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Antiangiogenic Therapy in the Treatment of Recurrent Medulloblastoma in the Adult: Case Report and Review of the Literature

Antiangiogenic Therapy in the Treatment of Recurrent Medulloblastoma in the Adult: Case Report... Hindawi Publishing Corporation Journal of Oncology Volume 2009, Article ID 247873, 4 pages doi:10.1155/2009/247873 Case Report Antiangiogenic Therapy in the Treatment of Recurrent Medulloblastoma in the Adult: Case Report and Review of the Literature Giuseppe Privitera, Grazia Acquaviva, Giovanni Carlo Ettorre, and Corrado Spatola U.O. Radiodiagnostica e Radioterapia Oncologica, AOU Policlinico “G. Rodolico”—Catania, Via Santa Sofia 78-95125—Catania, Italy Correspondence should be addressed to Corrado Spatola, cor spatola@hotmail.com Received 27 May 2009; Revised 9 August 2009; Accepted 3 November 2009 Recommended by David Ball Medulloblastoma is a rare tumor in central nervous system, with an even rarer occurrence in adulthood. The management of a recurrent disease is a medical challenge; chemotherapy has been used as the treatment of choice, while reirradiation has been employed in selected cases. We report the case of a 51-year-old man with recurrent medulloblastoma. He was treated with local reirradiation, chemotherapy, and antiangiogenic drug, with the latter giving the longer progression-free interval. The aim of this report is to show that recurrent medulloblastoma in adults can be approached with a multimodality treatment and that antiangiogenic therapy should have a role in the management of this disease. Copyright © 2009 Giuseppe Privitera et al. This is an open access article distributed under the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited. 1. Background [2]. The advent of new anticancer drugs tested in brain tumors, as for antiangiogenetic molecules, has only recently Medulloblastoma is a rare embryonal neuroepithelial tumor been employed in the treatment of medulloblastoma and it in central nervous system. It occurs most frequently in is to be expected that their use will increase in the future, in the cerebellum of children, but almost 20% of the medul- the light of a personalized therapy. loblastomas develop in adulthood. The overall frequency of medulloblastoma/PNET is very low, with the Central Brain 2. Case Report Tumour Registry of the USA reporting that this disease is 0.9% of all reported brain tumours, with an incidence of 0.24 We report the case of a 51-year-old man with recurrent per 100000 person-years. The peak age group is 0–4 years, medulloblastoma. His clinical history began in 1999, when progressively declining to 0.05/10 person-years for the 65- he developed symptoms of raised intracranial pressure with to-74 year age groups. This tumor occurs most frequently in dizziness and headache. A brain MR revealed a tumor in the men than women [1]. region of right ponto-cerebellar angle, 3 cm in maximum Whether medulloblastoma is the same tumor in adults diameter. The patient underwent a complete surgical resec- and in children is an open question in the adult population. tion, confirmed by a postsurgery MR, and a diagnosis of The standard therapy for medulloblastoma has been classic medulloblastoma, G IV WHO was performed. surgical resection followed by craniospinal irradiation (CSI). He received craniospinal irradiation (36 Gy), followed by The role of adjuvant chemotherapy is unclear in the adult a primary boost to the posterior fossa (18 Gy) with a total population. dose to that region of 54 Gy. The management of a recurrent disease is a medical After a 6-year period of event-free follow-up, in March challenge; chemotherapy has been used as the treatment of 2005 a surveillance MRI showed recurrent disease in cervical choice, while reirradiation has been utilized in selected cases and thoracic spinal cord. Thus, he received chemotherapy 2 Journal of Oncology mild hypertension, treated with ACE-inhibitors and a pro- longation of the infusion interval, with the administration of bevacizumab at a dose of 5 mg/kg every 21 days. In February 2008, the control MRI demonstrated a slight progressive disease in the cervical spine, consequently we returned to the previous treatment schedule of drug infusion every 14 days. After 3 months, the control MRI showed a reduction of the pathologic enhancement to the cervical spine. Thus, the treatment was continued for further 4 months until September 2008, without any relevant side effects. In October 2008, as effect of a cranial trauma, the patient was referred to the hospital for the appearance of clinical