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Abstract
The prognosis of brain tumors in children has improved for the last 2-3 decades. However, the prognosis remains dismal in patients with relapsed tumors. The outcome for infants and young children is also poor. For younger children, the ability to use of radiotherapy (RT) is very limited because of the unacceptable long-term adverse effects of RT. The prognosis is also not satisfactory when a large residual tumor remains after surgery or when leptomeningeal seeding is present at diagnosis. In this context, a strategy using high-dose chemotherapy and autologous stem cell transplantation (HDCT/autoSCT) has been explored to improve the prognosis of recurrent or high-risk brain tumors. It was found that at least some patients with relapsed tumors can be salvaged with HDCT/autoSCT. For infants and young children, it was possible to avoid or defer RT until 3 years of age while maintaining or improving survival rates. Investigators also have explored the efficacy of HDCT/autoSCT in patients with newly diagnosed embryonal tumors to further improve the survival rate or to reduce the craniospinal RT dose without jeopardizing the survival rate. Preliminary results were encouraging although the numbers of patients was small. Recently, a few investigators have evaluated the efficacy of sequential HDCT/autoSCT to further improve the outcome. This strategy is based on the hypothesis that further dose escalation might result in further improvement in survival rates. At present, the number of studies employing a sequential HDCT/autoSCT strategy is limited. However, preliminary results of these studies suggest that sequential HDCT/autoSCT may further improve outcomes.
Figures and Tables
Table 1
HDCT/autoSCT in recurrent brain tumors
HDCT, high-dose chemotherapy; autoSCT, autologous stem cell transplantation; CCG, Children's Cancer Group; MB, medulloblastoma; CTE, carboplatin+thiotepa+etoposide; EFS, event-free survival; BuT, busulfan+thiotepa; RT, radiotherapy; OS, overall survival; BT, brain tumor; PFS, progression-free survival; PNET, primitive neuroectodermal tumor; CT, chemotherapy; CyM, cyclophosphamide+melphalan; KSPNO, Korean Society of Pediatric Neuro-Oncology.
Table 2
HDCT/autoSCT in young children with malignant brain tumors
HDCT, high-dose chemotherapy; autoSCT, autologous stem cell transplantation; RT, radiotherapy; BT, brain tumor; CT, chemotherapy; CTE, carboplatin+thiotepa+etoposide; R+, residual tumor; EFS, event-free survival; OS, overall survival; MB, medulloblastoma; HD-MTX, high-dose methotrexate; CSI, craniospinal irradiation; CaT, carboplatin+thiotepa; M+, leptomeningeal seeding; PFS, progression-free survival; PNET, primitive neuroectodermal tumor; CyM, cyclophosphamide+melphalan; R0, no residual tumor; M0, no leptomeningeal seeding; BuM, busulfan+melphalan; KSPNO, Korean Society of Pediatric Neuro-Oncology; AE, anaplastic ependymoma; ATRT, atypical teratoid/rhabdoid tumor.
Table 3
HDCT/autoSCT in newly diagnosed high-risk embryonal tumors
HDCT, high-dose chemotherapy; autoSCT, autologous stem cell transplantation; RT, radiotherapy; MB, medulloblastoma; AR, average-risk; HR, high-risk; CSI, craniospinal irradiation; CDDP, cisplatin; Cy, cyclophosphamide; VCR, vincristine; EFS, event-free survival; OS, overall survival; PNET, primitive neuroectodermal tumor; CyM, Cy+melphalan; CTE, carboplatin+thiotepa+etoposide.
Table 4
HDCT/autoSCT in high-grade glioma
HDCT, high-dose chemotherapy; autoSCT, autologous stem cell transplantation; RT, radiotherapy; GM, glioblastoma multiforme; TE, thiotepa+etoposide; BTE, BCNU (carmustine)+TE; CTE, carboplatin+TE; EFS, event-free survival; AA, anaplastic astrocytoma; CCG, Children's Cancer Group; PFS, progression-free survival; AO, anaplastic oligodendroglioma; CT, chemotherapy; T, thiotepa.
