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Patterns of failure following treatment for medulloblastoma: is it necessary to treat the entire posterior fossa?
Int. J. Radiation Oncology Biol. Phys., Vol. 42, No. 1, pp. 143–146, 1998 Copyright © 1998 Elsevier Science Inc. Printed in the USA. All rights reserved 0360-3016/98 $19.00 1 .00
PII S0360-3016(98)000178-3
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Clinical Investigation PATTERNS OF FAILURE FOLLOWING TREATMENT FOR MEDULLOBLASTOMA: IS IT NECESSARY TO TREAT THE ENTIRE POSTERIOR FOSSA? NINA FUKUNAGA-JOHNSON, M.D.,* JASON H. LEE, M.D.,‡ HOWARD M. SANDLER, M.D.,* PATRICIA ROBERTSON, M.D.,† ELIZABETH MCNEIL, M.D.§ AND JOEL W. GOLDWEIN, M.D.‡
Departments of *Radiation Oncology and †Pediatrics, University of Michigan, Ann Arbor, MI; ‡Department of Radiation Oncology, University of Pennsylvania, Philadelphia, PA; and §Division of Neuro-oncology, Children’s Hospital of Philadelphia, Philadelphia, PA Purpose: Craniospinal radiation (CSRT) followed by a boost to the entire posterior fossa (PF) is standard postoperative therapy for patients with medulloblastoma. A large proportion of recurrences after treatment are local, with approximately 50 –70% of recurrences occurring in the PF. It is unclear, however, whether these failures are occurring in the original tumor bed or outside the tumor bed, but still within the PF. With improved diagnostic imaging, better definition of tumor volumes, and the use of three-dimensional conformal therapy (3D CRT), we may be able to restrict the boost volume to the tumor bed plus a margin without compromising local control. This retrospective study analyzes the patterns of failure within the PF in a series of patients treated with radiation therapy (RT). Methods: From July 1986 through February 1996, 114 patients >18 months and <18 years with medulloblastoma were treated at the University of Michigan and Children’s Hospital of Philadelphia, with RT following surgical resection. Of 114, 27 (24%) were found to have a recurrence and form the basis for this study. RT consisted of CSRT followed by a boost to the entire posterior fossa. Some patients received adjuvant chemotherapy. Patient’s preoperative magnetic resonance imaging (MRI) and/or computerized tomography (CT) studies were used to compare the original tumor volume with the specific region of local relapse. Failure was defined as MRI or CT evidence of recurrence or positive cerebrospinal fluid cytology. Relapse was scored as local, if it was within the original tumor bed, and regional if it was outside of the tumor bed but still within the PF. Results: The median age of the 27 patients who relapsed was 8.6 years. Three patients were <3 years old. Of 27, 21 had disease localized to the PF. Of 26, 22 patients received chemotherapy during their treatment regimen; 1 patient did not have information on systemic treatment. The median dose of RT to the craniospinal axis was 32.5 Gy and to the PF was 55.2 Gy. The median time to recurrence was 19.5 months. Local failure within the tumor bed as any component of first failure occurred in 52% (14 of 27) of all failures, but as the solitary site of first failure in only 2 of 27 failures. Of 14 patients who failed in the tumor bed, 11 also failed in the spine, 8 of 14 also failed within the PF but outside the tumor bed, and 7 of 14 failed in all three locations. Local failure within the PF but outside the tumor bed as any component of first failure occurred in 41% (11 of 27) of all failures, but as the solitary site of first failure in only 1 of 27 failures. Of 11 patients who failed in the PF but outside the tumor bed, 9 also failed in the spine, 8 also failed within the tumor bed, and 7 failed in the all three locations. Of the failures outside the tumor bed but still within the PF, 7 of 11 failed in the leptomeninges, 1 in the brainstem parenchyma, and 3 in the PF parenchyma. Of 7 who failed in the PF leptomeninges, 6 also failed within the spine. Failure within the spine as any component of first failure occurred in 70% (19 of 27) of all failures and as the only site of first failure in 5 of 27 patients. Of 19 patients who failed in the spine, 11 also failed in the tumor bed, 9 also failed within the PF but outside the tumor bed, and 9 failed in the all three locations. Conclusions: Leptomeningeal failure is a common component of failure and occurs in the leptomeninges of the PF, as well as the spine. Isolated tumor bed failure is a rarely observed event and occurred in only 2 of 27 failures described here. Similarly, parenchymal (nonleptomeningeal) failures in the PF but outside of the tumor bed were rare: 4 patients recurred in this manner, only 1 of whom was an isolated event without other sites of recurrence. Our data suggest that, when the entire PF is treated, very few failures develop in isolation in the PF outside the tumor bed. Further studies will be necessary to determine if RT to the tumor bed alone will suffice as opposed to a boost to the entire PF. The former approach, using 3D CRT, may minimize ototoxicity and other morbidity associated with full PF irradiation. © 1998 Elsevier Science Inc. Radiotherapy, Medulloblastoma.