signs of raised intracranial pressure, with sleepiness and headache, epilepsy with continuous crisis, and oliguria. A brain CT showed a subarachnoid frontal cerebral higroma, without the evidence of any vascular damage. For that reason, the patient was referred to the neurosurgeon, who (a) (b) performed a cerebro-spinal fluid drainage, and then to the intensive care unit for the life-saving treatments. The Figure 1: Spine MR showing the diffuse recurrent disease in the cytological study of the liquor was negative for cancer. cervical spine (on the left) and the complete response during the During the hospitalization there was no regression of the treatment with bevacizumab (on the right). clinical symptoms, so the patient died after 10 days from the admission (Table 1). with dacarbazine-etoposide-cisplatin (DEC) for 6 cycles; after four cycles of this treatment a grade III-IV neurotoxicity 3. Discussion and Conclusions was developed, so carboplatin was introduced in the place of cisplatin. Medulloblastoma of the cerebellum is an embryonal tumor, In November 2005 a disease progression was diagnosed, with a peak of incidence in children. with the evidence of recurrence in brainstem and cervical Not infrequently, about 20% of cases, it arises in adult- spinal cord: the patient was treated with procarbazine hood. There is the question as to whether the pathogenesis 2 2 (60 mg/m ) and lomustine (110 mg/m ) for 2 cycles. is the same in the adult form of the disease as the childhood After that, he underwent a reirradiation limited to the one [1–3]. This suggests that the prognosis and therapy of sites of recurrence (brainstem and cervical spinal cord) medulloblastoma could not be the same in all ages, but it is to a total dose of 24 Gy, with concomitant temozolomide necessary to personalize the treatment approach. 2 2 75 mg/m . Adjuvant temozolomide 200 mg/m was started The standard therapy for medulloblastoma has been after irradiation. surgical resection followed by craniospinal irradiation (CSI). A complete remission of the disease was demonstrated in Surgery plays a critical role in the management of this February 2006 and, for that reason, the same treatment was malignancy from both a diagnostic and therapeutic point continued for 13 cycles, until December 2006. During this of view, since the importance of complete resection is well period, the patient experienced a good quality of life and the recognized [4]. progression-free interval was almost one year (Figure 1). Cranio-spinal irradiation plays a key role in the manage- In January 2007 he had an MRI of the brain and of the ment of patients with this disease for many years, because spinal axis that showed recurrence in sacral spine (S1), thus it was the only treatment available and effective, but also we planned a new chemotherapeutic schedule, vincristine- because of the recognition that many chemotherapy drugs etoposide-ifosfamide, for 2 cycles, without any evidence of have difficulties to pass through the blood-brain barrier. response. A new control MRI evidenced a relapse in the The standard radiotherapy treatment counts a dose of 35 Gy brain and a stable disease to the spinal axis. For that reason, to 36 Gy with boost to the posterior fossa, thus giving a total in view of the short relapse-free interval and of the lack of of 55-56 Gy with a 5-year progression-free survival (PFS) and response to the conventional chemotherapeutic drugs, we overallsurvivalof50to65% [5, 6]. decided to enter the patient into an off-label treatment with The role of adjuvant chemotherapy is unclear, because bevacizumab. Thus, in July 2007 he started this treatment it was associated with a nonsignificant trend to prolonged with a dose of 5 mg/kg every 14 days. survival. Several randomized and nonrandomised studies After three months on bevacizumab, the restaging MR have demonstrated a survival benefit in pediatric medul- showed a complete disease regression, without any evidence loblastoma treated with chemotherapy, given after radiother- of disease in the brain and in the spinal axis. Therefore, apy [7–9]orbeforeit[10, 11]. Adjuvant or neoadjuvant he continued the same treatment schedule for further 4 chemotherapy plays also a key role in permitting a reduction months. During this period, the patient experienced only a in the dose of cranio-spinal irradiation; thus, chemotherapy Journal of Oncology 3 Table 1: Patient natural history. Date Treatments Comments Surgery (total resection)- April 1999 DFI/6 years Craniospinal irradiation (35 Gy) + boost PCF (18 Gy) total dose 54 Gy Relapse (cervico-dorsal spinal