Treatment of recurrent primitive neuroectodermal tumors (PNET) in children and adolescents with high-dose chemotherapy (HDC) and stem cell support: results of the HITREZ 97 multicentre trial

Abstract

Early studies with high-dose chemotherapy for treatment of relapsed cerebral PNET had shown modest efficacy but considerable toxicity. The HIT97 national trial tested a nonrandomized but stratified relapse protocol using either intensive chemotherapy, potentially high dose, or oral chemotherapy. 72 patients (59 disseminated) whose primary treatment had been surgery (97 %), radiotherapy (88 %), and/or chemotherapy (95 %) were enrolled in the intensive chemotherapy arm at diagnosis of relapse or resistance. As a window for this study they received two courses of a 96-hour infusion with carboplatin and etoposide. A response (complete or partial remission) was documented by MRI. Responders received two more cycles of this therapy and stem cell collection, before they received HDC (carboplatin, etoposide, thiotepa) and stem cell support. All possibilities of local therapy were to be explored and applied. After two courses of chemotherapy there was a 52 % response rate (41/72 patients). The median PFS and OS for all 72 patients were 11.6 and 21.1 months. Patients with medulloblastoma had a longer PFS and OS (12.6 and 22.6 months) than those with other PNETs (3.1 and 12.3 months). Favourable prognostic features were no new signs of clinical impairment and localised disease at relapse diagnosis. For the 27 patients who received HDC the median PFS and OS were 8.4 and 20.2 months, respectively. HDC did not benefit patients with resistant cerebral PNET and was associated with profound haematological and mucosal toxicity (90-100 % grade III, IV), infections (50 % grade III and IV) and severe ototoxicity (50 % grade III, 12.5 % grade IV). Treatment related mortality was 8 %. There was low long-term survival and only 2/72 patients are in continuous remission. Adding HDC in patients who responded to the initial courses of chemotherapy did not improve survival. Patients with relapsed cerebral PNET who respond to conventional chemotherapy do not profit from further augmentation to HDC.

Relapse patterns and outcome after relapse in standard risk medulloblastoma: a report from the HIT-SIOP-PNET4 study

“…The poor outcome after MB relapse for patients previously treated with radiotherapy is in line with other reports [ 3 , 4 , 11 , 14 , 15 ]. With regard to the use of HDSCR, there was hope that this approach would be of significant benefit in relapsed malignant brain tumours, and single institution reports showed encouraging results [ 16 ].…”

Blood-brain barrier disruption with low-intensity pulsed ultrasound for the treatment of pediatric brain tumors: a review and perspectives

“…Transcellular transport is activated, with formation and movement of vesicles from luminal to abluminal surfaces (6). Vesicles can also merge and form large fenestrations and then form transendothelial channels (7). Drugs (8) can cross the BBB through these intercellular and transcellular ways, and thus be delivered to the brain parenchyma.…”

“…drugs. 7 Intraarterial chemotherapy injection consists of locoregional delivery of the drug via the cerebral arteries; a systematic review and meta-analysis has shown that this invasive approach is not superior to intravenous chemotherapy in terms of efficacy and OS. 12 Osmotic disruption of the BBB is performed using hypertonic agents, such as mannitol, injected into a cerebral artery.…”

Salvage therapy for progressive, treatment-refractory or recurrent pediatric medulloblastoma: a systematic review protocol

“…The study population includes infants, children, adolescents, and young adults (up to and including age 21 years to capture different definitions) with diagnoses of progressive, treatment-refractory, or recurrent MB at the time of study recruitment or following initial treatment [20]. To reflect the earlier classification of MB as an infratentorial small round blue cell tumor, articles on recurrent MB, posterior fossa tumors, primitive neuroectodermal tumors (PNETs), and CNS sarcomas will be included during title and abstract screening [22]. Studies that aggregate children and young adults or children with different types of solid or CNS tumors will be included, provided that participant data and outcomes can be evaluated separately for each group.…”