Presented at the 1997 American Society of Therapeutic Radiology and Oncology. Reprint requests to: Nina Fukunaga-Johnson, M.D., Department of Radiation Oncology, Memorial Hospital, 615
N. Michigan St., South Bend, IN 46601. Accepted for publication 28 April 1998. 143
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Table 1. Clinical characteristics at diagnosis of 27 medulloblastoma patients who relapsed Age Gender (M:F) M0 M1–3
8.6 years (mean) (13:14) 21 6
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Table 2. Treatment characteristics of 27 medulloblastoma patients who relapsed
1.83–17 years (range) (48%:52%)
INTRODUCTION Primary central nervous system tumors are the most common solid tumors in children. Medulloblastomas account for approximately 20% of brain tumors in children. The peak age of incidence is 5 years, with most tumors occurring within the first decade of life. Radiation therapy (RT) along with surgical resection and chemotherapy are mainstays of medulloblastoma therapy, and have many associated side effects. Standard RT has been to administer up to 36 Gy to the entire craniospinal axis followed by a boost to the entire posterior fossa (PF) to 55 Gy. The treatment volume and doses of RT have changed little during the past 40 years. The treatment of these brain tumors has always been complicated by the side effects of the therapy. Gains made in diagnosis and treatment are often offset by long-term complications of therapy. In the modern imaging era, with better definition of the tumor, we may be able to restrict the boost volume and treat the tumor bed plus a margin of 1–2 cm. The majority of recurrences after standard treatment for medulloblastoma appear to be local, with approximately 55–70% of recurrences occurring in the PF (1–3). It is unclear, however, whether these PF failures are occurring in the original tumor bed or outside the tumor bed, but still within the PF. The use of three-dimensional conformal radiotherapy (3D CRT) provides the potential to define the target volume and ascertain the spatial relationship between the clinical target volume and neighboring critical healthy structures. Using this spatial information, one may design treatments that avoid unnecessary irradiation of tissues where the risk of relapse is low. In the setting of medulloblastoma therapy, the use of 3D CRT may be useful in sparing critical healthy brain and auditory structures. This work examines the patterns of failure within the PF in medulloblastoma patients treated with RT. MATERIALS AND METHODS Patient characteristics Between July 1986 and February 1996, 114 consecutive patients with medulloblastomas who were .18 months and ,18 years old and were treated at the University of Michigan and Children’s Hospital of Philadelphia, Department of Radiation Oncology, have been reviewed for this study. Of these 114 patients, 27 patients (24%) were found to have a recurrence. These 27 patients form the basis for our analysis, and Table 1 shows the patient characteristics of this group. Median age was 8.6 years (range 1.83–17 years). Three patients were ,3 years old. There were 6 patients
Radiation therapy doses Whole-brain dose Spine dose Posterior fossa boost Primary total dose* Surgical Resection Gross total resection Subtotal resection Unknown Chemotherapy†
Mean Dose, Gy
Dose Range, Gy
Patients
32.9 Gy 34.5 Gy 52.2 Gy 55.2 Gy
18–41.4 Gy 18–45 Gy 36–60 Gy 50–60 Gy
– – – –
– – –
14 12 1 22 of 26
* 6 pts had boost to tumor bed in addition to PF boost. † No information on 1 patient.
with leptomeningeal dissemination (M1-3) at diagnosis. Gross total resection was achieved in 14 patients and subtotal resection in 12 patients; 1 patient did not have information on resection (Table 2). Of 26 patients, 22 received chemotherapy during their treatment regimen; 1 patient did not have information on systemic treatment (Table 2). All patients were seen in follow-up and evaluation with CT and/or MRI of the brain at regular intervals of every 3– 6 months following treatment. There has been up to 10 years of follow-up. The median time to recurrence was 19.5 months (range 5–72 months). Radiotherapy technique All patients underwent initial simulation and, with few exceptions, were placed prone and immobilized using an aquaplast mask or a specialized board. Six patients were planned using 3D CRT. These 6 patients were those treated at the University of Michigan. This was accomplished by obtaining a planning CT imaging scan in the treatment position using 5-mm cuts through the brain. The CT data were entered into a 3D planning system and various structures, including the brain and PF, were outlined on each slice by the physician. The planning target volumes (PTVs) were expanded in 3D to account for patient setup and microscopic tumor uncertainty. The patients who were not planned with 3D-CRT were treated to the PF field that was determined by superimposing the saggital MRI on the simulation field. Custom cerrobend blocks were designed using Beam’s Eye View (BEV) and margins were adjusted to provide full target coverage. All patients were treated to their entire neuroaxis followed by a boost to the entire PF. Six patients had an additional boost to the tumor bed following a PF boost. The craniospinal RT technique was similar for all patients, and the PF boost was delivered via parallel-opposed photon beam, in most cases. One patient was treated using a cochlear-sparing technique using a wedge pair to the PF. Patients were treated using a 6-MV linear accelerator. Treatment was delivered at 1.8 –2.0 Gy daily fractions 5