cord) March 2005 Progression after 8 months Chemotherapy (dacarbazine-vp16- CDDP/carboplatin 6 cycles) Relapse (brain stem and cervical spinal cord) Chemotherapy (procarbazine-lomustine 2 cycles) November 2005 Partial response PFI 13 months Reirradiation (brainstem and spinal cord 24 Gy) plus concomitant temozolomide Temozolomide (13 cycles until December 2006) Relapse (sacral spinal) January 2007 Progressive disease Chemotherapy (vincristine-VP16-ifosfamide-2 cycles) Relapse (brain) April 2007 Complete response Targeted therapy (bevacizumab q.14 3 months) Arterious hypertension October 2007 Progressive disease Targeted therapy (bevacizumab q.21 4 months) Relapse (cervical spinal cord) February 2008 Partial response Targeted therapy (bevacizumab q.14 7 months until September 2008) October 2008 Cerebral hygroma/epileptic syndrome Death is to date a standard of care in pediatric medulloblastoma, The novel approaches such as small molecules, mon- whereas its role in adult setting is not determined due to the oclonal antibodies, and antiangiogenic therapies support rarity of the disease. the conventional treatment and they will increasingly allow The management of recurrent medulloblastoma is based personalized medical care. on the use of systemic chemotherapy. The role of reirra- The advent of new anticancer drugs tested in brain diation is still unclear. It has been employed in selected tumors has important consequence for personalized therapy. cases, as for patients with good performance status, longer Tumor vasculature is emerging as an important target progression-free interval, and who are not amenable to for antiangiogenic therapy. Slongo et al. demonstrated the stereotactic radiotherapy. The major argument against reir- expression of VEGF, VEGFR-1, and VEGFR-2 in human radiation with fractionated external beam radiotherapy medulloblastoma cell lines and the possible autocrine within the central nervous system is the cumulative CNS tox- mechanism of VEGF on medulloblastoma cell proliferation. icity. In the recent years, brain and spinal cord reirradiation Medulloblastoma cell lines present both VEGFR-1 and has had a reappraisal: several studies have shown a lower VEGFR-2. Targeting VEGF signaling may represent a new incidence of severe complication than previously reported therapeutic option in the treatment of medulloblastoma [2]. [13, 14]. The main factors determining tolerance of the CNS to In the case presented, the patient had a first recurrence irradiation seem to be total dose, interval to re-treatment, after a disease-free interval of 6 years. The patient was volume of brain irradiated, fraction size, use of chemother- approached initially by means of systemic chemotherapy, apy, and age of patient. with dacarbazine, etoposide and platin compounds, which There is not a gold standard chemotherapy treatment for results in a disease progression after 8 months, at the adult medulloblastoma. Multiagent treatment with CDDP, expenses of moderate neurotoxicity. Reirradiation was car- Carboplatin, CCNU, and vincristine is the more commonly ried out after an interval of about 7 years, employing a utilized treatment in high risk patients, demonstrating to standard fraction size and a low total dose, with concomitant increase the 5-year progression-free survival rate in children and adjuvant temozolomide. It results in a partial response to 85%[6, 12]. with a long progression-free interval of 13 months, without Herrlinger et al. [4] suggest that the second-line and major side effects, with the exception of a moderate cerebral third-line therapes should be offered to adult medulloblas- atrophy showed by the follow-up MR. toma patients. A small but significant survival benefit was The use of systemic chemotherapy at the third relapse has demonstrated for the use of chemotherapy for high risk not led to clinical benefit; for that reason we decided to make patients [4]. use of an off-label targeted therapy with an antiangiogenic 4 Journal of Oncology molecule, such as bevacizumab. This treatment results in of radiation therapy with and without CCNU, vincristine, and prednisone,” Journal of Neurosurgery, vol. 72, no. 4, pp. 572– a rapid and complete disappearance of brain and spinal 582, 1990. cord localizations. The only clinical relevant side effect [9] R.J.Packer, L. N. Sutton,J.W.Goldwein, et al., “Improved was a moderate hypertension, which leads us to increase survival with the use of adjuvant chemotherapy in the the interval between administration, from every 14 days treatment of medulloblastoma,” Journal of Neurosurgery, vol. to every 21 days. The every-three weeks schedule has not 74, no. 3, pp. 433–440, 1991. maintained the complete response gained by the every- [10] R.