Clinical Investigation
No Salvage Using High-Dose Chemotherapy Plus/Minus Reirradiation for Relapsing Previously Irradiated Medulloblastoma

https://doi.org/10.1016/j.ijrobp.2008.06.1930Get rights and content

Purpose

Myeloablative regimens were frequently used for medulloblastoma relapsing after craniospinal irradiation (CSI): in 1997–2002, we used repeated surgery, standard-dose and myeloablative chemotherapy, and reirradiation.

Methods and Materials

In 10 patients, reinduction included sequential high-dose etoposide, high-dose cyclophosphamide/vincristine, and high-dose carboplatin/vincristine, then two myeloablative courses with high-dose thiotepa (± carboplatin); 6 other patients received two of four courses of cisplatin/etoposide. Hematopoietic precursor mobilization followed high-dose etoposide or high-dose cyclophosphamide or cisplatin/etoposide therapy. After the overall chemotherapy program, reirradiation was prescribed when possible.

Results

Seventeen patients were treated: previous treatment included CSI of 19.5–36 Gy with posterior fossa/tumor boost and chemotherapy in 16 patients. Fifteen patients were in their first and 2 in their second and third relapses, respectively. First progression-free survival had lasted a median of 26 months. Relapse sites included leptomeninges in 9 patients, spine in 4 patients, posterior fossa in 3 patients, and brain in 1 patient. Three patients underwent complete resection of recurrence, and 10 underwent reirradiation. Twelve of 14 patients with assessable tumor had an objective response after reinduction; 2 experienced progression and were not given the myeloablative courses. Remission lasted a median of 16 months. Additional relapses appeared in 13 patients continuing the treatment. Fifteen patients died of progression and 1 died of pneumonia 13 months after relapse. The only survivor at 93 months had a single spinal metastasis that was excised and irradiated. Survival for the series as a whole was 11–93 months, with a median of 41 months.

Conclusions

Despite responses being obtained and ample use of surgery and reirradiation, second-line therapy with myeloablative schedules was not curative, barring a few exceptions. A salvage therapy for medulloblastoma after CSI still needs to be sought.

Introduction

Myeloablative chemotherapy has been used as a salvage treatment for patients with various relapsing solid tumors since successful experiences were reported in patients with hematologic diseases 1, 2. This strategy seemed particularly attractive in the last two decades for treating patients with relapsing embryonal central nervous system (CNS) tumors, such as medulloblastoma 3, 4.

Recent reports have clearly distinguished two groups of patients with relapsing medulloblastoma; however, i.e., children not undergoing irradiation at diagnosis because of their young age (<3–5 years old at the time) and older children who commonly underwent craniospinal irradiation (CSI) as part of their first treatment. Although myeloablative schedules can obtain a progression-free survival rate of approximately 50% in the former group, especially when coupled with radiation therapy (5), for the latter to be cured is exceptional.

We report on our institutional experience, gained from 1997 to 2002, of treating patients with relapsing medulloblastoma with a schedule containing high-dose chemotherapy followed by autologous stem cell rescue with reirradiation when possible.

Section snippets

Methods and Materials

All consecutive patients with a diagnosis of medulloblastoma that relapsed between 1997 and 2002 were offered this treatment strategy irrespective of disease-free interval, site of recurrence, number of previous relapses, and treatment received (although this never included myeloablative schedules). For the purpose of this report, we excluded younger children who had not undergone irradiation at first diagnosis.

Results

The patients' main features and treatments are listed in Table 1.

The series included 17 patients (13 males) with a median age at diagnosis of 6 years (range, 3–19 years) and a median age at relapse of 8 years.

In all patients, previous treatments had consisted of CSI plus a boost to the posterior fossa or tumor bed, plus chemotherapy in 16 of 17 patients. Two children had presented with metastatic disease at initial diagnosis. Total CSI dose had been 19.5 Gy in 7 patients (administered in

Discussion

The gold-standard treatment for childhood medulloblastoma, comprising reduced-dose CSI followed by chemotherapy, can afford a 3-year EFS rate greater than 80%, shown by widely applied treatment strategies (11). However, the approximately 20% of patients who experience relapse after irradiation cannot be cured by a salvage therapy, barring very rare exceptions (<5% of those who experience relapse) (12).

Retrieval therapy using high-dose myeloablative schedules has been widely applied to several

References (27)

  • F. Spreafico et al.