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Table 4. Sites of failure
Table 3. Patterns of failure Site of first failure
Only site of failure
Any component of failure
Tumor bed PF outside TB Spine Supratentorial Extraneural
2 (7%) 1 (3%) 5 (19%) 2 (7%) 2 (7%)
14 (52%) 11 (41%) 19 (70%) 7 (26%) 3 (11%)
days/week with continuous-course radiotherapy in all patients, except 5 who received hyperfractionated RT (1.00 Gy twice a day). The doses and volumes treated during this study period are given in Table 2. The mean dose of RT to the brain ranged from 18 – 41.4 Gy (mean 32.9 Gy) and to the spine from 18 – 45 Gy (mean 34.5 Gy). Three patients were given low-dose RT (18 Gy) to the craniospinal axis. A boost to the PF was given to all patients for a total dose of 36 – 60 Gy (mean, 52.2Gy). Six patients had an additional boost to the tumor bed following a PF boost for a total dose to the tumor bed of 50 – 60 Gy (mean, 55.2 Gy). Failure analysis Patient preoperative MRI and/or CT studies were used to compare the original tumor volume with the specific region of local relapse. Failure was defined as MRI or CT evidence of recurrence or positive cerebrospinal fluid cytology. Relapse was scored as follows: “PF within the tumor bed,” if failure was within the original tumor bed; “PF but outside the tumor bed,” if failure was outside of the tumor bed but still within the PF treatment field; “supratentorial” if failure was above the tentorium; “spinal” failure if there was MRI or myelogram evidence of disease within the spinal column or if there was positive cerebrospinal fluid (CSF); and “distant” if failure was outside the neuroaxis. RESULTS The median time to recurrence was 19.5 months. Of 27 patients who relapsed, 21 had disease localized to the PF at the time of diagnosis. Tables 3 and 4 demonstrate where these treatments failed as the only site or any component of failure. Any component of failure was documented if a treatment failed in a certain location, regardless of failures elsewhere. Local failure within the tumor bed as any component of failure occurred in 52% (14 of 27) of all failures, but as the solitary site of failure in only 2 of 27 failures (Table 3). Of 14 patients who had failure in the tumor bed, 11 also had failure in the spine, 8 also had failure within the PF but outside the tumor bed, and 7 had failure in the all three locations (Table 4). Local failure within the PF but outside the tumor bed as any component of failure occurred in 41% (11 of 27) of all failures, but as the solitary site of failure in only 1. Of 11 patients who had failure in the PF but outside the tumor bed, 9 also hd failure in the spine, 8 also within the tumor bed, and 7 in the all three locations. Of
Site of failure
Only site of failure
Any component of failure
TB 1 PF outside TB TB 1 spine PF outside TB 1 spine PF outside TB 1 supratentorial Spine 1 supratentorium TB 1 PF outside TB 1 spine
0 2 1 0 1 5
8 11 9 2 5 7
the failures outside the tumor bed, but still within the PF, 7 were in the leptomeninges, 1 in the brainstem parenchyma, and 3 in the PF parenchyma. Of 7 who had failure in the PF leptomeninges, 7 also had failure within the spine. Failure within the spine as any component of failure occurred in 70% (19 of 27) of all failures and as the only site of failure in 5 patients. Of 19 patients who had failure in the spine, 11 also had failure in the tumor bed, 9 also within the PF but outside the tumor bed, and 9 in all three locations. Of the 6 patients who presented with spinal disease, 5 had some component of spinal failure, and 2 only in the spine. Of the 6 patients who had an additional boost to the tumor bed, 1 had failure in the tumor bed only, and 4 had some component of TB failure, 2 had some component of PF failure outside the tumor bed but within the leptomeninges, and 5 had some component of spinal failure. Extent of surgical resection did not appear to have an impact on recurrence pattern (Table 5). DISCUSSION Craniospinal radiation followed by a boost to the entire PF is standard postoperative therapy for patients with medulloblastoma. A large proportion of recurrences after treatment are local, with approximately 55–70% occurring in the PF (1–3). It has been unclear, however, whether these failures are occurring in the original tumor bed or outside the tumor bed, but still within the PF. This study demonstrates that leptomeningeal failure is a common component of failure and occurrs in the leptomeninges of the posterior fossa, as well as the spine, in 74% of all the patients examined in our series. Isolated tumor bed failure was a rarely observed event and occurred in only 2 of 27 failures. Similarly, parenchymal (nonleptomeningeal) failures in the PF but outside of the tumor bed were rare: 4 patients had
Table 5. Percent of resection and recurrence Any component of failure
Gross total resection
Subtotal resection
TB PF outside TB Spine Supratentorial Distant
6 7 11 4 2
5 4 6 4 0