Acknowledgement
This study was supported by a grant from the National R&D Program for Cancer Control, Ministry of Health and Welfare, Republic of Korea (no. 0520300).
References
1. Taylor RE, Bailey CC, Robinson KJ, Weston CL, Walker DA, Ellison D, Ironside J, Pizer BL, Lashford LS. Outcome for patients with metastatic (M2-3) medulloblastoma treated with SIOP/UKCCSG PNET-3 chemotherapy. Eur J Cancer. 2005. 41:727–734.
2. Kortmann RD, Kuhl J, Timmermann B, Mittler U, Urban C, Budach V, Richter E, Willich N, Flentje M, Berthold F, Slavc I, Wolff J, Meisner C, Wiestler O, Sorensen N, Warmuth-Metz M, Bamberg M. Postoperative neoadjuvant chemotherapy before radiotherapy as compared to immediate radiotherapy followed by maintenance chemotherapy in the treatment of medulloblastoma in Pediatric: results of the German prospective randomized trial HIT '91. Int J Radiat Oncol Biol Phys. 2000. 46:269–279.
3. Zeltzer PM, Boyett JM, Finlay JL, Albright AL, Rorke LB, Milstein JM, Allen JC, Stevens KR, Stanley P, Li H, Wisoff JH, Geyer JR, McGuire-Cullen P, Stehbens JA, Shurin SB, Packer RJ. Metastasis stage, adjuvant treatment, and residual tumor are prognostic factors for medulloblastoma in children: conclusions from the Children's Cancer Group 921 randomized phase III study. J Clin Oncol. 1999. 17:832–845.
4. Duffner PK, Horowitz ME, Krischer JP, Friedman HS, Burger PC, Cohen ME, Sanford RA, Mulhern RK, James HE, Freeman CR, Seidel FG, Kun LE. Postoperative chemotherapy and delayed radiation in children less than three years of age with malignant brain tumors. N Engl J Med. 1993. 328:1725–1731.
5. Geyer JR, Zeltzer PM, Boyett JM, Rorke LB, Stanley P, Albright AL, Wisoff JH, Milstein JM, Allen JC, Finlay JL. Survival of infants with primitive neuroectodermal tumors or malignant ependymomas of the CNS treated with eight drugs in 1 day: a report from the Childrens Cancer Group. J Clin Oncol. 1994. 12:1607–1615.
6. Grill J, Sainte-Rose C, Jouvet A, Gentet JC, Lejars O, Frappaz D, Doz F, Rialland X, Pichon F, Bertozzi AI, Chastagner P, Couanet D, Habrand JL, Raquin MA, Le Deley MC, Kalifa C. French Society of Paediatric Oncology. Treatment of medulloblastoma with postoperative chemotherapy alone: an SFOP prospective trial in young children. Lancet Oncol. 2005. 6:573–580.
7. Bouffet E, Doz F, Demaille MC, Tron P, Roche H, Plantaz D, Thyss A, Stephan JL, Lejars O, Sariban E, Buclon M, Zucker JM, Brunat-Mentigny M, Bernard JL, Gentet JC. Improving survival in recurrent medulloblastoma: earlier detection, better treatment or still an impasse? Br J Cancer. 1998. 77:1321–1326.
8. Massimino M, Cohen KJ, Finlay JL. Is there a role for myeloablative chemotherapy with autologous hematopoietic cell rescue in the management of Pediatric high-grade astrocytomas? Pediatr Blood Cancer. 2010. 54:641–643.
9. Dunkel IJ, Boyett JM, Yates A, Rosenblum M, Garvin JH Jr, Bostrom BC, Goldman S, Sender LS, Gardner SL, Li H, Allen JC, Finlay JL. High-dose carboplatin, thiotepa, and etoposide with autologous stem-cell rescue for patients with recurrent medulloblastoma. Children's Cancer Group. J Clin Oncol. 1998. 16:222–228.
10. Ridola V, Grill J, Doz F, Gentet JC, Frappaz D, Raquin MA, Habrand JL, Sainte-Rose C, Valteau-Couanet D, Kalifa C. High-dose chemotherapy with autologous stem cell rescue followed by posterior fossa irradiation for local medulloblastoma recurrence or progression after conventional chemotherapy. Cancer. 2007. 110:156–163.