    Survival of adults treated for medulloblastoma using paediatric protocols

    Eur J Cancer

    (2005)
  • M.C. Chamberlain et al.

    Chronic oral VP-16 for recurrent medulloblastoma

    Pediatr Neurol

    (1997)
  • G. Schellong et al.

    Salvage therapy of progressive and recurrent Hodgkin's disease: Results from a multicenter study of the pediatric DAL/GPOH-HD study group

    J Clin Oncol

    (2005)
  • C. Messina et al.

    Autologous bone marrow transplantation for childhood acute lymphoblastic leukaemia in Italy. AIEOP/FONOP-TMO Group. Italian Association of Paediatric Haemato-Oncology

    Bone Marrow Transplant

    (1998)
  • J.L. Finlay

    The role of high-dose chemotherapy and stem cell rescue in the treatment of malignant brain tumors

    Bone Marrow Transplant

    (1996)
  • J.L. Finlay et al.

    Pilot study of high-dose thiotepa and etoposide with autologous bone marrow rescue in children and young adults with recurrent CNS tumors. Children's Cancer Group

    J Clin Oncol

    (1996)
  • S. Gururangan et al.

    Myeloablative chemotherapy with autologous bone marrow rescue in young children with recurrent malignant brain tumors

    J Clin Oncol

    (1998)
  • E.L. Kaplan et al.

    Non-parametric estimation from incomplete observation

    J Am Stat Assoc

    (1958)
  • R. Peto et al.

    Asymptomatically efficient rank invariant test procedures

    J R Stat Soc [A]

    (1972)
  • F. Fossati Bellani et al.

    Medulloblastoma. Results of a sequential combined treatment

    Cancer

    (1984)
  • G. Cefalo et al.

    Intensive sequential chemotherapy (CT) plus hyperfractionated-accelerated radiotherapy (HART) for metastatic medulloblastoma: Preliminary results

    Neurooncology

    (2001)
  • R.J. Packer et al.

    Phase III study of craniospinal radiation therapy followed by adjuvant chemotherapy for newly diagnosed average-risk medulloblastoma

    J Clin Oncol

    (2006)
  • E. Bouffet et al.

    Improving survival in recurrent medulloblastoma: Earlier detection, better treatment or still an impasse?

    Br J Cancer

    (1998)

    • Cited by (40)

    • Surgery for recurrent medulloblastoma: A review

      2021, Neurochirurgie
      Citation Excerpt :

      The authors do not comment whether the surgery itself was a significant influence on outcome; however, they acknowledge that the two longest survivors had localized disease and had undergone complete resection. In another study that also employed myeloablative chemotherapy in association with surgery and repeat radiotherapy, outcomes were also poor [17]. Between 1997 and 2002, three of 17 patients underwent complete resection of their single recurrence in the spine or posterior fossa.

    • Marrow-Ablative Chemotherapy With Autologous Hematopoietic Progenitor Cell Rescue in Brain Tumors

      2018, Handbook of Brain Tumor Chemotherapy, Molecular Therapeutics, and Immunotherapy: Second Edition

    • Liposomal cytarabine for the treatment of leptomeningeal dissemination of central nervous system tumours in children and adolescents

      2016, Anales de Pediatria

    • Childhood medulloblastoma

      2016, Critical Reviews in Oncology/Hematology
      Citation Excerpt :

      This option, which has been used with some success, is to be considered investigational only and it is not successful in older children that have already received craniospinal irradiation. In this age group, in fact, approximately 20% of patients who experience relapse after irradiation cannot be cured by salvage therapy, barring very rare exceptions (<5% of those who experience relapse) (Minn et al., 2001; Bouffet et al., 1998; Massimino et al., 2009; Pizer et al., 2011). In older children who received craniospinal radiation as part of their initial therapy, re-operation, followed by focal radiation with conformal techniques or proton beam, might be an option for solitary recurrences and should be considered on a case-by-case basis (Saran et al., 2008).

    • Salvage Therapy for Childhood Medulloblastoma: A Single Center Experience

      2019, Canadian Journal of Neurological Sciences

    • Evolution of Systemic Therapy in Medulloblastoma Including Irradiation-Sparing Approaches

      2023, Diagnostics
    View all citing articles on Scopus

    Supported in part by the Associazione Italiano perla Ricerca Sul Cancro and Associazione Bianca Garavaglia (Busto Arsizio Varese).

    Conflict of interest: none.

    View full text
    Copyright © 2009 Elsevier Inc. All rights reserved.