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recurrence in this manner, only 1 of which was an isolated event without other sites of recurrence. One of the largest series published in the CT era has demonstrated that local failure as any component of failure occurred in 55% of patients, but was the only site of first failure in 14% of patients (3). However, the definition of local failure was “posterior fossa” and was not broken down between PF within tumor bed or PF outside the tumor bed. One recent study from Switzerland investigated the possibility of treating the tumor bed only in patients with supratentorial primitive neuroectodermal tumors (4). This dosimetric study was undertaken to demonstrate that confining the treatment to the tumor bed only significantly decreased irradiation to healthy brain. Our study also demonstrates a similar behavior of the spine and the PF with respect to leptomeningeal failures. A recent report from the CCG confirms that, although the original site of disease is at high risk for relapse, the entire neuroaxis remains at significant risk and a more aggressive approach to local control in the neuroaxis is warranted (5). Although randomized trials comparing 3D CRT to conventional radiation therapy have not been performed, it appears that treatment technique may be an important factor in achieving local control for medulloblastoma (6, 7). When whole-brain irradiation margins were judged to miss the inferior portion of the frontal and temporal lobes, an increase in supratentorial failure was observed (7). The use of 3D CRT inpatients with parameningeal rhabodmyosarcoma of the head and neck has demonstrated an improvement in dosimetric coverage of the target volume over 2D treatment techniques (8). With better diagnostic imaging studies and, thus, better definition of the tumor, we may be able to restrict the boost volume and treat the tumor bed with a margin instead of the entire PF. The use of 3D CRT facilitates this type of localization and reduction in target volume and can achieve additional tissue sparing. CONCLUSIONS These data suggest that, when the entire PF is treated, very few failures develop in isolation in the PF outside the tumor bed. Given the similar behavior between the spine and the PF with respect to leptomeningeal failures, it may be logical to treat the leptomeninges of the craniospinal axis to a uniform dose and boost only the tumor bed to the final desired dose. This analysis is the first in a series of studies that will be necessary before it is known if we can “safely” reduce the size and volume of the PF boost field. Because
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the entire PF was treated in all of the patients in this series, we can only know that there is not an excessive number of out-of-tumor-bed relapses under these conditions. Had we found an excessive number of relapses in isolation outside the tumor bed, the implications would obviously be different. Further studies will be necessary to determine if RT to the tumor bed alone will suffice as opposed to a boost to the entire PF. Perhaps such studies could begin using restricted PF fields on infants who potentially suffer most from the use of larger fields. A boost to the tumor bed only using 3D conformal therapy and/or more restricted volumes may minimize ototoxicity and other morbidity associated with full PF irradiation in these patients. REFERENCES 1. Tarbell, N. J.; Loeffler, J. S.; Silver, B.; Lynch, E.; Lavally, B. L.; Kupsky, W. J.; Scott, M.; Sallan, S. E. The change in patterns of relapse in medulloblastoma.Cancer 68:1600 –1604; 1991. 2. Hughes, E. N.; Shillito, J.; Sallan, S. E.; Loeffler, J. S.; Cassady, J. R.; Tarbell, N. J. Medulloblastoma at the Joint Center for Radiation Therapy between 1968 and 1984. The influence of radiation dose on the patterns of failure and survival. Cancer 61:1992–1998; 1988. 3. Merchant, T. E.; Wang, M-H.; Haida, T.; Lindsley, K. L.; Finlay, J.; Dunkel, I. J.; Rosenblum, M. K.; Leibel, S. A. Medulloblastoma: Long term results for patients treated with definitive radiation therapy during the computed tomography era. Int. J. Radiat. Oncol. Biol. Phys. 36:29 –35; 1996. 4. Miralbell, R.; Lomax, A.; Bortfeld, T.; Rouzaud, M.; Carrie, C. Potential role of proton therapy in the treatment of pediatric medulloblastoma/primitive neuroectodermal tumors: reduction of the supratentorial target volume. Int. J. Radiat. Oncol. Biol. Phys. 38:477– 484; 1997. 5. Yao, J. S.; Mehta, M. P.; Boyett, J. M.; Li, H.; Donahue, B.; Rorke, L. B.; Zeltzer. P. M. The effect of M-stage on patterns of failure in posterior fossa primitive neuroectodermal tumors treated on CCG-921: a phase III study in a high risk patient population. Int. J. Radiat. Oncol. Biol. Phys. 38:469 – 476; 1997. 6. Grabenbauer, G. G.; Beck, J. D.; Erhardt, J.; Seegenschmiedt, M. H.; Seyer, H.; Thierauf, P.; Sauer, R. Postoperative radiotherapy of medulloblastoma. Impact of radiation quality on treatment outcome. Am. J. Clin. Oncol. 19(1):73–7; 1996. 7. Miralbell, R.; Bleher, A.; Huguenin, P.; Ries, G.; Kann, R.; Mirimanoff, R. O.; Notter, M.; Nouet, P.; Bieri, S.; Thum, P.; Toussi, H. Pediatric medulloblastoma: radiation treatment technique and patterns of failure. Int. J. Radiat. Oncol. Biol. Phys. 37:523–529; 1997. 8. Michalski, J. M.; Sur, R. K.; Harms, W. B.; Purdy, J.A. Three dimensional conformal radiation therapy in pediatric parameningeal rhabdomyosarcomas. Int. J. Radiat. Oncol. Biol. Phys. 33:985–991; 1995.