11. Shih CS, Hale GA, Gronewold L, Tong X, Laningham FH, Gilger EA, Srivastava DK, Kun LE, Gajjar A, Fouladi M. High-dose chemotherapy with autologous stem cell rescue for children with recurrent malignant brain tumors. Cancer. 2008. 112:1345–1353.
12. Sung KW, Yoo KH, Cho EJ, Koo HH, Lim DH, Shin HJ, Ahn SD, Ra YS, Choi ES, Ghim TT. High-dose chemotherapy and autologous stem cell rescue in children with newly diagnosed high-risk or relapsed medulloblastoma or supratentorial primitive neuroectodermal tumor. Pediatr Blood Cancer. 2007. 48:408–415.
13. Park JE, Kang J, Yoo KH, Sung KW, Koo HH, Lim DH, Shin HJ, Kang HJ, Park KD, Shin HY, Kim IH, Cho BK, Im HJ, Seo JJ, Park HJ, Park BK, Ahn HS. Efficacy of high-dose chemotherapy and autologous stem cell transplantation in patients with relapsed medulloblastoma: a report on The Korean Society for Pediatric Neuro-Oncology (KSPNO)-S-053 Study. J Korean Med Sci. 2010. 25:1160–1166.
14. Raghuram CP, Moreno L, Zacharoulis S. Is there a role for high dose chemotherapy with hematopoietic stem cell rescue in patients with relapsed supratentorial PNET? J Neurooncol. 2012. 106:441–447.
15. Bouffet E. The role of myeloablative chemotherapy with autologous hematopoietic cell rescue in central nervous system germ cell tumors. Pediatr Blood Cancer. 2010. 54:644–646.
16. Fouladi M, Gilger E, Kocak M, Wallace D, Buchanan G, Reeves C, Robbins N, Merchant T, Kun LE, Khan R, Gajjar A, Mulhern R. Intellectual and functional outcome of children 3 years old or younger who have CNS malignancies. J Clin Oncol. 2005. 23:7152–7160.
17. Packer RJ, Gurney JG, Punyko JA, Donaldson SS, Inskip PD, Stovall M, Yasui Y, Mertens AC, Sklar CA, Nicholson HS, Zeltzer LK, Neglia JP, Robison LL. Long-term neurologic and neurosensory sequelae in adult survivors of a Pediatric brain tumor: Pediatric cancer survivor study. J Clin Oncol. 2003. 21:3255–3261.
18. Duffner PK, Cohen ME, Voorhess ML, MacGillivray MH, Brecher ML, Panahon A, Gilani BB. Long-term effects of cranial irradiation on endocrine function in children with brain tumors: a prospective study. Cancer. 1985. 56:2189–2193.
19. Mason WP, Grovas A, Halpern S, Dunkel IJ, Garvin J, Heller G, Rosenblum M, Gardner S, Lyden D, Sands S, Puccetti D, Lindsley K, Merchant TE, O'Malley B, Bayer L, Petriccione MM, Allen J, Finlay JL. Intensive chemotherapy and bone marrow rescue for young children with newly diagnosed malignant brain tumors. J Clin Oncol. 1998. 16:210–221.
20. Chi SN, Gardner SL, Levy AS, Knopp EA, Miller DC, Wisoff JH, Weiner HL, Finlay JL. Feasibility and response to induction chemotherapy intensified with high-dose methotrexate for young children with newly diagnosed high-risk disseminated medulloblastoma. J Clin Oncol. 2004. 22:4881–4887.
21. Fangusaro J, Finlay J, Sposto R, Ji L, Saly M, Zacharoulis S, Asgharzadeh S, Abromowitch M, Olshefski R, Halpern S, Dubowy R, Comito M, Diez B, Kellie S, Hukin J, Rosenblum M, Dunkel I, Miller DC, Allen J, Gardner S. Intensive chemotherapy followed by consolidative myeloablative chemotherapy with autologous hematopoietic cell rescue (AuHCR) in young children with newly diagnosed supratentorial primitive neuroectodermal tumors (sPNETs): report of the Head Start I and II experience. Pediatr Blood Cancer. 2008. 50:312–318.
