.5/nl were reached on day 10 (median; range [8][9][10][11][12][13][14][15][16][17][18][19][20][21][22]. Rising unsupported platelet numbers of 450/nl were noted by day 22 (median; range 12-51).…”

“…Therefore, thiotepa has been considered for HDC. It has been studied at doses of 750-900 mg 2 as single drug in children with solid tumors, [18][19][20] in combination with other drugs as consolidation for solid tumors 21,22 and in children with myeloid malignancies. 23 Owing to its good penetration into the CNS, HDC studies in brain tumors have included thiotepa.…”