-D. Kortmann, J. Kuhl, ¨ B. Timmermann, et al., “Post- two weeks schedule, so the treatment was restarted at the operative neoadjuvant chemotherapy before radiotherapy as previous schedule, with a new antihypertensive therapy. compared to immediate radiotherapy followed by mainte- Consequently, the follow-up MR showed again a response in nance chemotherapy in the treatment of medulloblastoma in the spinal cord. childhood: results of the German prospective randomized trial During the treatment with bevacizumab, the patient HIT ’91,” International Journal of Radiation Oncology Biology experienced a good quality of life, with a progression-free Physics, vol. 46, no. 2, pp. 269–279, 2000. interval of almost 17 months. The death was not attributable [11] P. M. Zeltzer, J. M. Boyett, J. L. Finlay, et al., “Metastasis to a disease progression, neither to a treatment side effects. stage, adjuvant treatment, and residual tumor are prognostic The aim of this case report is to show that recurrent factors for medulloblastoma in children: conclusions from the medulloblastoma in adults can be approached with a mul- Children’s Cancer Group 921 randomized phase III study,” Journal of Clinical Oncology, vol. 17, no. 3, pp. 832–845, 1999. timodality therapy by means of radiotherapy, chemotherapy, and targeted therapy. [12] P. S. Gaynon,L.J.Ettinger,E.S.Baum, S. E. Siegel,M. D. Krailo, and G. D. Hammond, “Carboplatin in childhood In conclusion, angiogenesis seems to play a key role in the brain tumors. A Children’s Cancer Study Group Phase II trial,” progression of medulloblastoma, and clinicians have sought Cancer, vol. 66, no. 12, pp. 2465–2469, 1990. to develop effective and less toxic antiangiogenic strategies, [13] M. L. Slongo, B. Molena, A. M. Brunati, et al., “Functional including the inhibition or destruction of abnormal blood VEGF and VEGF receptors are expressed in human medul- vessels using either antiangiogenic or vascular disrupting loblastomas,” Neuro-Oncology, vol. 9, no. 4, pp. 384–392, 2007. agents [15]. [14] I. Sardi, D. Cavalieri, and M. Massimino, “Emerging treat- ments and gene expression profiling in high-risk medulloblas- toma,” Pediatric Drugs, vol. 9, no. 2, pp. 81–96, 2007. References [15] F. Grizzi, C. Weber, and A. Di Ieva, “Antiangiogenic strategies in medulloblastoma: reality or mystery,” Pediatric Research, [1] CBTRUS Executive Team Central Brain Tumor Registry of the vol. 63, no. 5, pp. 584–590, 2008. United States, “Primary brain tumors in the United States, 1992–1997,” Statistical Report, CBTRUS, Chicago, Ill, USA, [2] G. S. Bauman, P. K. Sneed, W. M. Wara, et al., “Reirradiation of primary CNS tumors,” International Journal of Radiation Oncology Biology Physics, vol. 36, no. 2, pp. 433–441, 1996. [3] M. T. Giordana, P. Cavalla, A. Dutto, L. Borsotti, A. Chio, ` and D. Schiffer, “Is medulloblastoma the same tumor in children and adults?” Journal of Neuro-Oncology, vol. 35, no. 2, pp. 169– 176, 1997. [4] U. Herrlinger, A. Steinbrecher, J. Rieger, et al., “Adult medul- loblastoma: prognostic factors and response to therapy at diagnosis and at relapse,” Journal of Neurology, vol. 252, no. 3, pp. 291–299, 2005. [5] R. Taylor, C. L. Bailey, and K. Robinson, “Results of ran- domized study of pre-radiation chemotherapy vs radiotherapy alone for non metastatic (M0-1) medulloblastoma: the SIOP UKCCSG PNET study,” Journal of Clinical Oncology, vol. 21, pp. 1581–1591, 2003. [6] R. J. Packer, L. N. Sutton, R. Elterman, et al., “Outcome for children with medulloblastoma treated with radiation and cisplatin, CCNU, and vincristine chemotherapy,” Journal of Neurosurgery, vol. 81, no. 5, pp. 690–698, 1994. [7] D.M.Tait, H. Thornton-Jones,H.J.G.Bloom,J.Lemerle,and P. Morris-Jones, “Adjuvant chemotherapy for medulloblas- toma: the first multi-centre control trial of the International Society of Paediatric Oncology (SIOP I),” European Journal of Cancer, vol. 26, no. 4, pp. 464–469, 1990. [8] A. E. Evans, R. D. T. Jenkin, R. Sposto, et al., “The treatment of medulloblastoma. 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Antiangiogenic Therapy in the Treatment of Recurrent Medulloblastoma in the Adult: Case Report and Review of the Literature

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Hindawi Publishing Corporation
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Copyright © 2009 Giuseppe Privitera et al. This is an open access article distributed under the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.
