Long-Term Effects of Therapy
Radiation Therapy
Given the improved outcomes in
the treatment of pediatric brain tumors,
increasing concern has been
given to the effects of irradiation on
the developing brain in survivors. Irradiation
to the brain can adversely affect neurocognitive function and resultant
quality of life.[15] In children
and adults, cranial irradiation also frequently
causes damage to the hypothalamic-
pituitary axis, including
deficiency in growth hormone, hypothyroid,
and gonadal dysfunction.[31]
In addition to neuroendocrine effects,
cranial irradiation increases a patient's
risk for a second malignancy. In a
retrospective review of 111 cases of
intracranial GCTs, at a median followup
of 115 months, the incidence of
secondary brain neoplasm was 4.8%.
This incidence is expected to increase
with time, and the estimated incidence
over 19 years is 16.8%.[15]
The effects of irradiation have been
shown to have a more detrimental effect
in younger patients as opposed to
older patients. Age at diagnosis has
been positively correlated with overall
psychosocial and physical health
summary scores in studies examining
quality of life after cranial radiotherapy.[
32,33]
It is difficult to determine the effects
of irradiation on patients with
CNS GCTs, as they often have significant
deficits prior to the initiation of
radiation therapy.[33] In 2002, Merchant
et al evaluated pre- and posttreatment
neurocognitive function,
and found no significant differences
in IQ scores after patients received
25.6 Gy of craniospinal irradiation
and a 50.4-Gy boost to the primary
site. The patient group studied, however,
was small, consisting of 12 patients
with CNS GCTS aged 9 to 16
years old.[34] Further prospective
studies need to be obtained with preand
posttreatment analysis of neurocognitive
function.
In addition to neurocognitive dysfunction,
irradiation is associated with
endocrine dysfunction. However patients
with CNS germ cell tumors often
present with neuroendocrine
deficits prior to any therapy.[35] In a
1998 report on the SFOP experience,
Bouffet et al observed that 29 of 57
patients presented with growth hormone
deficiency or panhypopituitarism
and short stature.[17] In treating
these patients, the risk of short stature
with craniospinal irradiation needed
to be considered, regardless of age at
presentation.
Chemotherapy
Chemotherapy, on the other hand,
has been associated with a variety of
short- and long-term toxicities. Platinum-
based agents carry the risk primarily
of renal tubular nephropathy
and hearing loss. Etoposide is associated
with an increased risk of secondary
leukemia, and the pulmonary
toxicity of bleomycin has been well
described. In addition, cyclophosphamide
has been associated with sterility
and bladder fibrosis.
Conclusions
The excellent outcome of patients
with pure CNS germinoma and the
morbidity associated with standard
radiation therapy justifies attempts to
limit both the total irradiation dose
and field size, with or without chemotherapy,
and to limit surgery to a
biopsy for diagnostic purposes. In contrast,
the poor outcome of NGGCTs
justifies a more aggressive approach
employing chemotherapy and irradiation,
and in select cases, surgical resection.
Additional cooperative,
international studies are needed to
optimize treatment strategy relative
to tumor histology and the patient.
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ONCOLOGY. Vol. 19 No. 6 Central Nervous System Germ Cell Tumors: Controversies in Diagnosis and Treatment
By RIMA F. JUBRAN, MD, MPH
Assistant Professor of Pediatrics JONATHAN FINLAY, MB, ChB Professor of Pediatrics Director, Neural Tumors Program Childrens Hospital Los Angeles The Keck School of Medicine University of Southern California Los Angeles, California | May 1, 2005
THOMAS E. MERCHANT, DO, PhD ARNOLD C. PAULINO, MD
1. Shibamoto Y, Takahashi M, Sasai K: Prognosis
of intracranial germinoma with
syncytiotrophoblastic giant cells treated with
radiation therapy. Int J Radiat Oncol Biol Phys
37:505-510, 1997.
