J Neurosurg 74:720-728, 1991
Postoperative radiotherapy in the management of spinal cord ependymoma STEPHEN J. WH1TAKER,M.R.C.P., F.R.C.R., E m c M. BESSELL~PH.D., M.R.C.P.F.R.C.R., SuE E. ASHLEY,PH.D., H. J. G. BLOOM,M.D., F.R.C.P., F.R.C.R., F.A.C.R., B. ANTHONY BELL, M.D., F.R.C.S., AND MICHAEL BRADA, M.R.C.P.F.R.C.R.
Academic Unit qf Radiotherapy and Oncolvgy and Computing Department, Royal Marsden Ho,spitat, Sutton, and Department of Neurosurgery, Atkinson Morley~ Hospital, Wimbledon, England v- Fifty-eight patients with histologically verified spinal cord ependymomas were treated at the Royal Marsden Hospital and Atkinson Morley's Hospital between 1950 and 1987. The median age in this series was 40 years (range I to 79 years) and the male:female ratio was 1.8:1. Ten patients had tumors in the cervical cord and 10 in the thoracic cord; 14 tumors involved the COMUSmedullaris and 24 the cauda equina. Forty ependymomas were grade 1 and 13 were grades II to IV (in five patients there was insufficient material for grading). Eleven patients underwent biopsy only, 33 had partial or subtotal resection, and 14 had complete resection. Fortythree patients received postoperative radiotherapy. The median follow-up period was 70 months (range 3 to 408 months). Cause-specific survival rates were 74% and 68% at 5 and 10 years, respectively. On univariate analysis, age, histological grade, postoperative neurological function, and era of treatment were significant prognostic factors for survival. The histological grade was the only significant independent prognostic factor. The relative risk of death from ependymoma was 9.0 for patients wilh tumor grades II to IV compared to grade I (p < 0.005, 95% confidence interval 2.7 to 30). The survival rates of patients following complete excision were significantly better compared to those after incomplete surgery (p < 0.025). The majority of completely resected neoplasms were low-grade cauda equina tumors. Despite incomplete surgery, 5- and 10-year progression-free survival rates following radical radiotherapy were both 59%, and cause-specific survival rates were 69% at 5 years and 62% at 10 years. This suggests that radiotherapy may achieve long-term tumor control in over half of those patients with residual spinal ependymoma.
KEY WORDS
spinal tumor
PINAL cord ependymomas comprise less than 2% of all central nervous system (CNS) neoplasms but represent 15% of spinal cord tumors and up to 60% of spinal cord gliomas. ~.~7 Management of these tumors evolved empirically and optimal therapy is based on retrospective analyses of survival, patterns of relapse, and treatment morbidity. Conventional treatment of patients with suspected spinal cord ependymoma includes surgery to obtain a histological diagnosis and to resect tumor where this is possible. The degree of resectability varies from biopsy alone, through partial or subtotal resection, to complete excision. It has been estimated that no more than 60% of patients have complete resection. "~Although modern microsurgical techniques have increased the resection rate, this is often at the cost of increased morbidity; ~-~ thus, a substantial proportion of patients have residual tumor which may be controlled with postoperative radiation therapy.
S
720
ependymoma
radiation therapy
prognostic factor
The extent of surgical resection and the role of postoperative radiation therapy are controversial topics. Some centers advocate minimal surgery and radical irradiation,~3.24 while many neurosurgeons report excellent results with radical excision alone. 4.~'.'~ We report our study of a large series of patients with spinal cord ependymoma treated by surgery either alone or with postoperative radiation therapy, and we attempt to define optimum treatment strategies for this rare tumor.
Clinical Material and Methods Patient Population Between 1950 and 1987, 74 patients with histologically verified spinal cord ependymoma were seen at the Royal Marsden Hospital and Atkinson Morley's Hospital. Sixteen patients were excluded: eight had recurrent disease after previous treatment elsewhere, and eight with primary disease received postoperative radi-
J. Neurosurg. / Volume 74~May, 1991
Postoperative radiotherapy for spinal cord ependymoma TABLE 1 Pretreatmenr characterAlics 0(58 patients with .v~inal cord
el)en(t|'l~lol~7o Treatment Group Characteristic
Total Cases
Surgery& RT*
Surgery
43 30:13 4I 1-65
15 7:8 37 13-79
58 37:21 40.5 1-79
28 6 3 I 5
12 1 2 0 0
40 7 5 1 5
11 30 2
0 3 12
11 33 14
no. of cases sex (M:F) median age (yrs) age range (yrs) histologicalgrade I
11 Ill IV ungraded extent of surgery biopsy partial/subtotal total resection * RT = radiation therapy.
ation therapy at other centers. Fifty-eight patients were treated entirely at one or both hospitals and form the basis of this report. Fifteen patients underwent surgery alone, and 43 received postoperative radiation therapy, reflecting a consistent policy of referral of most patients with residual disease for irradiation, Patients' age, sex, extent of surgery, and tumor histological grade are shown by treatment group in Table 1 and Fig. 1. The male:female ratio for the whole group was 1.8:1. All patients underwent preoperative myelography with cytological examination of the cerebrospinal fluid (CSF). A further six patients had computerized tomography (CT) myelography; magnetic resonance (MR) imaging was carried out in one patient. The diagnosis was confirmed by histological study in all cases and in 53 patients the tumor was graded according to the classification of Mabon, et at.'5 (Table 1). In five patients insufficient material was obtained for grading. The distribution of patients by tumor site is shown in Fig. 2. Thirty-eight (66%) of the 58 ependymomas involved the conus medullaris or cauda equina. The majority of the cervical and thoracic cord tumors extended over three to five spinal segments. Two cervical ependymomas involved the whole of the cervical cord and one thoracic ependymoma affected the entire thoracic cord. Two cauda equina tumors also extended over more than one region with destruction of the sacrum in one patient and the L-5 vertebra in the other. In 50 patients in whom adequate records were available (10 with surgery alone and 40 with postoperative irradiation), an assessment of neurological performance status was made retrospectively by recording the limb power and mobility at presentation, immediately after surgery, and more than 3 months after completion of all treatment. A change in power or mobility on subsequent follow-up examination was also noted.
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FIG. 1. Age distribution of patients by treatment group. S = surgery alone (15 patients); S/RT = surgery and postoperative irradiation (43 patients). Median age for the group with surgery alone was 37 years (range 13 to 79 years) and for the postoperation irradiation group was 41 years (range I to 65 years).
Fl(~. 2. Distribution of tumors by site and treatment group. S = surgery alone, S/RT = surgery and postoperative irradiation. The majority of tumors were extramedullary at the conus medullaris or cauda equina sites. Twenty percent of patients treated surgically alone had entirely intramedullary tumors compared to 40% of those having postoperative irradiation (difference not statistically significant).
Surgery Patients underwent laminectomy and posterior myelotomy, with tumor removal by blunt dissection under the operating microscope and, since the 1970's, by aspiration with the Cavitron ultrasonic surgical aspirator.* Where a plane of cleavage could not be defined, * Ultrasonic surgical aspirator manufactured by Cavitron Surgical Systems, Inc., Stamford, Connecticut. 721
S. J. Whitaker, et aL subtotal excision or biopsy was performed. The extent of surgery was defined as total, subtotal (including all degrees of partial resection), or biopsy only, as judged by the neurosurgeon at the time of operation. The dura was usually closed at the end of the procedure, occasionally requiting a fascial graft. Total resection was achieved in 14 patients (12 with surgery alone and two with postoperative irradiation). Ten (42%) of 24 patients with cauda equina tumors and two (14%) of 14 patients with ependymoma in the conus medullaris underwent complete resection. None of the patients with intramedullary tumors at other sites had complete tumor excision. Thirty-three patients had subtotal or partial resection and 30 of these underwent postoperative radiation therapy. All 11 patients treated with biopsy only were irradiated. Twelve (80%) of 15 patients treated by surgery alone had grade I tumors confined to the conus and cauda equina.
ependymoma of the conus medullaris and cauda equina were treated by a direct, spade-shaped field from T-6 to S-4 and T-12 to S-4, respectively, to a maximum dose of 40 Gy in 28 fractions over 589 weeks, with boosts of 10 Gy in seven fractions or 15 Gy in 11 fractions. The tumor site thus received a total dose of 50 Gy in 35 fractions for conus medullaris tumors and 55 Gy in 39 fractions for cauda equina tumors.