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Clinical Investigation PATTERNS OF FAILURE FOLLOWING TREATMENT FOR MEDULLOBLASTOMA: IS IT NECESSARY TO TREAT THE ENTIRE POSTERIOR FOSSA? NINA FUKUNAGA-JOHNSON, M.D.,* JASON H. LEE, M.D.,‡ HOWARD M. SANDLER, M.D.,* PATRICIA ROBERTSON, M.D.,† ELIZABETH MCNEIL, M.D.§ AND JOEL W. GOLDWEIN, M.D.‡
Departments of *Radiation Oncology and †Pediatrics, University of Michigan, Ann Arbor, MI; ‡Department of Radiation Oncology, University of Pennsylvania, Philadelphia, PA; and §Division of Neuro-oncology, Children’s Hospital of Philadelphia, Philadelphia, PA Purpose: Craniospinal radiation (CSRT) followed by a boost to the entire posterior fossa (PF) is standard postoperative therapy for patients with medulloblastoma. A large proportion of recurrences after treatment are local, with approximately 50 –70% of recurrences occurring in the PF. It is unclear, however, whether these failures are occurring in the original tumor bed or outside the tumor bed, but still within the PF. With improved diagnostic imaging, better definition of tumor volumes, and the use of three-dimensional conformal therapy (3D CRT), we may be able to restrict the boost volume to the tumor bed plus a margin without compromising local control. This retrospective study analyzes the patterns of failure within the PF in a series of patients treated with radiation therapy (RT). Methods: From July 1986 through February 1996, 114 patients >18 months and <18 years with medulloblastoma were treated at the University of Michigan and Children’s Hospital of Philadelphia, with RT following surgical resection. Of 114, 27 (24%) were found to have a recurrence and form the basis for this study. RT consisted of CSRT followed by a boost to the entire posterior fossa. Some patients received adjuvant chemotherapy. Patient’s preoperative magnetic resonance imaging (MRI) and/or computerized tomography (CT) studies were used to compare the original tumor volume with the specific region of local relapse. Failure was defined as MRI or CT evidence of recurrence or positive cerebrospinal fluid cytology. Relapse was scored as local, if it was within the original tumor bed, and regional if it was outside of the tumor bed but still within the PF. Results: The median age of the 27 patients who relapsed was 8.6 years. Three patients were <3 years old. Of 27, 21 had disease localized to the PF. Of 26, 22 patients received chemotherapy during their treatment regimen; 1 patient did not have information on systemic treatment. The median dose of RT to the craniospinal axis was 32.5 Gy and to the PF was 55.2 Gy. The median time to recurrence was 19.5 months. Local failure within the tumor bed as any component of first failure occurred in 52% (14 of 27) of all failures, but as the solitary site of first failure in only 2 of 27 failures. Of 14 patients who failed in the tumor bed, 11 also failed in the spine, 8 of 14 also failed within the PF but outside the tumor bed, and 7 of 14 failed in all three locations. Local failure within the PF but outside the tumor bed as any component of first failure occurred in 41% (11 of 27) of all failures, but as the solitary site of first failure in only 1 of 27 failures. Of 11 patients who failed in the PF but outside the tumor bed, 9 also failed in the spine, 8 also failed within the tumor bed, and 7 failed in the all three locations. Of the failures outside the tumor bed but still within the PF, 7 of 11 failed in the leptomeninges, 1 in the brainstem parenchyma, and 3 in the PF parenchyma. Of 7 who failed in the PF leptomeninges, 6 also failed within the spine. Failure within the spine as any component of first failure occurred in 70% (19 of 27) of all failures and as the only site of first failure in 5 of 27 patients. Of 19 patients who failed in the spine, 11 also failed in the tumor bed, 9 also failed within the PF but outside the tumor bed, and 9 failed in the all three locations. Conclusions: Leptomeningeal failure is a common component of failure and occurs in the leptomeninges of the PF, as well as the spine. Isolated tumor bed failure is a rarely observed event and occurred in only 2 of 27 failures described here. Similarly, parenchymal (nonleptomeningeal) failures in the PF but outside of the tumor bed were rare: 4 patients recurred in this manner, only 1 of whom was an isolated event without other sites of recurrence. Our data suggest that, when the entire PF is treated, very few failures develop in isolation in the PF outside the tumor bed. Further studies will be necessary to determine if RT to the tumor bed alone will suffice as opposed to a boost to the entire PF. The former approach, using 3D CRT, may minimize ototoxicity and other morbidity associated with full PF irradiation. © 1998 Elsevier Science Inc. Radiotherapy, Medulloblastoma.
