High-dose carboplatin, thiotepa, and etoposide with autologous stem cell rescue for patients with previously irradiated recurrent medulloblastoma

Abstract

Recurrent medulloblastoma is highly lethal in previously irradiated patients. Previously irradiated patients with M-0-M-3 recurrences who achieved a minimal disease state prior to protocol enrollment received carboplatin (Calvert formula with area under the curve = 7 mg/mL min, maximum 500 mg/m(2)/day) on days -8 to -6, and thiotepa (300 mg/m(2)/day) and etoposide (250 mg/m(2)/day) on days -5 to -3, followed by autologous stem cell rescue (ASCR) on day 0. Twenty-five patients, aged 7.6-44.7 years (median 13.8 years) at ASCR, were treated. Three (12%) died of treatment-related toxicities within 30 days of ASCR, due to multiorgan system failure (n = 2) and aspergillus infection with veno-occlusive disease (n = 1). Tumor recurred in 16 at a median of 8.5 months (range 2.3-58.5 months). Six are event-free survivors at a median of 151.2 months post-ASCR (range 127.2-201.6 months). The Kaplan-Meier estimate of median overall survival is 26.8 months (95% CI: 11.9-51.1 months) and of event-free survival (EFS) and overall survival are both 24% (95% CI: 9.8%-41.7%) at 10 years post-ASCR. M-0 (vs M-1 + ) recurrence prior to protocol, lack of tissue confirmation of relapse, and initial therapy of radiation therapy (RT) alone (vs RT + chemotherapy) were not significantly associated with better EFS (P = .33, .34, and .27, respectively). Trends toward better EFS were noted in patients (n = 5) who received additional RT as part of their retrieval therapy (P = .07) and whose recurrent disease was demonstrated to be sensitive to reinduction chemotherapy (P = .09). This retrieval strategy provides long-term EFS for some patients with previously irradiated recurrent medulloblastoma. The use of additional RT may be associated with better outcome.

Changes Mimicking New Leptomeningeal Disease After Intensity-Modulated Radiotherapy for Medulloblastoma

“…Recurrent medulloblastoma has a dismal prognosis (18)(19)(20)(21)(22)(23)(24). Therefore, the distinction between radiographic changes related to normal tissue damage by chemoradiotherapy and true disease progression affects the patient's subsequent treatment and prognosis.…”

Decreased morbidity and mortality of autologous hematopoietic transplants for children with malignant central nervous system tumors: the ‘Head Start’ trials, 1991–2009

“…Contemporaneously as well as subsequently, children with recurrent medulloblastoma, supratentorial primitive neuro-ectodermal tumor and high-grade gliomas were being treated with intensified chemotherapy including marrow-ablative chemotherapy and autologous hematopoietic cell rescue (AuHCR). [6][7][8][9][10] Furthermore, in young children relapsing after standard-dose chemotherapy regimens without irradiation, the French Society of Pediatric Oncology reported 50% EFS at a median of 31 months (n = 20) and with treatment-related mortality (TRM) at 5%. 11 Subsequently, with longer follow-up, the Memorial Sloan Kettering Cancer Center and the Children's Cancer Group (MSKCC/CCG-9883) reported in a similar cohort of young children 50% EFS at a median of 5 years and TRM at 10%.…”

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

“…The use of high-dose chemotherapy with AHCR in the treatment of recurrent malignant brain tumors has been investigated with promising responses observed in patients with recurrent medulloblastoma, PNET, highgrade glioma and primary CNS germ cell tumors. 4,5,18 It has also been employed in very young children 19,20,22,23 in an attempt to avoid the deleterious long-term consequences of radiotherapy. 24 Previously successful myeloablative regimes often involved combinations of thiotepa, etoposide, carboplatin, carmustine and topotecan.…”

“…2,3 High-dose, myeloablative chemotherapy with AHCR is frequently adopted in an attempt to improve the dismal survival rates in these patients and has shown improved outcomes when compared with standard chemotherapy treatment. 4,5 Dunkel et al 4 evaluated the use of high-dose carboplatin, thiotepa and etoposide with AHCR in adults and children with recurrent medulloblastoma, reporting event-free survivals of 34% at 3 years. Finlay et al 5 demonstrated that pediatric patients with recurrent malignant astrocytomas and minimal disease treated with thiotepa and etoposide-based chemotherapy regimens and AHCR had 4-year survival estimates of 46% compared with 0% for those treated with conventional chemotherapy.…”

“…9 When administered daily at 200 mg/m 2 for 5 days every 28 days, temozolomide showed a tolerable toxicity profile in children, with myelosuppression being the most common side-effect reported. 9,13 The current study builds upon prior research with high-dose chemotherapy and AHCR 4,[14][15][16][17][18][19][20] with the addition of temozolomide in place of etoposide. 4,15 The primary objective of this study was to define the maximum tolerated dose (MTD) of temozolomide administered twice daily in combination with myeloablative 1 doses of thiotepa and carboplatin with AHCR in patients with either recurrent high-grade brain tumors with minimal residual disease or those with newly diagnosed brain tumors with minimal residual disease following conventional therapy.…”