Chemotherapy Four patients received initial and/or adjuvant chemotherapy. The rationale was to improve local control and reduce the risk of seeding? Chemotherapy comprised vincristine, 1.0 mg/sq m weekly during radiotherapy; three patients also received maintenance chemotherapy with vincristine, 1.4 mg/sq m weekly for 3 weeks and a single 100-mg/sq m dose of 1-(2-chloroethyl)-3-cyclohexyl-l-nitrosourea (CCNU) orally, with this regimen repeated every 6 weeks for 1 year. Five patients received similar schedules of chemotherapy for recurrent disease, usually after reoperation.
Radiation Therapy Thirty-nine patients received megavoltage irradiation (4 to 8 MeV on a linear accelerator or telecobalt), while four patients were treated with orthovoltage radiation therapy for at least part of their course. Eighteen patients, most with high-grade or extensive tumors, received radiation therapy to the entire CNS. They were treated prone with head immobilization and the whole neuraxis was irradiated to a minimum dose of 30 Gy in 20 to 25 fractions over 4 to 5 weeks (Fig. 3). A tumor boost of 20 Gy in 10 to 15 fractions over 2 to 3 weeks was given with margins of two to four spinal segments. The tumor thus received a minimum dose of 50 Gy in 35 fractions over 7 weeks. The minimum dose was prescribed to the mean spinal cord depth; recently, individualized spinal compensators have been used to reduce dose inhomogeneity. Twenty-five patients underwent spinal irradiation alone. Whole-spine radiation therapy was given to six patients with cervical or thoracic tumors. Patients with
Follow- Up Monitoring The median follow-up period was 70 months (range 3 to 408 months), with a median of 31 months for patients treated with surgery alone and 71 months for the group with postoperative irradiation. Patients were followed by regular clinical examination with radiological investigation when indicated. Due to the often long natural history of ependymomas and the frequency of neurological deficits after initial therapy, it is difficult to determine the complete eradication of the disease. We have therefore recorded "progression of disease" as indicated by deterioration of previously stable neurological signs or symptoms. Progressive disease was confirmed radiologically in all cases and surgically in three.
FIG. 3. Extent of irradiation and dose as used for various primary sites in this series.
FIG. 4. Actuarial cause-specific survival rates of all 58 patients with spinal ependymoma. Forty-three patients were alive at 5 years and 39 at 10 years postsurgery.
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P o s t o p e r a t i v e r a d i o t h e r a p y for spinal c o r d e p e n d y m o m a This rigorous investigation eliminated deterioration due to late sequelae of surgery or radiotherapy. Survival figures were assessed as "cause-specific" which took into account treatment-related deaths and deaths from the complications of chronic paraplegia (even if postmortem examination failed to reveal residual or recurrenl tumor).
Statistical Analysis Actuarial progression-free and cause-specific survival rates were calculated by the life-table method of Kaplan and Meier and the difference was analyzed by log-rank test. -~~ The independent effect of prognostic variables was tested by the Cox multivariate procedure. ~ The influence of treatment was tested by its inclusion in the proportional-hazard model after correction for all the other prognostic variables. Results
Survival Rales The overall survival rates in the 58 patients with spinal cord ependymoma were 68% and 62% at 5 and I0 years, respectively. The majority of deaths were directly or indirectly due to tumor with cause-specific 5- and 10-year survival rates of 74% and 68%, respectively (Fig. 4). There were three intercurrent deaths: one patient died postoperatively from a myocardial infarction and two patients who received radiation therapy died after 4 years, one from myocardial infarction and one from a subdural hemorrhage.
Local Control The disease progressed immediately after treatment in five patients and after apparent disease control at a median time to progression of 12 months (range 7
FI(;. 5. Actuarial cause-specific survival rates by age at diagnosis comparing those under 40 years versus those of 40 years or older. The number of patients alive at 0, 5, and 10 years was 29, 26, and 26 for those aged under 40 years, and 29, 17. and 13 for those aged 40 years or older (p < 0.005).
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to 44 months) in another eight. The progression-free survival rates were 74% and 68% at 5 and 10 years, respectively, which is identical to the cause-specific survival rate, indicating little salvage of patients with progressive disease.
Prognostic Variables and Univariate Analysis Univariate analysis was performed for patients prior to treatment and for tumor-related prognostic variables. The results were similar for both cause-specific and overall survival. The risk of tumor progression or death from ependymoma was significantly higher for older patients (_> 40 years vs. < 40 years; Fig. 5, p < 0.005), high-grade tumors (grade I vs. grades II to IV; Fig. 6, p < 0.005), patients with poor neurological function after treatment (p < 0.05), and patients treated less recently (pre-1970 vs. 1970 and later, p < 0.01, data not shown). There was a statistically significant trend for improved progression-free survival times (but not for cause-specific survival times) and for cauda equina tumors versus other tumor sites (p < 0.05). Gender and age (adults vs. children) were not significant prognostic variables for tumor control or survival. Patients treated by surgery alone compared to those receiving postoperative radiation therapy were younger (median age 37 vs. 41 years, Table 1) and had more grade I tumors (80% vs. 65%) and a higher rate of complete resection (67% vs. 5%). The rate of complete resection was the only difference reaching statistical significance (p < 0.05).
Mulliva riale Analysis A multivariate analysis using a step-up proportionalhazard model was performed to investigate the effect
Fl(;. 6. Actuarial cause-specific survival rates by histological grade (grade I vs. grade II vs. grades III/IV). Ungraded patients were excluded but the survival curve for them was similar to that of grade I. The number of patients alive at 0, 5, and 10 years was 40, 34. and 34 for grade I: 7,4, and 1 for grade It; and 5, 2, and 2 for grades Ill/IV (p < 0.005). 723
S. J. Whitaker, et al. of prognostic variables (identified on univariate analysis) on rates of survival and freedom from tumor progression. Histological grade was the major statistically significant independent variable, with a relative risk of ependymoma progression of 9.8 (95% confidence interval 3.3 to 30) and of death from ependymoma of 9.0 (95% confidence interval 2.7 to 30) for patients with tumor grades tt to IV. After stratification by histological grade (grade I vs. grades !I to IV with ungraded tumors excluded), no other prognostic variable remained statistically significant. However, the small number of "events" (progression or death) may have obscured any real differences. Age was an independent variable when all patients were included in the model. There was a relative risk of death from ependymoma of 5.7 for older patients (_> 40 years) compared to younger patients (< 40 years). However, age and histological grade were highly correlated and, when five patients with ungraded tumors were excluded from the model, age was no longer a significant independent factor. [n addition, stratification by age revealed a significant survival difference by grade only in older patients (_> 40 years, Fig. 7); however, only three of 28 patients less than 40 years of age had grade It to IV tumors compared to 10 of 25 patients aged 40 years or older.
patients who received postoperative radiation therapy were 69% and 63% at 5 and 10 years, respectively, and 92% at both 5 and 10 years for those treated by surgery alone (Fig. 9). This difference was not statistically significant (95% confidence intervals at 10 years; 45% to 77% for the postoperatively irradiated group vs. 57% to 99% for the group with surgery alone). The progression-free survival rates were 59% and 54% at 5 and 10 years, respectively, for the postoperative radiation therapy group and 92% for the group with surgery alone. This difference also failed to reach statistical significance. The dose and extent o f radiation therapy and the use of chemotherapy did not affect tumor control 'or patient survival (p = not significant). The patients receiving adjuvant chemotherapy had a 5-year cause-specific survival rate of 67% compared to 70% for those not receiving chemotherapy (p = not significant). Vincristine and CCNU were used as salvage treatment in five of eight patients whose disease progressed and only one patient showed an objective response with stabilization of neurological signs for 489 years. Three other patients with progression at the primary site received vincristine and CCNU and lived 10, 11, and 24 months with subjective improvement in pain.