Presented at the 1997 American Society of Therapeutic Radiology and Oncology. Reprint requests to: Nina Fukunaga-Johnson, M.D., Department of Radiation Oncology, Memorial Hospital, 615
N. Michigan St., South Bend, IN 46601. Accepted for publication 28 April 1998. 143
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Table 1. Clinical characteristics at diagnosis of 27 medulloblastoma patients who relapsed Age Gender (M:F) M0 M1–3
8.6 years (mean) (13:14) 21 6
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Table 2. Treatment characteristics of 27 medulloblastoma patients who relapsed
1.83–17 years (range) (48%:52%)
INTRODUCTION Primary central nervous system tumors are the most common solid tumors in children. Medulloblastomas account for approximately 20% of brain tumors in children. The peak age of incidence is 5 years, with most tumors occurring within the first decade of life. Radiation therapy (RT) along with surgical resection and chemotherapy are mainstays of medulloblastoma therapy, and have many associated side effects. Standard RT has been to administer up to 36 Gy to the entire craniospinal axis followed by a boost to the entire posterior fossa (PF) to 55 Gy. The treatment volume and doses of RT have changed little during the past 40 years. The treatment of these brain tumors has always been complicated by the side effects of the therapy. Gains made in diagnosis and treatment are often offset by long-term complications of therapy. In the modern imaging era, with better definition of the tumor, we may be able to restrict the boost volume and treat the tumor bed plus a margin of 1–2 cm. The majority of recurrences after standard treatment for medulloblastoma appear to be local, with approximately 55–70% of recurrences occurring in the PF (1–3). It is unclear, however, whether these PF failures are occurring in the original tumor bed or outside the tumor bed, but still within the PF. The use of three-dimensional conformal radiotherapy (3D CRT) provides the potential to define the target volume and ascertain the spatial relationship between the clinical target volume and neighboring critical healthy structures. Using this spatial information, one may design treatments that avoid unnecessary irradiation of tissues where the risk of relapse is low. In the setting of medulloblastoma therapy, the use of 3D CRT may be useful in sparing critical healthy brain and auditory structures. This work examines the patterns of failure within the PF in medulloblastoma patients treated with RT. MATERIALS AND METHODS Patient characteristics Between July 1986 and February 1996, 114 consecutive patients with medulloblastomas who were .18 months and ,18 years old and were treated at the University of Michigan and Children’s Hospital of Philadelphia, Department of Radiation Oncology, have been reviewed for this study. Of these 114 patients, 27 patients (24%) were found to have a recurrence. These 27 patients form the basis for our analysis, and Table 1 shows the patient characteristics of this group. Median age was 8.6 years (range 1.83–17 years). Three patients were ,3 years old. There were 6 patients
Radiation therapy doses Whole-brain dose Spine dose Posterior fossa boost Primary total dose* Surgical Resection Gross total resection Subtotal resection Unknown Chemotherapy†
Mean Dose, Gy
Dose Range, Gy
Patients
32.9 Gy 34.5 Gy 52.2 Gy 55.2 Gy
18–41.4 Gy 18–45 Gy 36–60 Gy 50–60 Gy
– – – –
– – –
14 12 1 22 of 26
* 6 pts had boost to tumor bed in addition to PF boost. † No information on 1 patient.
with leptomeningeal dissemination (M1-3) at diagnosis. Gross total resection was achieved in 14 patients and subtotal resection in 12 patients; 1 patient did not have information on resection (Table 2). Of 26 patients, 22 received chemotherapy during their treatment regimen; 1 patient did not have information on systemic treatment (Table 2). All patients were seen in follow-up and evaluation with CT and/or MRI of the brain at regular intervals of every 3– 6 months following treatment. There has been up to 10 years of follow-up. The median time to recurrence was 19.5 months (range 5–72 months). Radiotherapy technique All patients underwent initial simulation and, with few exceptions, were placed prone and immobilized using an aquaplast mask or a specialized board. Six patients were planned using 3D CRT. These 6 patients were those treated at the University of Michigan. This was accomplished by obtaining a planning CT imaging scan in the treatment position using 5-mm cuts through the brain. The CT data were entered into a 3D planning system and various structures, including the brain and PF, were outlined on each slice by the physician. The planning target volumes (PTVs) were expanded in 3D to account for patient setup and microscopic tumor uncertainty. The patients who were not planned with 3D-CRT were treated to the PF field that was determined by superimposing the saggital MRI on the simulation field. Custom cerrobend blocks were designed using Beam’s Eye View (BEV) and margins were adjusted to provide full target coverage. All patients were treated to their entire neuroaxis followed by a boost to the entire PF. Six patients had an additional boost to the tumor bed following a PF boost. The craniospinal RT technique was similar for all patients, and the PF boost was delivered via parallel-opposed photon beam, in most cases. One patient was treated using a cochlear-sparing technique using a wedge pair to the PF. Patients were treated using a 6-MV linear accelerator. Treatment was delivered at 1.8 –2.0 Gy daily fractions 5