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Abstract

Hindawi Publishing Corporation Journal of Oncology Volume 2009, Article ID 247873, 4 pages doi:10.1155/2009/247873 Case Report Antiangiogenic Therapy in the Treatment of Recurrent Medulloblastoma in the Adult: Case Report and Review of the Literature Giuseppe Privitera, Grazia Acquaviva, Giovanni Carlo Ettorre, and Corrado Spatola U.O. Radiodiagnostica e Radioterapia Oncologica, AOU Policlinico “G. Rodolico”—Catania, Via Santa Sofia 78-95125—Catania, Italy Correspondence should be addressed to Corrado Spatola, cor spatola@hotmail.com Received 27 May 2009; Revised 9 August 2009; Accepted 3 November 2009 Recommended by David Ball Medulloblastoma is a rare tumor in central nervous system, with an even rarer occurrence in adulthood. The management of a recurrent disease is a medical challenge; chemotherapy has been used as the treatment of choice, while reirradiation has been employed in selected cases. We report the case of a 51-year-old man with recurrent medulloblastoma. He was treated with local reirradiation, chemotherapy, and antiangiogenic drug, with the latter giving the longer progression-free interval. The aim of this report is to show that recurrent medulloblastoma in adults can be approached with a multimodality treatment and that antiangiogenic therapy should have a role in the management of this disease. Copyright © 2009 Giuseppe Privitera et al. This is an open access article distributed under the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited. 1. Background [2]. The advent of new anticancer drugs tested in brain tumors, as for antiangiogenetic molecules, has only recently Medulloblastoma is a rare embryonal neuroepithelial tumor been employed in the treatment of medulloblastoma and it in central nervous system. It occurs most frequently in is to be expected that their use will increase in the future, in the cerebellum of children, but almost 20% of the medul- the light of a personalized therapy. loblastomas develop in adulthood. The overall frequency of medulloblastoma/PNET is very low, with the Central Brain 2. Case Report Tumour Registry of the USA reporting that this disease is 0.9% of all reported brain tumours, with an incidence of 0.24 We report the case of a 51-year-old man with recurrent per 100000 person-years. The peak age group is 0–4 years, medulloblastoma. His clinical history began in 1999, when progressively declining to 0.05/10 person-years for the 65- he developed symptoms of raised intracranial pressure with to-74 year age groups. This tumor occurs most frequently in dizziness and headache. A brain MR revealed a tumor in the men than women [1]. region of right ponto-cerebellar angle, 3 cm in maximum Whether medulloblastoma is the same tumor in adults diameter. The patient underwent a complete surgical resec- and in children is an open question in the adult population. tion, confirmed by a postsurgery MR, and a diagnosis of The standard therapy for medulloblastoma has been classic medulloblastoma, G IV WHO was performed. surgical resection followed by craniospinal irradiation (CSI). He received craniospinal irradiation (36 Gy), followed by The role of adjuvant chemotherapy is unclear in the adult a primary boost to the posterior fossa (18 Gy) with a total population. dose to that region of 54 Gy. The management of a recurrent disease is a medical After a 6-year period of event-free follow-up, in March challenge; chemotherapy has been used as the treatment of 2005 a surveillance MRI showed recurrent disease in cervical choice, while reirradiation has been utilized in selected cases and thoracic spinal cord. Thus, he received chemotherapy 2 Journal of Oncology mild hypertension, treated with ACE-inhibitors and a pro- longation of the infusion interval, with the administration of bevacizumab at a dose of 5 mg/kg every 21 days. In February 2008, the control MRI demonstrated a slight progressive disease in the cervical spine, consequently we returned to the previous treatment schedule of drug infusion every 14 days. After 3 months, the control MRI showed a reduction of the pathologic enhancement to the cervical spine. Thus, the treatment was continued for further 4 months until September 2008, without any relevant side effects. In October 2008, as effect of a cranial trauma, the patient was referred to the hospital for the appearance of clinical signs of raised intracranial pressure, with sleepiness