Influence Off Therapy
Of the eight patients in the postoperative radiation therapy group whose disease progressed or recurred after initial control, six had tumorgrowth at the primary, site within the high-dose radiotherapy field; in the other two, tumor recurred first at an intracranial site. The six patients with relapse at the primary site alone underwent further surgery (four cases) and/or chemotherapy
There was a statistically significant trend for improved periods of survival and progression-free survival for patients treated with more complete surgery (p < 0.025, Fig. 8). The cause-specific survival rates for
FIG. 7. Actuarial cause-specific survival rates by age and histological grade. The number of" patients alive at 0, 5, and 10 years was 25, 22, and 22 for tumor grade I patients under 40 years of age; 3, 3, and 3 for tumor grade II to IV patients aged under 40 years of age; 15, 12, and 12 for tumor grade l patients aged 40 years or over: and 10, 3, and 1 for tumor grade II to IV patients aged 40 years or over (p < 0.005). Five ungraded patients were excluded. 724
Sites of Progression and Inlracranial Tumors
FIG. 8. Actuarial cause-specific survival rates by extent of surgery. The number of patients alive at 0, 5, and 10 years was 14, 14, and 14 for those with total resection; 11, 10, and 8 for those with subtotal resection; 22, 12, and 12 for those with partial resection; and 1 l, 7, and 5 for those with biopsy only (p < 0.01).
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P o s t o p e r a t i v e r a d i o t h e r a p y for spinal c o r d e p e n d y m o m a (five cases); despite this, all six died at a median of 5 months (range 1 to 54 months) after the diagnosis of progression. Of the two patients whose tumor first recurred at an intracranial site, both suffered subsequent progression in the spine 6 and 28 months later. One patient died despite further efforts at salvage with radiotherapy and chemotherapy; the other was successfully treated with resection and radical radiation therapy, and remains well and progression-free 30 years later. One additional patient whose disease progressed first at the primary site developed an intracranial ependymoma 6 months later which was unsuccessfully treated by surgery and radiation therapy. None of the patients with intracranial relapse showed initial positive CSF cytology. Neither of the two patients with initially positive CSF cytology had evidence of spinal seeding. Neurological Function Of 50 evaluable patients, 36 (72%) had impaired mobility at presentation but none was paraplegic. The degree of neurological function was similar in both groups of patients. Following surgery and irradiation, 30% of patients improved and 60% remained with stable symptoms and signs. All patients with deteriorating signs had progressive disease. The addition of postoperative radiation therapy was not associated with late neurological deterioration as there were no cases of radiation myelopathy.
Discussion McCormick, et al., w have recently expressed reservations about studies reporting improved control with postoperative radiation therapy which include small
FIG. 9. Actuarial cause-specificsurvival rates by treatment group. The number of patients alive at 0, 5, and 10 years was 15, 14, and 14 for those with surgery alone, and 43, 29, and 25 for those with surgery and postoperative irradiation (p > 0.1, not significant). J. Neurosurg. / Volume 74/May, 1991
series with limited follow-up periods, have inadequate control groups of unirradiated patients, and lack discussion of the role of surgery. Our study has tried to avoid these deficiencies. We have identified important prognostic factors and have attempted to assess the value of postoperative radiotherapy in the management of patients with spinal cord ependymomas. Of necessity this has been retrospective and covered an era which has seen improvements in diagnosis, surgery, and radiotherapy. Prognostic Variables The actuarial survival rates of all 58 patients were 68% at 5 years and 62% at 10 years, and cause-specific survival rates were 74% at 5 years and 68% at 10 years. A review of the literature (Table 2), has revealed survival rates from different centers which vary from 25% at 5 years in children 2~ to I00% for patients with completely resected low-grade cauda equina tumors. T M ~9,3J Many of these series include small numbers of highly selected patients or exclusion of postoperative deaths j2 or of patients having tumor biopsy only. ~8 Others have considered disease progression within 2 months of surgery as surgical failure24 A variety of prognostic factors have been identified on univariate analyses. These include the extent of resection,2L'~3' tumor site, ~~.~2.~7.~ age,2~.24 histological subtype or grade, 6''s duration of symptoms, ~2and neurological performance status. 9 We have identified age, histological grade, neurological performance status after treatment, and era of treatment as statistically significant variables for cause-specific and progression-free survival on univariate analysis. Complete surgical excision and a cauda equina tumor site were also associated with improved survival times. On multivariate analysis, only histological grade remained an independent prognostic factor. Extent of Surgery We have demonstrated excellent tumor control and patient survival with low morbidity following complete resection of low-grade cauda equina tumors, as reported by other a u t h o r s . 6A~ McCormick, et a/., 17 described excellent long-term control and a low morbidity rate in a consecutive series of 23 patients overa 12-year period. All patients had complete resection, despite six presenting with recurrent tumor after previous surgery and radiation therapy. The authors stressed that every attempt should be made to completely resect benign ependymomas. Cooper and Epstein4 reported on 14 patients with intramedullary ependymomas recurring within 32 months of initial surgery with or without irradiation. They achieved what they considered "99-100% resections" in 12 of these and subtotal resection in the remaining two patients. Unfortunately, the long-term survival and tumor control results were not reported. In our experience, the chance of tumor control and
725
S. J. W h i t a k e r , et al. long-term survival in patients with recurrent tumors is poor, and extensive salvage procedures may be effective only in patients with low-grade tumors. However, with improved microsurgical techniques and earlier diagnosis through CT and MR imaging, more tumors may be amenable to complete resection in skilled hands. Radiation Therapy The value of postoperative irradiation in local control is debated in the literature. Many authors have reported a benefit for patients with residual tumor, 2~~ .~2 while others have documented excellent survival after surgery alone.4.6.~o.~,~7 In this series, the actuarial progressionfree survival rates at 10 years were 92% and 63% for patients treated by surgery alone and those receiving postoperative irradiation, respectively. The two groups differed in the distribution of a number of prognostic factors, particularly in the extent of surgery, and the difference in survival even though not statistically significant is most likely due to this unequal distribution. Patients with residual tumor who received postoperative irradiation had an actuarial progression-free survival rate of 59% at 10 years (Fig. 8). While this may reflect the long natural history of the disease, it can be seen that the survival curves in Fig. 8 tend to plateau,
