SIOPE-ENCCA Case Studies: Successful palliation of metastatic medulloblastoma with oral etoposide and risedronate
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Author: S. Wilne1, L. MacPherson2, M. Brundler2, D. Ford3, D. Walker1, A. Peet2
1Nottingham University Hospitals NHS Trust, Nottingham, United Kingdom, 2Birmingham Children's Hospital NHS Foundation Trust, Birmingham, United Kingdom, 3University Hospitals Birmingham NHS Foundation Trust, Birmingham, United Kingdom.
Expected learning outcome:
1. Recognition that systemic metastases occur in medulloblastoma and can occur years after initial presentation
2. The importance of bisphosphonates in the management of metastatic bone disease. These agents are frequently used in adult oncology but are rarely used in paediatric practice.
3. The possible synergistic action of bisphosphonates with chemotherapy in the management of metastatic bone disease.
Medulloblastoma is the most common malignant brain tumour in children. Metastatic spread has occurred in up to 35% of children by diagnosis. The five year survival for children with non-metastatic disease is reported to be up to 80%. The presence of metastatic disease results in much worse survival with a 30-40% reported five year survival (1). Development of extra-neural metastases in medulloblastoma is usually associated with rapid disease progression. We report the prolonged palliation of medulloblastoma metastatic to bone with oral etoposide and risedronate.
The patient presented in October 2004, age eight, with a four month history of headache, vomiting and lethargy. Imaging showed a mass arising from the cerebellar vermis, a separate mass in the infundibular recess of the third ventricle and hydrocephalus (figure 1). Excision biopsy of the cerebellar mass showed medulloblastoma (figure 2). Bone marrow aspirates and trephines showed no evidence of further metastatic disease. The patient was treated with high dose cyclophosphamide followed by stem cell harvest and cisplatin and etoposide as per the POG 9031 protocol (2). Radiotherapy was scheduled for after the fourth course of chemotherapy however disease progression was noted on reassessment imaging and radiotherapy (55.8Gy to the posterior fossa, 40Gy to the craniospinal axis, 44.4Gy to the infundibulum) was therefore brought forward to after the second course. Following radiotherapy he received continuation chemotherapy with two courses of weekly vincristine and oral etoposide (50mg/m2 for 21 out of 28 days). Treatment finished August 2005.
In May 2008 the patient developed severe (unable to walk) right hip pain. Imaging was abnormal (figure 3). Biopsy confirmed metastatic disease in the femoral metaphysis (figure 4) Palliative chemotherapy with oral etoposide was started in September 2008 (50mg/m2 21 out of 28 days). Oral risedronate 35mg weekly was started in November 2008. Pain resolved rapidly and function returned to normal. Oral etoposide was stopped after twelve courses however risedronate continues. Imaging after 12 courses of etoposide showed resolution of the pelvic and left femoral lesions and reduction in size of the right femoral lesion (figure 5). At last review (June 2010) the patient remains asymptomatic on risedronate monotherapy.
As the efficacy of CNS directed treatment for paediatric malignant brain tumours improves it is likely that the frequency of late, systemic metastases will increase. Bisphosphonates are standard care for the management of bone metastatic disease in adults, improving quality of life and reducing skeletal events (3). In paediatric practice they are used in the management of osteogenesis imperfecta and to treat osteoporosis and hypercalcaemia (4) however there is no published information about their use in bony metastatic disease in children. There is evidence that bisphosphonates have a synergistic anti-tumour action when administered with chemotherapy in patients with osteosarcoma (5) and this may have occurred in this case. The efficacy of oral etoposide and risedronate in our patient suggests that this regime merits use in other children developing bony metastatic disease.
Figure 1: MRI October 2004 (diagnosis). There is a heterogeneous mass arising from the cerebellar vermis and hydrocephalus.
MRI October 2004 (diagnosis). There is a heterogeneous mass arising from the cerebellar vermis and hydrocephalus.
Figure 2: Histology of cerebellar mass. There are sheets of small round blue cells. Immunohistochemistry demonstrated CD56 positivity, characteristic of medulloblastoma.
Figure 3: MRI of pelvis August 2008. There are extensive enhancing abnormalities in the pelvis and both femora.
MRI of pelvis August 2008. There are extensive enhancing abnormalities in the pelvis and both femora.
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Figure 4: Low and high power views of biopsy of bone lesion identified at relapse. Normal marrow is replaced by sheets of small round blue cells characteristic of medulloblastoma. This was confirmed on immunohistochemistry which showed CD56 positivity.
Low and high power views of biopsy of bone lesion identified at relapse. Normal marrow is replaced by sheets of small round blue cells characteristic of medulloblastoma. This was confirmed on immunohistochemistry which showed CD56 positivity.
Figure 5: MRI pelvis October 2009. There is resolution of the abnormalities in the pelvis and left femur and reduction in the size of abnormality in the right femur.
MRI pelvis October 2009. There is resolution of the abnormalities in the pelvis and left femur and reduction in the size of abnormality in the right femur.
- Medulloblastoma: new insights into biology and treatment. Pizer, B. and Clifford, S. Archives of Disease in Childhood Education and Practice 2008, 93: 137-144.
- Outcome for children with high stage medulloblastoma: results of the Pediatric Oncology Group 9031 study. Tarbell, N. J. et al. International Journal of Radiation Oncology Biology Physics 1999, 48(Suppl): 179.
- Treatment on bone metastases and bone pain with bisphosphonates. Lipton, A. Supportive Cancer Therapy 2007, 4(2): 92-100.
- Recent advances. Bisphosphonate treatment of bone disease. Shaw, N.J. and Bishop, N. J. Archives of Disease in Childhood 2005, 90: 494-499.
- Combined effects of a third-generation bisphosphonate, zoledronic acid with other anticancer agents against murine osteosarcoma. Horie, N. et al. British Journal of Cancer 2007, 96(2): 255-261.
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