and headache, epilepsy with continuous crisis, and oliguria. A brain CT showed a subarachnoid frontal cerebral higroma, without the evidence of any vascular damage. For that reason, the patient was referred to the neurosurgeon, who (a) (b) performed a cerebro-spinal fluid drainage, and then to the intensive care unit for the life-saving treatments. The Figure 1: Spine MR showing the diffuse recurrent disease in the cytological study of the liquor was negative for cancer. cervical spine (on the left) and the complete response during the During the hospitalization there was no regression of the treatment with bevacizumab (on the right). clinical symptoms, so the patient died after 10 days from the admission (Table 1). with dacarbazine-etoposide-cisplatin (DEC) for 6 cycles; after four cycles of this treatment a grade III-IV neurotoxicity 3. Discussion and Conclusions was developed, so carboplatin was introduced in the place of cisplatin. Medulloblastoma of the cerebellum is an embryonal tumor, In November 2005 a disease progression was diagnosed, with a peak of incidence in children. with the evidence of recurrence in brainstem and cervical Not infrequently, about 20% of cases, it arises in adult- spinal cord: the patient was treated with procarbazine hood. There is the question as to whether the pathogenesis 2 2 (60 mg/m ) and lomustine (110 mg/m ) for 2 cycles. is the same in the adult form of the disease as the childhood After that, he underwent a reirradiation limited to the one [1–3]. This suggests that the prognosis and therapy of sites of recurrence (brainstem and cervical spinal cord) medulloblastoma could not be the same in all ages, but it is to a total dose of 24 Gy, with concomitant temozolomide necessary to personalize the treatment approach. 2 2 75 mg/m . Adjuvant temozolomide 200 mg/m was started The standard therapy for medulloblastoma has been after irradiation. surgical resection followed by craniospinal irradiation (CSI). A complete remission of the disease was demonstrated in Surgery plays a critical role in the management of this February 2006 and, for that reason, the same treatment was malignancy from both a diagnostic and therapeutic point continued for 13 cycles, until December 2006. During this of view, since the importance of complete resection is well period, the patient experienced a good quality of life and the recognized [4]. progression-free interval was almost one year (Figure 1). Cranio-spinal irradiation plays a key role in the manage- In January 2007 he had an MRI of the brain and of the ment of patients with this disease for many years, because spinal axis that showed recurrence in sacral spine (S1), thus it was the only treatment available and effective, but also we planned a new chemotherapeutic schedule, vincristine- because of the recognition that many chemotherapy drugs etoposide-ifosfamide, for 2 cycles, without any evidence of have difficulties to pass through the blood-brain barrier. response. A new control MRI evidenced a relapse in the The standard radiotherapy treatment counts a dose of 35 Gy brain and a stable disease to the spinal axis. For that reason, to 36 Gy with boost to the posterior fossa, thus giving a total in view of the short relapse-free interval and of the lack of of 55-56 Gy with a 5-year progression-free survival (PFS) and response to the conventional chemotherapeutic drugs, we overallsurvivalof50to65% [5, 6]. decided to enter the patient into an off-label treatment with The role of adjuvant chemotherapy is unclear, because bevacizumab. Thus, in July 2007 he started this treatment it was associated with a nonsignificant trend to prolonged with a dose of 5 mg/kg every 14 days. survival. Several randomized and nonrandomised studies After three months on bevacizumab, the restaging MR have demonstrated a survival benefit in pediatric medul- showed a complete disease regression, without any evidence loblastoma treated with chemotherapy, given after radiother- of disease in the brain and in the spinal axis. Therefore, apy [7–9]orbeforeit[10, 11]. Adjuvant or neoadjuvant he continued the same treatment schedule for further 4 chemotherapy plays also a key role in permitting a reduction months. During this period, the patient experienced only a in the dose of cranio-spinal irradiation; thus, chemotherapy Journal of Oncology 3 Table 1: Patient natural history. Date Treatments Comments Surgery (total resection)- April 1999 DFI/6 years