thus indicating that a significant proportion of patients achieved long-term control. Therefore, an advantage for postoperative radiation therapy in patients with residual tumor is suggested. In the present series, the addition of postoperative radiation therapy was not associated with deterioration of neurological performance status, either at completion of treatment or long term. Indeed, in many patients, function improved after irradiation. This may relate as much to continued rehabilitation and improvement in strength after surgery as to the antitumor effect of irradiation in those with residual macroscopic tumor postoperatively. The optimal dose of irradiation is a matter of controversy. The majority of authors recommend doses of 40 to 50 G y . 9'13"z9'24'~5 Marks and Adler ~6 commented that 40 Gy was adequate as they found a very low rate of local recurrence in low-grade totally resected myxopapillary tumors " . . . irrespective of the dose given." An alternative interpretation of the data is that these patients do not require irradiation. We found no statistically significant difference in freedom from progression for any dose between 40 and 50 Gy; however, the majority of patients received 50 Gy to the tumor site. This dose reflected the policy of the Royal Marsden Hospital based on the maximum dose which the cord
TABLE 2 Review o f 377 patients reported with .spinal cord ependymoma giving 5- and lO-year survival figures* Period of Study
Patient Ages (yrs)
1960-1963 1953-1974 1967-1977 1976-1988 1950-1987
all ages all ages all ages 19-70 all ages
intramed all sites intramed (all tot res) intramed all sites
1941-1957
20-65
Salazar, el al., 1975 Mork & L0ken, 1977 Koloelson, et al., 1980 Guidetti, et al., 1981
1960-1971 1953-1974 1962-1979 1951-1978
all all all all
Marks & Adler, 1982
1954-1976
all ages
Pesehel, et al., 1983 Garrett & Simpson, 1983 Read, 1984
1965-1981 1958-1980 1956-1980
Ilgren, et al., 1984 Sonneland, et al., 1985 Garcia, 1985
1938-1982 1924-1983
> 18 all ages > 16 < 16 all ages all ages all ages
Shaw, et al., 1986 Linstadt, et al., 1989
1963-1983 1957-1986
> 16 all ages
Whitaker, et al., 1991
1950-1987
all ages
cauda equina (extramed) all sites intramed cauda equina all sites all sites all sites intramed cauda equina intramed cauda equina all sites all sites all sites all sites all sites cauda equina intramed cauda equina all sites all localized all diffuse sites all sites
Authors & Year surgery alone Greenwood, 1963 Mork & Lcken, 1977 Fischer & Mansuy, 1980 McCormick, et al., 1990 Whitaker, et al., 1 9 9 1 surgery & radiation therapy Ayres, 1958 Slooff, et al., 1964
ages ages ages ages
Spinal Site
Survival Rate (%)
No. of Cases
5-Year
10-Year
9 34 16 23 15
89 97 86 100 92
-74 --92
18 169
19 16 12 34 10 7 8 9 41 22 4 42 77 8 10 22 18 3 43
88 88 mean survival (yrs): 17 (tot res) 10.5 (subtot res) 14 (lot res) 5 (subtot res) 70 50 82 75 100 73 97 81 100 100 57 57 83 83 100 -83 -70 70 25 25 65 60 100 100 60 -100 -95 95 93 93 50 -74 68
* Intramed = intramedullary; extramed = extramedullary; tot res = total resection; and subtot res = subtotal and partial resection.
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Postoperative radiotherapy for spinal cord ependymoma can safely tolerate; -'~ failure to demonstrate a doseresponse for a control group may simply reflect the small number of patients receiving lower doses. The extent of the CNS which should be irradiated is also debatable. Craniospinal irradiation is considered by some authors to be of value in patients with highgrade intracranial ependymomas, s2~ but its role in spinal cord ependymomas is not established. The most common location of progression is at the primary site; in our series, of three patients with intracranial relapse, two had received whole-CNS irradiation and both later had disease progression in the spine. There is therefore little evidence that the addition of cranial irradiation, particularly in well-resected low-grade tumors, has a survival or tumor control advantage. A review of 259 patients from 14 publications revealed a 5.8% incidence of intracraniai relapse (Table 3) which is similar to our findings. Garrett and Simpson ~ found no statistically significant survival advantage for a larger irradiated CNS volume and recommended localized radiation therapy up to 50 Gy except for high-grade lesions with a definite risk of the spinal ependymoma being a seedling from an occult infratentorial primary tumor. Chemotherapy
The number of patients receiving adjuvant chemotherapy with vincristine and CCNU was too small to demonstrate any benefit for either progression-free or cause-specific survival. When these drugs were used in patients with local progression of tumor, some patients showed symptomatic improvement (reduced local pain) but only one had a sustained objective response. Reoperation followed by chemotherapy and re-irradiation did not halt the progression of tumor at a previously
TABLE 3 Incidence of intracranial relapse in patients with primary spinal ependymoma Authors & Year Sagerman, el al., 1965 Fokes & Earle, 1969 Scott, 1974 Salazar, et al., 1975 Shuman, et al., 1975 Schwade, el al., 1978 Fischer& Mansuy, 1980 Kopelson, et al., 1980 Marks & Adler, 1982 Garrett & Simpson, 1983 Read, 1984 Shaw, et al., 1986 Linstadt, et al., 1989 diffuse disease localizeddisease Whitaker, et al., 1991 total cases
No. of Intracranial Relapses 1 2 0 0 0 0 1 1 1 3 I 1 1 0 3 15
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Total Cases 3 4 3 19 7 12 16 12 15 41 26 22 3 18 58 259
irradiated site. This concurs with reported experience, although Kopelson, et al.,13 described successful salvage in one patient with a recurrence at 3 months postoperatively who was treated with radiotherapy and chemotherapy, and tumor control for 11 years in a further patient with tumor progression. Conclusions The survival rate of patients with totally resected low-grade ependymomas is excellent. Postoperative radiation therapy in patients with incompletely resected tumors is associated with good long-term survival times without late radiation damage to the spinal cord with doses of 45 to 55 G y in fractions of 1.2 to 1.5 Gy. Although the exact role for radiation therapy remains undefined, the low morbidity and long-term survival rates in patients with residual tumor suggest its value for these patients. Acknowledgments We are grateful for the cooperation from our neurosurgical colleagues at Atkinson Morley's Hospital and The National Hospital for Nervous Diseases who have referred patients for further treatment. We gratefully acknowledge the help of the medical records departments of both hospitals and Miss Lindsay Pegus of the Medical Art Department, Royal Marsden Hospital. References 1. Ayres WW: Ependymoma of the cauda equina. A report of the clinicopathologic aspects and follow-up studies of 18 cases. Milit Med 122:10-35, 1958 2. Barone BM, Elvidge AR: Ependymomas. A clinical survey. J Neurosurg 33:428-438, 1970 3. Bloom HJG: Intracranial tumors: response and resistance to therapeutic endeavors, 1970-1980. Int J Radiat Oncol Biol Phys 8:1083-1113, 1982 4. Cooper PR, Epstein F: Radical resection of intramedullary spinal cord tumors in adults. Recent experience in 29 patients. J Neurosurg 63:492-499, 1985 5. Cox DR: Regression models and life tables (with discussion). J R Stat Soc (B) 34:187-220, 1972 6. Fischer G, Mansuy L: Total removal of intramedullary ependymomas: follow-up study of 16 cases. Surg Neurol 14:243-249, 1980 7. Fokes EC Jr, Earle KM: Ependymomas: clinical and pathological aspects. J Neurosurg 30:585-594, 1969 8. Garcia DM: Primary spinal cord tumors treated with surgery and postoperative irradiation. Int J Radiat Oncol Biol Phys ll:1133-1139, 1985 9. Garrett PG, Simpson WJK: Ependymomas: results of radiation treatment. Int J Radiat Oncol Biol Phys 9: 1121-1124, 1983 10. Greenwood J Jr: lntramedullary tumors of the spinal cord. A follow-up study after total surgical removal. J Neurosurg 20:665-668, 1963 11. Guidetti B, Mercuri S, Vagnozzi R: Long-term results of the surgical treatment of 129 intramedullary spinal gliomas. J Neurosurg 54:323-330, 1981 12. llgren EM, Stiller CA, Hughes JT, et al: Ependymomas: a clinical and pathologic study. Part 11- - survival features. Clin Neuropathol 3:122-127, 1984 727