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Table 4. Sites of failure
Table 3. Patterns of failure Site of first failure
Only site of failure
Any component of failure
Tumor bed PF outside TB Spine Supratentorial Extraneural
2 (7%) 1 (3%) 5 (19%) 2 (7%) 2 (7%)
14 (52%) 11 (41%) 19 (70%) 7 (26%) 3 (11%)
days/week with continuous-course radiotherapy in all patients, except 5 who received hyperfractionated RT (1.00 Gy twice a day). The doses and volumes treated during this study period are given in Table 2. The mean dose of RT to the brain ranged from 18 – 41.4 Gy (mean 32.9 Gy) and to the spine from 18 – 45 Gy (mean 34.5 Gy). Three patients were given low-dose RT (18 Gy) to the craniospinal axis. A boost to the PF was given to all patients for a total dose of 36 – 60 Gy (mean, 52.2Gy). Six patients had an additional boost to the tumor bed following a PF boost for a total dose to the tumor bed of 50 – 60 Gy (mean, 55.2 Gy). Failure analysis Patient preoperative MRI and/or CT studies were used to compare the original tumor volume with the specific region of local relapse. Failure was defined as MRI or CT evidence of recurrence or positive cerebrospinal fluid cytology. Relapse was scored as follows: “PF within the tumor bed,” if failure was within the original tumor bed; “PF but outside the tumor bed,” if failure was outside of the tumor bed but still within the PF treatment field; “supratentorial” if failure was above the tentorium; “spinal” failure if there was MRI or myelogram evidence of disease within the spinal column or if there was positive cerebrospinal fluid (CSF); and “distant” if failure was outside the neuroaxis. RESULTS The median time to recurrence was 19.5 months. Of 27 patients who relapsed, 21 had disease localized to the PF at the time of diagnosis. Tables 3 and 4 demonstrate where these treatments failed as the only site or any component of failure. Any component of failure was documented if a treatment failed in a certain location, regardless of failures elsewhere. Local failure within the tumor bed as any component of failure occurred in 52% (14 of 27) of all failures, but as the solitary site of failure in only 2 of 27 failures (Table 3). Of 14 patients who had failure in the tumor bed, 11 also had failure in the spine, 8 also had failure within the PF but outside the tumor bed, and 7 had failure in the all three locations (Table 4). Local failure within the PF but outside the tumor bed as any component of failure occurred in 41% (11 of 27) of all failures, but as the solitary site of failure in only 1. Of 11 patients who had failure in the PF but outside the tumor bed, 9 also hd failure in the spine, 8 also within the tumor bed, and 7 in the all three locations. Of
Site of failure
Only site of failure
Any component of failure
TB 1 PF outside TB TB 1 spine PF outside TB 1 spine PF outside TB 1 supratentorial Spine 1 supratentorium TB 1 PF outside TB 1 spine
0 2 1 0 1 5
8 11 9 2 5 7
the failures outside the tumor bed, but still within the PF, 7 were in the leptomeninges, 1 in the brainstem parenchyma, and 3 in the PF parenchyma. Of 7 who had failure in the PF leptomeninges, 7 also had failure within the spine. Failure within the spine as any component of failure occurred in 70% (19 of 27) of all failures and as the only site of failure in 5 patients. Of 19 patients who had failure in the spine, 11 also had failure in the tumor bed, 9 also within the PF but outside the tumor bed, and 9 in all three locations. Of the 6 patients who presented with spinal disease, 5 had some component of spinal failure, and 2 only in the spine. Of the 6 patients who had an additional boost to the tumor bed, 1 had failure in the tumor bed only, and 4 had some component of TB failure, 2 had some component of PF failure outside the tumor bed but within the leptomeninges, and 5 had some component of spinal failure. Extent of surgical resection did not appear to have an impact on recurrence pattern (Table 5). DISCUSSION Craniospinal radiation followed by a boost to the entire PF is standard postoperative therapy for patients with medulloblastoma. A large proportion of recurrences after treatment are local, with approximately 55–70% occurring in the PF (1–3). It has been unclear, however, whether these failures are occurring in the original tumor bed or outside the tumor bed, but still within the PF. This study demonstrates that leptomeningeal failure is a common component of failure and occurrs in the leptomeninges of the posterior fossa, as well as the spine, in 74% of all the patients examined in our series. Isolated tumor bed failure was a rarely observed event and occurred in only 2 of 27 failures. Similarly, parenchymal (nonleptomeningeal) failures in the PF but outside of the tumor bed were rare: 4 patients had
Table 5. Percent of resection and recurrence Any component of failure
Gross total resection
Subtotal resection
TB PF outside TB Spine Supratentorial Distant
6 7 11 4 2
5 4 6 4 0