Craniospinal irradiation (35 Gy) + boost PCF (18 Gy) total dose 54 Gy Relapse (cervico-dorsal spinal cord) March 2005 Progression after 8 months Chemotherapy (dacarbazine-vp16- CDDP/carboplatin 6 cycles) Relapse (brain stem and cervical spinal cord) Chemotherapy (procarbazine-lomustine 2 cycles) November 2005 Partial response PFI 13 months Reirradiation (brainstem and spinal cord 24 Gy) plus concomitant temozolomide Temozolomide (13 cycles until December 2006) Relapse (sacral spinal) January 2007 Progressive disease Chemotherapy (vincristine-VP16-ifosfamide-2 cycles) Relapse (brain) April 2007 Complete response Targeted therapy (bevacizumab q.14 3 months) Arterious hypertension October 2007 Progressive disease Targeted therapy (bevacizumab q.21 4 months) Relapse (cervical spinal cord) February 2008 Partial response Targeted therapy (bevacizumab q.14 7 months until September 2008) October 2008 Cerebral hygroma/epileptic syndrome Death is to date a standard of care in pediatric medulloblastoma, The novel approaches such as small molecules, mon- whereas its role in adult setting is not determined due to the oclonal antibodies, and antiangiogenic therapies support rarity of the disease. the conventional treatment and they will increasingly allow The management of recurrent medulloblastoma is based personalized medical care. on the use of systemic chemotherapy. The role of reirra- The advent of new anticancer drugs tested in brain diation is still unclear. It has been employed in selected tumors has important consequence for personalized therapy. cases, as for patients with good performance status, longer Tumor vasculature is emerging as an important target progression-free interval, and who are not amenable to for antiangiogenic therapy. Slongo et al. demonstrated the stereotactic radiotherapy. The major argument against reir- expression of VEGF, VEGFR-1, and VEGFR-2 in human radiation with fractionated external beam radiotherapy medulloblastoma cell lines and the possible autocrine within the central nervous system is the cumulative CNS tox- mechanism of VEGF on medulloblastoma cell proliferation. icity. In the recent years, brain and spinal cord reirradiation Medulloblastoma cell lines present both VEGFR-1 and has had a reappraisal: several studies have shown a lower VEGFR-2. Targeting VEGF signaling may represent a new incidence of severe complication than previously reported therapeutic option in the treatment of medulloblastoma [2]. [13, 14]. The main factors determining tolerance of the CNS to In the case presented, the patient had a first recurrence irradiation seem to be total dose, interval to re-treatment, after a disease-free interval of 6 years. The patient was volume of brain irradiated, fraction size, use of chemother- approached initially by means of systemic chemotherapy, apy, and age of patient. with dacarbazine, etoposide and platin compounds, which There is not a gold standard chemotherapy treatment for results in a disease progression after 8 months, at the adult medulloblastoma. Multiagent treatment with CDDP, expenses of moderate neurotoxicity. Reirradiation was car- Carboplatin, CCNU, and vincristine is the more commonly ried out after an interval of about 7 years, employing a utilized treatment in high risk patients, demonstrating to standard fraction size and a low total dose, with concomitant increase the 5-year progression-free survival rate in children and adjuvant temozolomide. It results in a partial response to 85%[6, 12]. with a long progression-free interval of 13 months, without Herrlinger et al. [4] suggest that the second-line and major side effects, with the exception of a moderate cerebral third-line therapes should be offered to adult medulloblas- atrophy showed by the follow-up MR. toma patients. A small but significant survival benefit was The use of systemic chemotherapy at the third relapse has demonstrated for the use of chemotherapy for high risk not led to clinical benefit; for that reason we decided to make patients [4]. use of an off-label targeted therapy with an antiangiogenic 4 Journal of Oncology molecule, such as bevacizumab. This treatment results in of radiation therapy with and without CCNU, vincristine, and prednisone,” Journal of Neurosurgery, vol. 72, no. 4, pp. 572– a rapid and complete disappearance of brain and spinal 582, 1990. cord localizations. The only clinical relevant side effect [9] R.J.Packer, L. N. Sutton,J.W.Goldwein, et al., “Improved was a moderate hypertension, which leads us to increase survival with the use of adjuvant chemotherapy in the the interval between administration, from every 14 days treatment of medulloblastoma,” Journal of Neurosurgery, vol. to every 21 days. The every-three weeks schedule has not 74, no. 3, pp. 433–440, 1991. maintained the complete response gained by the every- [10] R.