S. J. Whitaker, et al. 13. Kopelson G, Linggood RM, Kleinman GM, et al: Management of intramedallary spinal cord tumors. Radiology 135:473-479, 1980 14. Linstadt DE, Wara WM, Leibel SA, et al: Postoperative radiotherapy of spinal cord tumors. Int J Radiat Oneol Biol Phys 16:1397-1403, 1989 15. Mabon RF, Svien HJ, Kernohan JW, et al: Ependymomas. Proc Staff Meet Mayo Clin 24:65-71, 1949 16. Marks JE, Adler SJ: A comparative study of ependymomas by site of origin, lnt J Radiat Oneol Biol Phys 8: 73-83, 1982 17. McCormick PC, Torres R, Post KD, et al: lntramedullary ependymoma of the spinal cord. J Neurosurg 72: 523-532, 1990 18. M0rk SJ, LOken AC: Ependymoma. A follow-up study of 101 cases. Cancer 40:907-915, 1977 19. Peschel RE, Kapp DS, Cardinale F, et al: Ependymomas of the spinal cord. Int J Radiat Oncol Biol Phys 9: 1093-1096, 1983 20. Peto R, Pike MC, Armitage P, et al: Design and analysis of randomised clinical trials requiring prolonged observation of each patient. 2: Analysis and examples. Br J Cancer 35:1-39, 1977 21. Read G: The treatment of ependymoma of the brain or spinal canal with radiotherapy: a report of 79 cases. Clin Radiol 35:163-166, 1984 22. Sagerman RH, Bagshaw MA, Hanbery J: Considerations in the treatment of ependymoma. Radiology 84: 401-408, 1965 23. Salazar OM: A better understanding of CNS seeding and a brighter outlook for post-operatively irradiated patients with ependymomas. Int J Radiat Oncol Biol Phys 9: 1231-1234, 1983 24. Salazar OM, Rubin R, Bassano D, et al: Improved survival of patients with intracranial ependymomas by irradiation: dose selection and field extension. Cancer 35: 1563-1573, 1975
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25. Schwade JG, Wara WM, Sheline GE, et al: Management of primary spinal cord tumors. Int d Radiat Oneoi Biol Phys 4:389-393, 1978 26. Scott M: Infiltrating ependymomas of the cauda equina. Treatment by conservative surgery plus radiotherapy. J Neurosurg 41:446-448, 1974 27. Shaw EG, Evans RG, Scheithauer BW, et al: Radiotherapeutic management of adult intraspinal ependymomas. Int J Radial Oncol Biol Phys 12:323-327, 1986 28. Sheline GE, Wara WM, Smith V: Therapeutic irradiation and brain injury. Int J Radiat Oncol Biol Phys 6: 1215-1228, 1980 29. Shuman RM, Alvord EC, Leech RW: The biology of childhood ependymomas. Arch Neurol 32:731-739, 1975 30. SloolT JL, Kernohan JW, MacCarty CS: Primary lntramedullary Tumors of the Spinal Cord and Filum Terminale. Philadelphia: WB Saunders, 1964 31. Sonneland PRL, Scheithauer BW, Onofrio BM: Myxopapillary ependymoma. A clinical and immunocytochemical study of 77 cases. Cancer 56:883-893, 1985 32. Wood EH, Berne AS, Taveras JM: The value of radiation therapy in the management of intrinsic tumors of the spinal cord. Radiology 63:11-24, 1954 Manuscript received June 27, 1990. Accepted in final form October 23, 1990. This work was supported by the Cancer Research Campaign and the Royal Marsden Hospital. Professor H. J. G. Bloom died on December 21, 1988. Present address for Dr. Bessell: Department of Clinical Oncology, Nottingham General Hospital, Park Row, Nottingham, England. Address reprint requests to: Michael Brada, M.R.C.P., F.R.C.R., Academic Unit of Radiotherapy and Oncology, Royal Marsden Hospital, Downs Road, Sutton, Surrey SM2 5PT, England.
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Postoperative radiotherapy in the management of spinal cord ependymoma STEPHEN J. WH1TAKER,M.R.C.P., F.R.C.R., E m c M. BESSELL~PH.D., M.R.C.P.F.R.C.R., SuE E. ASHLEY,PH.D., H. J. G. BLOOM,M.D., F.R.C.P., F.R.C.R., F.A.C.R., B. ANTHONY BELL, M.D., F.R.C.S., AND MICHAEL BRADA, M.R.C.P.F.R.C.R.
Academic Unit qf Radiotherapy and Oncolvgy and Computing Department, Royal Marsden Ho,spitat, Sutton, and Department of Neurosurgery, Atkinson Morley~ Hospital, Wimbledon, England v- Fifty-eight patients with histologically verified spinal cord ependymomas were treated at the Royal Marsden Hospital and Atkinson Morley's Hospital between 1950 and 1987. The median age in this series was 40 years (range I to 79 years) and the male:female ratio was 1.8:1. Ten patients had tumors in the cervical cord and 10 in the thoracic cord; 14 tumors involved the COMUSmedullaris and 24 the cauda equina. Forty ependymomas were grade 1 and 13 were grades II to IV (in five patients there was insufficient material for grading). Eleven patients underwent biopsy only, 33 had partial or subtotal resection, and 14 had complete resection. Fortythree patients received postoperative radiotherapy. The median follow-up period was 70 months (range 3 to 408 months). Cause-specific survival rates were 74% and 68% at 5 and 10 years, respectively. On univariate analysis, age, histological grade, postoperative neurological function, and era of treatment were significant prognostic factors for survival. The histological grade was the only significant independent prognostic factor. The relative risk of death from ependymoma was 9.0 for patients wilh tumor grades II to IV compared to grade I (p < 0.005, 95% confidence interval 2.7 to 30). The survival rates of patients following complete excision were significantly better compared to those after incomplete surgery (p < 0.025). The majority of completely resected neoplasms were low-grade cauda equina tumors. Despite incomplete surgery, 5- and 10-year progression-free survival rates following radical radiotherapy were both 59%, and cause-specific survival rates were 69% at 5 years and 62% at 10 years. This suggests that radiotherapy may achieve long-term tumor control in over half of those patients with residual spinal ependymoma.
KEY WORDS
spinal tumor
PINAL cord ependymomas comprise less than 2% of all central nervous system (CNS) neoplasms but represent 15% of spinal cord tumors and up to 60% of spinal cord gliomas. ~.~7 Management of these tumors evolved empirically and optimal therapy is based on retrospective analyses of survival, patterns of relapse, and treatment morbidity. Conventional treatment of patients with suspected spinal cord ependymoma includes surgery to obtain a histological diagnosis and to resect tumor where this is possible. The degree of resectability varies from biopsy alone, through partial or subtotal resection, to complete excision. It has been estimated that no more than 60% of patients have complete resection. "~Although modern microsurgical techniques have increased the resection rate, this is often at the cost of increased morbidity; ~-~ thus, a substantial proportion of patients have residual tumor which may be controlled with postoperative radiation therapy.
S
720
ependymoma
radiation therapy
prognostic factor
The extent of surgical resection and the role of postoperative radiation therapy are controversial topics. Some centers advocate minimal surgery and radical irradiation,~3.24 while many neurosurgeons report excellent results with radical excision alone. 4.~'.'~ We report our study of a large series of patients with spinal cord ependymoma treated by surgery either alone or with postoperative radiation therapy, and we attempt to define optimum treatment strategies for this rare tumor.