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recurrence in this manner, only 1 of which was an isolated event without other sites of recurrence. One of the largest series published in the CT era has demonstrated that local failure as any component of failure occurred in 55% of patients, but was the only site of first failure in 14% of patients (3). However, the definition of local failure was “posterior fossa” and was not broken down between PF within tumor bed or PF outside the tumor bed. One recent study from Switzerland investigated the possibility of treating the tumor bed only in patients with supratentorial primitive neuroectodermal tumors (4). This dosimetric study was undertaken to demonstrate that confining the treatment to the tumor bed only significantly decreased irradiation to healthy brain. Our study also demonstrates a similar behavior of the spine and the PF with respect to leptomeningeal failures. A recent report from the CCG confirms that, although the original site of disease is at high risk for relapse, the entire neuroaxis remains at significant risk and a more aggressive approach to local control in the neuroaxis is warranted (5). Although randomized trials comparing 3D CRT to conventional radiation therapy have not been performed, it appears that treatment technique may be an important factor in achieving local control for medulloblastoma (6, 7). When whole-brain irradiation margins were judged to miss the inferior portion of the frontal and temporal lobes, an increase in supratentorial failure was observed (7). The use of 3D CRT inpatients with parameningeal rhabodmyosarcoma of the head and neck has demonstrated an improvement in dosimetric coverage of the target volume over 2D treatment techniques (8). With better diagnostic imaging studies and, thus, better definition of the tumor, we may be able to restrict the boost volume and treat the tumor bed with a margin instead of the entire PF. The use of 3D CRT facilitates this type of localization and reduction in target volume and can achieve additional tissue sparing. CONCLUSIONS These data suggest that, when the entire PF is treated, very few failures develop in isolation in the PF outside the tumor bed. Given the similar behavior between the spine and the PF with respect to leptomeningeal failures, it may be logical to treat the leptomeninges of the craniospinal axis to a uniform dose and boost only the tumor bed to the final desired dose. This analysis is the first in a series of studies that will be necessary before it is known if we can “safely” reduce the size and volume of the PF boost field. Because
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the entire PF was treated in all of the patients in this series, we can only know that there is not an excessive number of out-of-tumor-bed relapses under these conditions. Had we found an excessive number of relapses in isolation outside the tumor bed, the implications would obviously be different. Further studies will be necessary to determine if RT to the tumor bed alone will suffice as opposed to a boost to the entire PF. Perhaps such studies could begin using restricted PF fields on infants who potentially suffer most from the use of larger fields. A boost to the tumor bed only using 3D conformal therapy and/or more restricted volumes may minimize ototoxicity and other morbidity associated with full PF irradiation in these patients. REFERENCES 1. Tarbell, N. J.; Loeffler, J. S.; Silver, B.; Lynch, E.; Lavally, B. L.; Kupsky, W. J.; Scott, M.; Sallan, S. E. The change in patterns of relapse in medulloblastoma.Cancer 68:1600 –1604; 1991. 2. Hughes, E. N.; Shillito, J.; Sallan, S. E.; Loeffler, J. S.; Cassady, J. R.; Tarbell, N. J. Medulloblastoma at the Joint Center for Radiation Therapy between 1968 and 1984. The influence of radiation dose on the patterns of failure and survival. Cancer 61:1992–1998; 1988. 3. Merchant, T. E.; Wang, M-H.; Haida, T.; Lindsley, K. L.; Finlay, J.; Dunkel, I. J.; Rosenblum, M. K.; Leibel, S. A. Medulloblastoma: Long term results for patients treated with definitive radiation therapy during the computed tomography era. Int. J. Radiat. Oncol. Biol. Phys. 36:29 –35; 1996. 4. Miralbell, R.; Lomax, A.; Bortfeld, T.; Rouzaud, M.; Carrie, C. Potential role of proton therapy in the treatment of pediatric medulloblastoma/primitive neuroectodermal tumors: reduction of the supratentorial target volume. Int. J. Radiat. Oncol. Biol. Phys. 38:477– 484; 1997. 5. Yao, J. S.; Mehta, M. P.; Boyett, J. M.; Li, H.; Donahue, B.; Rorke, L. B.; Zeltzer. P. M. The effect of M-stage on patterns of failure in posterior fossa primitive neuroectodermal tumors treated on CCG-921: a phase III study in a high risk patient population. Int. J. Radiat. Oncol. Biol. Phys. 38:469 – 476; 1997. 6. Grabenbauer, G. G.; Beck, J. D.; Erhardt, J.; Seegenschmiedt, M. H.; Seyer, H.; Thierauf, P.; Sauer, R. Postoperative radiotherapy of medulloblastoma. Impact of radiation quality on treatment outcome. Am. J. Clin. Oncol. 19(1):73–7; 1996. 7. Miralbell, R.; Bleher, A.; Huguenin, P.; Ries, G.; Kann, R.; Mirimanoff, R. O.; Notter, M.; Nouet, P.; Bieri, S.; Thum, P.; Toussi, H. Pediatric medulloblastoma: radiation treatment technique and patterns of failure. Int. J. Radiat. Oncol. Biol. Phys. 37:523–529; 1997. 8. Michalski, J. M.; Sur, R. K.; Harms, W. B.; Purdy, J.A. Three dimensional conformal radiation therapy in pediatric parameningeal rhabdomyosarcomas. Int. J. Radiat. Oncol. Biol. Phys. 33:985–991; 1995.