-D. Kortmann, J. Kuhl, ¨ B. Timmermann, et al., “Post- two weeks schedule, so the treatment was restarted at the operative neoadjuvant chemotherapy before radiotherapy as previous schedule, with a new antihypertensive therapy. compared to immediate radiotherapy followed by mainte- Consequently, the follow-up MR showed again a response in nance chemotherapy in the treatment of medulloblastoma in the spinal cord. childhood: results of the German prospective randomized trial During the treatment with bevacizumab, the patient HIT ’91,” International Journal of Radiation Oncology Biology experienced a good quality of life, with a progression-free Physics, vol. 46, no. 2, pp. 269–279, 2000. interval of almost 17 months. The death was not attributable [11] P. M. Zeltzer, J. M. Boyett, J. L. Finlay, et al., “Metastasis to a disease progression, neither to a treatment side effects. stage, adjuvant treatment, and residual tumor are prognostic The aim of this case report is to show that recurrent factors for medulloblastoma in children: conclusions from the medulloblastoma in adults can be approached with a mul- Children’s Cancer Group 921 randomized phase III study,” Journal of Clinical Oncology, vol. 17, no. 3, pp. 832–845, 1999. timodality therapy by means of radiotherapy, chemotherapy, and targeted therapy. [12] P. S. Gaynon,L.J.Ettinger,E.S.Baum, S. E. Siegel,M. D. Krailo, and G. D. Hammond, “Carboplatin in childhood In conclusion, angiogenesis seems to play a key role in the brain tumors. A Children’s Cancer Study Group Phase II trial,” progression of medulloblastoma, and clinicians have sought Cancer, vol. 66, no. 12, pp. 2465–2469, 1990. to develop effective and less toxic antiangiogenic strategies, [13] M. L. Slongo, B. Molena, A. M. Brunati, et al., “Functional including the inhibition or destruction of abnormal blood VEGF and VEGF receptors are expressed in human medul- vessels using either antiangiogenic or vascular disrupting loblastomas,” Neuro-Oncology, vol. 9, no. 4, pp. 384–392, 2007. agents [15]. [14] I. Sardi, D. Cavalieri, and M. Massimino, “Emerging treat- ments and gene expression profiling in high-risk medulloblas- toma,” Pediatric Drugs, vol. 9, no. 2, pp. 81–96, 2007. References [15] F. Grizzi, C. Weber, and A. Di Ieva, “Antiangiogenic strategies in medulloblastoma: reality or mystery,” Pediatric Research, [1] CBTRUS Executive Team Central Brain Tumor Registry of the vol. 63, no. 5, pp. 584–590, 2008. United States, “Primary brain tumors in the United States, 1992–1997,” Statistical Report, CBTRUS, Chicago, Ill, USA, [2] G. S. Bauman, P. K. Sneed, W. M. Wara, et al., “Reirradiation of primary CNS tumors,” International Journal of Radiation Oncology Biology Physics, vol. 36, no. 2, pp. 433–441, 1996. [3] M. T. Giordana, P. Cavalla, A. Dutto, L. Borsotti, A. Chio, ` and D. Schiffer, “Is medulloblastoma the same tumor in children and adults?” Journal of Neuro-Oncology, vol. 35, no. 2, pp. 169– 176, 1997. [4] U. Herrlinger, A. Steinbrecher, J. Rieger, et al., “Adult medul- loblastoma: prognostic factors and response to therapy at diagnosis and at relapse,” Journal of Neurology, vol. 252, no. 3, pp. 291–299, 2005. [5] R. Taylor, C. L. Bailey, and K. Robinson, “Results of ran- domized study of pre-radiation chemotherapy vs radiotherapy alone for non metastatic (M0-1) medulloblastoma: the SIOP UKCCSG PNET study,” Journal of Clinical Oncology, vol. 21, pp. 1581–1591, 2003. [6] R. J. Packer, L. N. Sutton, R. Elterman, et al., “Outcome for children with medulloblastoma treated with radiation and cisplatin, CCNU, and vincristine chemotherapy,” Journal of Neurosurgery, vol. 81, no. 5, pp. 690–698, 1994. [7] D.M.Tait, H. Thornton-Jones,H.J.G.Bloom,J.Lemerle,and P. Morris-Jones, “Adjuvant chemotherapy for medulloblas- toma: the first multi-centre control trial of the International Society of Paediatric Oncology (SIOP I),” European Journal of Cancer, vol. 26, no. 4, pp. 464–469, 1990. [8] A. E. Evans, R. D. T. Jenkin, R. Sposto, et al., “The treatment of medulloblastoma. 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