2. Matsutani M, Takakura K, Sano K: Primary intracranial germ cell tumors: Pathology and treatment. Prog Exp Tumor Res 30:307-312, 1987. 3. Weiner HL, Finlay JL: Surgery in the management of primary intracranial germ cell tumors. Childs Nerv Syst 15:770-773, 1999. 4. Sawamura Y, de Tribolet N, Ishii N, et al: Management of primary intracranial germinomas: Diagnostic surgery or radical resection? J Neurosurg 87:262-266, 1997. 5. Sawamura Y, Kato T, Ikeda J, et al: Teratomas of the central nervous system: Treatment considerations based on 34 cases. J Neurosurg 89:728-737, 1998. 6. Branzelli MC, Patte C, Bouffet E, et al: Non-metastatic intracranial germinomas. The experience of the French Society of Pediatric Oncology. Cancer 80:1792-1797, 1997. 7. Brada M, Rajan B: Spinal seeding in cranial germinomas. Br J Cancer 61:339-340, 1990. 8. Bamberg M, Kortmann R-D, Calaminus G, et al: Radiation therapy for intracranial germinoma: Results of the German Cooperative Prospective trials MAKEI 83/86/89. J Clin Oncol 17:2585-2592, 1999. 9. Ayoyama H, Shirato H, Kakuto Y, et al: Pathologically-proven intracranial germinoma treated with radiation therapy. Radiother Oncol 47:201-205, 1998. 10. Shibamoto Y, Takahashi M, Abe M, et al: Reduction of radiation dose for intracranial germinoma: A prospective study. Br J Cancer 70:984-989, 1994. 11. Buckner JC, Peethambram PP, Smithson WA, et al: Phase II trial of primary chemotherapy followed by reduced dose radiation for CNS germ cell tumor. J Clin Oncol 17:933-940, 1999. 12. Allen JC, Darosso RC, Donahue B, et al: A phase II trial of preirradiation carboplatin in newly diagnosed germinoma of the central nervous system. Cancer 74:940-944, 1994. 13. Matsutani M, Sano K, Takakura K, et al: Primary intracranial germ cell tumors: A clinical analysis of 153 histologically verified cases. J Neurosurg 86:446-455, 1997. 14. Fouladi M, Grant R, Baruchel S, et al: Comparison of survival outcomes in patients with intracranial germinomas treated with radiation alone versus reduced-dose radiation and chemotherapy. Childs Nerv Syst 14:596-601, 1998. 15. Sawamura Y, Shirato H, Ikeda J, et al: Induction chemotherapy followed by reduced volume radiation therapy for newly diagnosed CNS germinoma. J Neurosurg 88:66-72, 1998. 16. Sawamura Y, Ikeda J, Shirato H, et al: Germ cell tumors of the central nervous system: Treatment considerations based on 111 cases and their long term clinical outcomes. Eur J Cancer 34:104-110, 1998. 17. Bouffet E, Baranzelli MC, Patte C, et al: Combined treatment modality for intracranial germinomas: Results of a multicentre SFOP experience. Br J Cancer 79:1199-1204, 1999. 18. Rappaport R, Brauner R: Growth and endocrine disorders secondary to cranial radiation. Pediatr Res 25:561-567, 1989. 19. Matsutani M, Japanese Pediatric Brian Tumor Study Group: Combined chemotherapy and radiation therapy for CNS germ cell tumors— the Japanese experience. J Neurooncol 54:311-316, 2001. 20. Aoyama H, Shirato H, Ikeda J, et al: Induction chemotherapy followed by low dose involved field radiotherapy for intracranial germ cell tumors. J Clin Oncol 20:857-865, 2002. 21. Shibamoto Y, Sasai K, Kokubo M, et al: Salvage radiation therapy for intracranial germinoma recurring after primary chemotherapy. J Neurooncol 44:181-185, 1999. 22. Balmaceda C, Heller G, Rosenblum M, et al: Chemotherapy without radiation—a novel approach for newly diagnosed CNS germ cell tumors: Results of an international cooperative trial. J Clin Oncol 14:2908-2915, 1996. 23. Borg M: Germ cell tumors of the central nervous system in children: Controversies in radiotherapy. Med Pediatr Oncol 40:367-374, 2003. 24. Robertson PL, DaRosso RC, Allen JC: Improved prognosis of intracranial non-germinoma germ cell tumors with multimodality therapy. J Neurooncol 32:71-80, 1997. 25. Kellie SJ, Boyce H, Dunkel IJ, et al: Primary chemotherapy for intracranial nongerminomatous germ cell tumors: Results of the Second International CNS Germ Cell Study Group protocol. J Clin Oncol 22:846-853, 2004. 26. Garre ML, El-Hossainy MO, Fondelli P, et al: Is chemotherapy effective therapy for intracranial immature teratoma? A case report. Cancer 77:977-982, 1996. 27. Gobel U, Schneider DT, Calaminus G, et al: Germ cell tumors in childhood and adolescence. Ann Oncol 11:263-271, 2000. 28. Merchant TE, Davis BJ, Sheldon JM, et al: Radiation therapy for relapsed CNS germinoma after primary chemotherapy. J Clin Oncol 16:204-209, 1998. 29. Modak S, Gardner S, Dunkel I, et al: Thiotepa based high dose chemotherapy with autologous stem cell rescue in patients with recurrent or progressive CNS germ cell tumors. J Clin Oncol 22;1934-1943, 2004. 30. Mahoney DH Jr, Strother D, Camitta B, et al: High dose melphalan and cyclophosphamide with autologous bone marrow rescue for recurrent/progressive malignant brain tumors in children: A pilot Pediatric Oncology Group study. J Clin Oncol 14:382-388, 1996. 31. Constine LS, Woolf PD, Cann D, et al: Hypothalamic-pituitary dysfunction after radiation for brain tumors. N Engl J Med 328:87-94, 1993. 32. Sands SA, Kellie SJ, Davidow AL, et al: Long term quality of life and neuropsychologic functioning for patients with CNS germ cell tumors: From the First International CNS Germ Cell Tumor Study. Neur Oncol 3:174-183, 2001. 33. Sutton LN, Radcliffe J, Goldwein JW, et al: Quality of life of adult survivors of germinomas treated with craniospinal irradiation. Neurosurgery 46:1292-1298, 1999. 34. Merchant TE, Sherwood SH, Mulhern RK, et al: CNS germinoma: Disease control and long term functional outcome for 12 children treated with craniospinal irradiation. Int J Radiat Oncol Biol Phys 46:1171-1176, 2000. 35. Merchant TE, Williams T, Smith JL, et al: Preirradiation endocrinopathies in pediatric brain tumor patients determined by dynamic tests of endocrine function. Int J Radiat Oncol Biol Phys 54:45-50, 2002. CancerNetwork on Facebook
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