Clinical Material and Methods Patient Population Between 1950 and 1987, 74 patients with histologically verified spinal cord ependymoma were seen at the Royal Marsden Hospital and Atkinson Morley's Hospital. Sixteen patients were excluded: eight had recurrent disease after previous treatment elsewhere, and eight with primary disease received postoperative radi-
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Postoperative radiotherapy for spinal cord ependymoma TABLE 1 Pretreatmenr characterAlics 0(58 patients with .v~inal cord
el)en(t|'l~lol~7o Treatment Group Characteristic
Total Cases
Surgery& RT*
Surgery
43 30:13 4I 1-65
15 7:8 37 13-79
58 37:21 40.5 1-79
28 6 3 I 5
12 1 2 0 0
40 7 5 1 5
11 30 2
0 3 12
11 33 14
no. of cases sex (M:F) median age (yrs) age range (yrs) histologicalgrade I
11 Ill IV ungraded extent of surgery biopsy partial/subtotal total resection * RT = radiation therapy.
ation therapy at other centers. Fifty-eight patients were treated entirely at one or both hospitals and form the basis of this report. Fifteen patients underwent surgery alone, and 43 received postoperative radiation therapy, reflecting a consistent policy of referral of most patients with residual disease for irradiation, Patients' age, sex, extent of surgery, and tumor histological grade are shown by treatment group in Table 1 and Fig. 1. The male:female ratio for the whole group was 1.8:1. All patients underwent preoperative myelography with cytological examination of the cerebrospinal fluid (CSF). A further six patients had computerized tomography (CT) myelography; magnetic resonance (MR) imaging was carried out in one patient. The diagnosis was confirmed by histological study in all cases and in 53 patients the tumor was graded according to the classification of Mabon, et at.'5 (Table 1). In five patients insufficient material was obtained for grading. The distribution of patients by tumor site is shown in Fig. 2. Thirty-eight (66%) of the 58 ependymomas involved the conus medullaris or cauda equina. The majority of the cervical and thoracic cord tumors extended over three to five spinal segments. Two cervical ependymomas involved the whole of the cervical cord and one thoracic ependymoma affected the entire thoracic cord. Two cauda equina tumors also extended over more than one region with destruction of the sacrum in one patient and the L-5 vertebra in the other. In 50 patients in whom adequate records were available (10 with surgery alone and 40 with postoperative irradiation), an assessment of neurological performance status was made retrospectively by recording the limb power and mobility at presentation, immediately after surgery, and more than 3 months after completion of all treatment. A change in power or mobility on subsequent follow-up examination was also noted.
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FIG. 1. Age distribution of patients by treatment group. S = surgery alone (15 patients); S/RT = surgery and postoperative irradiation (43 patients). Median age for the group with surgery alone was 37 years (range 13 to 79 years) and for the postoperation irradiation group was 41 years (range I to 65 years).
Fl(~. 2. Distribution of tumors by site and treatment group. S = surgery alone, S/RT = surgery and postoperative irradiation. The majority of tumors were extramedullary at the conus medullaris or cauda equina sites. Twenty percent of patients treated surgically alone had entirely intramedullary tumors compared to 40% of those having postoperative irradiation (difference not statistically significant).
Surgery Patients underwent laminectomy and posterior myelotomy, with tumor removal by blunt dissection under the operating microscope and, since the 1970's, by aspiration with the Cavitron ultrasonic surgical aspirator.* Where a plane of cleavage could not be defined, * Ultrasonic surgical aspirator manufactured by Cavitron Surgical Systems, Inc., Stamford, Connecticut. 721
S. J. Whitaker, et aL subtotal excision or biopsy was performed. The extent of surgery was defined as total, subtotal (including all degrees of partial resection), or biopsy only, as judged by the neurosurgeon at the time of operation. The dura was usually closed at the end of the procedure, occasionally requiting a fascial graft. Total resection was achieved in 14 patients (12 with surgery alone and two with postoperative irradiation). Ten (42%) of 24 patients with cauda equina tumors and two (14%) of 14 patients with ependymoma in the conus medullaris underwent complete resection. None of the patients with intramedullary tumors at other sites had complete tumor excision. Thirty-three patients had subtotal or partial resection and 30 of these underwent postoperative radiation therapy. All 11 patients treated with biopsy only were irradiated. Twelve (80%) of 15 patients treated by surgery alone had grade I tumors confined to the conus and cauda equina.
ependymoma of the conus medullaris and cauda equina were treated by a direct, spade-shaped field from T-6 to S-4 and T-12 to S-4, respectively, to a maximum dose of 40 Gy in 28 fractions over 589 weeks, with boosts of 10 Gy in seven fractions or 15 Gy in 11 fractions. The tumor site thus received a total dose of 50 Gy in 35 fractions for conus medullaris tumors and 55 Gy in 39 fractions for cauda equina tumors.
Chemotherapy Four patients received initial and/or adjuvant chemotherapy. The rationale was to improve local control and reduce the risk of seeding? Chemotherapy comprised vincristine, 1.0 mg/sq m weekly during radiotherapy; three patients also received maintenance chemotherapy with vincristine, 1.4 mg/sq m weekly for 3 weeks and a single 100-mg/sq m dose of 1-(2-chloroethyl)-3-cyclohexyl-l-nitrosourea (CCNU) orally, with this regimen repeated every 6 weeks for 1 year. Five patients received similar schedules of chemotherapy for recurrent disease, usually after reoperation.
Radiation Therapy Thirty-nine patients received megavoltage irradiation (4 to 8 MeV on a linear accelerator or telecobalt), while four patients were treated with orthovoltage radiation therapy for at least part of their course. Eighteen patients, most with high-grade or extensive tumors, received radiation therapy to the entire CNS. They were treated prone with head immobilization and the whole neuraxis was irradiated to a minimum dose of 30 Gy in 20 to 25 fractions over 4 to 5 weeks (Fig. 3). A tumor boost of 20 Gy in 10 to 15 fractions over 2 to 3 weeks was given with margins of two to four spinal segments. The tumor thus received a minimum dose of 50 Gy in 35 fractions over 7 weeks. The minimum dose was prescribed to the mean spinal cord depth; recently, individualized spinal compensators have been used to reduce dose inhomogeneity. Twenty-five patients underwent spinal irradiation alone. Whole-spine radiation therapy was given to six patients with cervical or thoracic tumors. Patients with
Follow- Up Monitoring The median follow-up period was 70 months (range 3 to 408 months), with a median of 31 months for patients treated with surgery alone and 71 months for the group with postoperative irradiation. Patients were followed by regular clinical examination with radiological investigation when indicated. Due to the often long natural history of ependymomas and the frequency of neurological deficits after initial therapy, it is difficult to determine the complete eradication of the disease. We have therefore recorded "progression of disease" as indicated by deterioration of previously stable neurological signs or symptoms. Progressive disease was confirmed radiologically in all cases and surgically in three.
FIG. 3. Extent of irradiation and dose as used for various primary sites in this series.
FIG. 4. Actuarial cause-specific survival rates of all 58 patients with spinal ependymoma. Forty-three patients were alive at 5 years and 39 at 10 years postsurgery.
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P o s t o p e r a t i v e r a d i o t h e r a p y for spinal c o r d e p e n d y m o m a This rigorous investigation eliminated deterioration due to late sequelae of surgery or radiotherapy. Survival figures were assessed as "cause-specific" which took into account treatment-related deaths and deaths from the complications of chronic paraplegia (even if postmortem examination failed to reveal residual or recurrenl tumor).