22. Thorarinsdottir HK, Rood B, Kamani N, Lafond D, Perez-Albuerne E, Loechelt B, Packer RJ, MacDonald TJ. Outcome for children <4 years of age with malignant central nervous system tumors treated with high-dose chemotherapy and autologous stem cell rescue. Pediatr Blood Cancer. 2007. 48:278–284.
23. Sung KW, Lim do H, Lee SH, Yoo KH, Koo HH, Kim JH, Suh YL, Joung YS, Shin HJ. Tandem high-dose chemotherapy and autologous stem cell transplantation for anaplastic ependymoma in children younger than 3 years of age. J Neurooncol. 2012. 107:335–342.
24. Park ES, Sung KW, Baek HJ, Park KD, Park HJ, Won SC, Lim DH, Kim HS. Tandem high-dose chemotherapy and autologous stem cell transplantation in young children with atypical teratoid/rhabdoid tumor of the central nervous system. J Korean Med Sci. 2012. 27:135–140.
25. Rutkowski S, Bode U, Deinlein F, Ottensmeier H, Warmuth-Metz M, Soerensen N, Graf N, Emser A, Pietsch T, Wolff JE, Kortmann RD, Kuehl J. Treatment of early Pediatric medulloblastoma by postoperative chemotherapy alone. N Engl J Med. 2005. 352:978–986.
26. Gajjar A, Chintagumpala M, Ashley D, Kellie S, Kun LE, Merchant TE, Woo S, Wheeler G, Ahern V, Krasin MJ, Fouladi M, Broniscer A, Krance R, Hale GA, Stewart CF, Dauser R, Sanford RA, Fuller C, Lau C, Boyett JM, Wallace D, Gilbertson RJ. Risk-adapted craniospinal radiotherapy followed by high-dose chemotherapy and stem-cell rescue in children with newly diagnosed medulloblastoma (St Jude Medulloblastoma-96): long-term results from a prospective, multicentre trial. Lancet Oncol. 2006. 7:813–820.
27. Chintagumpala M, Hassall T, Palmer S, Ashley D, Wallace D, Kasow K, Merchant TE, Krasin MJ, Dauser R, Boop F, Krance R, Woo S, Cheuk R, Lau C, Gilbertson R, Gajjar A. A pilot study of risk-adapted radiotherapy and chemotherapy in patients with supratentorial PNET. Neuro Oncol. 2009. 11:33–40.
28. Finlay JL, Dhall G, Boyett JM, Dunkel IJ, Gardner SL, Goldman S, Yates AJ, Rosenblum MK, Stanley P, Zimmerman RA, Wallace D, Pollack IF, Packer RJ. Children's Cancer Group. Myeloablative chemotherapy with autologous bone marrow rescue in children and adolescents with recurrent malignant astrocytoma: outcome compared with conventional chemotherapy: a report from the Children's Oncology Group. Pediatr Blood Cancer. 2008. 51:806–811.
29. Grovas AC, Boyett JM, Lindsley K, Rosenblum M, Yates AJ, Finlay JL. Regimen-related toxicity of myeloablative chemotherapy with BCNU, thiotepa, and etoposide followed by autologous stem cell rescue for children with newly diagnosed glioblastoma multiforme: report from the Children's Cancer Group. Med Pediatr Oncol. 1999. 33:83–87.
30. Massimino M, Gandola L, Luksch R, Spreafico F, Riva D, Solero C, Giangaspero F, Locatelli F, Podda M, Bozzi F, Pignoli E, Collini P, Cefalo G, Zecca M, Casanova M, Ferrari A, Terenziani M, Meazza C, Polastri D, Scaramuzza D, Ravagnani F, Fossati-Bellani F. Sequential chemotherapy, high-dose thiotepa, circulating progenitor cell rescue, and radiotherapy for Pediatric high-grade glioma. Neuro Oncol. 2005. 7:41–48.
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