Statistical Analysis Actuarial progression-free and cause-specific survival rates were calculated by the life-table method of Kaplan and Meier and the difference was analyzed by log-rank test. -~~ The independent effect of prognostic variables was tested by the Cox multivariate procedure. ~ The influence of treatment was tested by its inclusion in the proportional-hazard model after correction for all the other prognostic variables. Results
Survival Rales The overall survival rates in the 58 patients with spinal cord ependymoma were 68% and 62% at 5 and I0 years, respectively. The majority of deaths were directly or indirectly due to tumor with cause-specific 5- and 10-year survival rates of 74% and 68%, respectively (Fig. 4). There were three intercurrent deaths: one patient died postoperatively from a myocardial infarction and two patients who received radiation therapy died after 4 years, one from myocardial infarction and one from a subdural hemorrhage.
Local Control The disease progressed immediately after treatment in five patients and after apparent disease control at a median time to progression of 12 months (range 7
FI(;. 5. Actuarial cause-specific survival rates by age at diagnosis comparing those under 40 years versus those of 40 years or older. The number of patients alive at 0, 5, and 10 years was 29, 26, and 26 for those aged under 40 years, and 29, 17. and 13 for those aged 40 years or older (p < 0.005).
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to 44 months) in another eight. The progression-free survival rates were 74% and 68% at 5 and 10 years, respectively, which is identical to the cause-specific survival rate, indicating little salvage of patients with progressive disease.
Prognostic Variables and Univariate Analysis Univariate analysis was performed for patients prior to treatment and for tumor-related prognostic variables. The results were similar for both cause-specific and overall survival. The risk of tumor progression or death from ependymoma was significantly higher for older patients (_> 40 years vs. < 40 years; Fig. 5, p < 0.005), high-grade tumors (grade I vs. grades II to IV; Fig. 6, p < 0.005), patients with poor neurological function after treatment (p < 0.05), and patients treated less recently (pre-1970 vs. 1970 and later, p < 0.01, data not shown). There was a statistically significant trend for improved progression-free survival times (but not for cause-specific survival times) and for cauda equina tumors versus other tumor sites (p < 0.05). Gender and age (adults vs. children) were not significant prognostic variables for tumor control or survival. Patients treated by surgery alone compared to those receiving postoperative radiation therapy were younger (median age 37 vs. 41 years, Table 1) and had more grade I tumors (80% vs. 65%) and a higher rate of complete resection (67% vs. 5%). The rate of complete resection was the only difference reaching statistical significance (p < 0.05).
Mulliva riale Analysis A multivariate analysis using a step-up proportionalhazard model was performed to investigate the effect
Fl(;. 6. Actuarial cause-specific survival rates by histological grade (grade I vs. grade II vs. grades III/IV). Ungraded patients were excluded but the survival curve for them was similar to that of grade I. The number of patients alive at 0, 5, and 10 years was 40, 34. and 34 for grade I: 7,4, and 1 for grade It; and 5, 2, and 2 for grades Ill/IV (p < 0.005). 723
S. J. Whitaker, et al. of prognostic variables (identified on univariate analysis) on rates of survival and freedom from tumor progression. Histological grade was the major statistically significant independent variable, with a relative risk of ependymoma progression of 9.8 (95% confidence interval 3.3 to 30) and of death from ependymoma of 9.0 (95% confidence interval 2.7 to 30) for patients with tumor grades tt to IV. After stratification by histological grade (grade I vs. grades !I to IV with ungraded tumors excluded), no other prognostic variable remained statistically significant. However, the small number of "events" (progression or death) may have obscured any real differences. Age was an independent variable when all patients were included in the model. There was a relative risk of death from ependymoma of 5.7 for older patients (_> 40 years) compared to younger patients (< 40 years). However, age and histological grade were highly correlated and, when five patients with ungraded tumors were excluded from the model, age was no longer a significant independent factor. [n addition, stratification by age revealed a significant survival difference by grade only in older patients (_> 40 years, Fig. 7); however, only three of 28 patients less than 40 years of age had grade It to IV tumors compared to 10 of 25 patients aged 40 years or older.
patients who received postoperative radiation therapy were 69% and 63% at 5 and 10 years, respectively, and 92% at both 5 and 10 years for those treated by surgery alone (Fig. 9). This difference was not statistically significant (95% confidence intervals at 10 years; 45% to 77% for the postoperatively irradiated group vs. 57% to 99% for the group with surgery alone). The progression-free survival rates were 59% and 54% at 5 and 10 years, respectively, for the postoperative radiation therapy group and 92% for the group with surgery alone. This difference also failed to reach statistical significance. The dose and extent o f radiation therapy and the use of chemotherapy did not affect tumor control 'or patient survival (p = not significant). The patients receiving adjuvant chemotherapy had a 5-year cause-specific survival rate of 67% compared to 70% for those not receiving chemotherapy (p = not significant). Vincristine and CCNU were used as salvage treatment in five of eight patients whose disease progressed and only one patient showed an objective response with stabilization of neurological signs for 489 years. Three other patients with progression at the primary site received vincristine and CCNU and lived 10, 11, and 24 months with subjective improvement in pain.
Influence Off Therapy
Of the eight patients in the postoperative radiation therapy group whose disease progressed or recurred after initial control, six had tumorgrowth at the primary, site within the high-dose radiotherapy field; in the other two, tumor recurred first at an intracranial site. The six patients with relapse at the primary site alone underwent further surgery (four cases) and/or chemotherapy
There was a statistically significant trend for improved periods of survival and progression-free survival for patients treated with more complete surgery (p < 0.025, Fig. 8). The cause-specific survival rates for
FIG. 7. Actuarial cause-specific survival rates by age and histological grade. The number of" patients alive at 0, 5, and 10 years was 25, 22, and 22 for tumor grade I patients under 40 years of age; 3, 3, and 3 for tumor grade II to IV patients aged under 40 years of age; 15, 12, and 12 for tumor grade l patients aged 40 years or over: and 10, 3, and 1 for tumor grade II to IV patients aged 40 years or over (p < 0.005). Five ungraded patients were excluded. 724
Sites of Progression and Inlracranial Tumors
FIG. 8. Actuarial cause-specific survival rates by extent of surgery. The number of patients alive at 0, 5, and 10 years was 14, 14, and 14 for those with total resection; 11, 10, and 8 for those with subtotal resection; 22, 12, and 12 for those with partial resection; and 1 l, 7, and 5 for those with biopsy only (p < 0.01).
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P o s t o p e r a t i v e r a d i o t h e r a p y for spinal c o r d e p e n d y m o m a (five cases); despite this, all six died at a median of 5 months (range 1 to 54 months) after the diagnosis of progression. Of the two patients whose tumor first recurred at an intracranial site, both suffered subsequent progression in the spine 6 and 28 months later. One patient died despite further efforts at salvage with radiotherapy and chemotherapy; the other was successfully treated with resection and radical radiation therapy, and remains well and progression-free 30 years later. One additional patient whose disease progressed first at the primary site developed an intracranial ependymoma 6 months later which was unsuccessfully treated by surgery and radiation therapy. None of the patients with intracranial relapse showed initial positive CSF cytology. Neither of the two patients with initially positive CSF cytology had evidence of spinal seeding. Neurological Function Of 50 evaluable patients, 36 (72%) had impaired mobility at presentation but none was paraplegic. The degree of neurological function was similar in both groups of patients. Following surgery and irradiation, 30% of patients improved and 60% remained with stable symptoms and signs. All patients with deteriorating signs had progressive disease. The addition of postoperative radiation therapy was not associated with late neurological deterioration as there were no cases of radiation myelopathy.
Discussion McCormick, et al., w have recently expressed reservations about studies reporting improved control with postoperative radiation therapy which include small
FIG. 9. Actuarial cause-specificsurvival rates by treatment group. The number of patients alive at 0, 5, and 10 years was 15, 14, and 14 for those with surgery alone, and 43, 29, and 25 for those with surgery and postoperative irradiation (p > 0.1, not significant). J. Neurosurg. / Volume 74/May, 1991
series with limited follow-up periods, have inadequate control groups of unirradiated patients, and lack discussion of the role of surgery. Our study has tried to avoid these deficiencies. We have identified important prognostic factors and have attempted to assess the value of postoperative radiotherapy in the management of patients with spinal cord ependymomas. Of necessity this has been retrospective and covered an era which has seen improvements in diagnosis, surgery, and radiotherapy. Prognostic Variables The actuarial survival rates of all 58 patients were 68% at 5 years and 62% at 10 years, and cause-specific survival rates were 74% at 5 years and 68% at 10 years. A review of the literature (Table 2), has revealed survival rates from different centers which vary from 25% at 5 years in children 2~ to I00% for patients with completely resected low-grade cauda equina tumors. T M ~9,3J Many of these series include small numbers of highly selected patients or exclusion of postoperative deaths j2 or of patients having tumor biopsy only. ~8 Others have considered disease progression within 2 months of surgery as surgical failure24 A variety of prognostic factors have been identified on univariate analyses. These include the extent of resection,2L'~3' tumor site, ~~.~2.~7.~ age,2~.24 histological subtype or grade, 6''s duration of symptoms, ~2and neurological performance status. 9 We have identified age, histological grade, neurological performance status after treatment, and era of treatment as statistically significant variables for cause-specific and progression-free survival on univariate analysis. Complete surgical excision and a cauda equina tumor site were also associated with improved survival times. On multivariate analysis, only histological grade remained an independent prognostic factor. Extent of Surgery We have demonstrated excellent tumor control and patient survival with low morbidity following complete resection of low-grade cauda equina tumors, as reported by other a u t h o r s . 6A~ McCormick, et a/., 17 described excellent long-term control and a low morbidity rate in a consecutive series of 23 patients overa 12-year period. All patients had complete resection, despite six presenting with recurrent tumor after previous surgery and radiation therapy. The authors stressed that every attempt should be made to completely resect benign ependymomas. Cooper and Epstein4 reported on 14 patients with intramedullary ependymomas recurring within 32 months of initial surgery with or without irradiation. They achieved what they considered "99-100% resections" in 12 of these and subtotal resection in the remaining two patients. Unfortunately, the long-term survival and tumor control results were not reported. In our experience, the chance of tumor control and
725
S. J. W h i t a k e r , et al. long-term survival in patients with recurrent tumors is poor, and extensive salvage procedures may be effective only in patients with low-grade tumors. However, with improved microsurgical techniques and earlier diagnosis through CT and MR imaging, more tumors may be amenable to complete resection in skilled hands. Radiation Therapy The value of postoperative irradiation in local control is debated in the literature. Many authors have reported a benefit for patients with residual tumor, 2~~ .~2 while others have documented excellent survival after surgery alone.4.6.~o.~,~7 In this series, the actuarial progressionfree survival rates at 10 years were 92% and 63% for patients treated by surgery alone and those receiving postoperative irradiation, respectively. The two groups differed in the distribution of a number of prognostic factors, particularly in the extent of surgery, and the difference in survival even though not statistically significant is most likely due to this unequal distribution. Patients with residual tumor who received postoperative irradiation had an actuarial progression-free survival rate of 59% at 10 years (Fig. 8). While this may reflect the long natural history of the disease, it can be seen that the survival curves in Fig. 8 tend to plateau,
thus indicating that a significant proportion of patients achieved long-term control. Therefore, an advantage for postoperative radiation therapy in patients with residual tumor is suggested. In the present series, the addition of postoperative radiation therapy was not associated with deterioration of neurological performance status, either at completion of treatment or long term. Indeed, in many patients, function improved after irradiation. This may relate as much to continued rehabilitation and improvement in strength after surgery as to the antitumor effect of irradiation in those with residual macroscopic tumor postoperatively. The optimal dose of irradiation is a matter of controversy. The majority of authors recommend doses of 40 to 50 G y . 9'13"z9'24'~5 Marks and Adler ~6 commented that 40 Gy was adequate as they found a very low rate of local recurrence in low-grade totally resected myxopapillary tumors " . . . irrespective of the dose given." An alternative interpretation of the data is that these patients do not require irradiation. We found no statistically significant difference in freedom from progression for any dose between 40 and 50 Gy; however, the majority of patients received 50 Gy to the tumor site. This dose reflected the policy of the Royal Marsden Hospital based on the maximum dose which the cord
TABLE 2 Review o f 377 patients reported with .spinal cord ependymoma giving 5- and lO-year survival figures* Period of Study
Patient Ages (yrs)
1960-1963 1953-1974 1967-1977 1976-1988 1950-1987
all ages all ages all ages 19-70 all ages
intramed all sites intramed (all tot res) intramed all sites
1941-1957
20-65
Salazar, el al., 1975 Mork & L0ken, 1977 Koloelson, et al., 1980 Guidetti, et al., 1981
1960-1971 1953-1974 1962-1979 1951-1978
all all all all
Marks & Adler, 1982
1954-1976
all ages
Pesehel, et al., 1983 Garrett & Simpson, 1983 Read, 1984
1965-1981 1958-1980 1956-1980
Ilgren, et al., 1984 Sonneland, et al., 1985 Garcia, 1985
1938-1982 1924-1983
> 18 all ages > 16 < 16 all ages all ages all ages
Shaw, et al., 1986 Linstadt, et al., 1989
1963-1983 1957-1986
> 16 all ages
Whitaker, et al., 1991
1950-1987
all ages
cauda equina (extramed) all sites intramed cauda equina all sites all sites all sites intramed cauda equina intramed cauda equina all sites all sites all sites all sites all sites cauda equina intramed cauda equina all sites all localized all diffuse sites all sites
Authors & Year surgery alone Greenwood, 1963 Mork & Lcken, 1977 Fischer & Mansuy, 1980 McCormick, et al., 1990 Whitaker, et al., 1 9 9 1 surgery & radiation therapy Ayres, 1958 Slooff, et al., 1964
ages ages ages ages
Spinal Site
Survival Rate (%)
No. of Cases
5-Year
10-Year
9 34 16 23 15
89 97 86 100 92
-74 --92
18 169
19 16 12 34 10 7 8 9 41 22 4 42 77 8 10 22 18 3 43
88 88 mean survival (yrs): 17 (tot res) 10.5 (subtot res) 14 (lot res) 5 (subtot res) 70 50 82 75 100 73 97 81 100 100 57 57 83 83 100 -83 -70 70 25 25 65 60 100 100 60 -100 -95 95 93 93 50 -74 68
* Intramed = intramedullary; extramed = extramedullary; tot res = total resection; and subtot res = subtotal and partial resection.
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Postoperative radiotherapy for spinal cord ependymoma can safely tolerate; -'~ failure to demonstrate a doseresponse for a control group may simply reflect the small number of patients receiving lower doses. The extent of the CNS which should be irradiated is also debatable. Craniospinal irradiation is considered by some authors to be of value in patients with highgrade intracranial ependymomas, s2~ but its role in spinal cord ependymomas is not established. The most common location of progression is at the primary site; in our series, of three patients with intracranial relapse, two had received whole-CNS irradiation and both later had disease progression in the spine. There is therefore little evidence that the addition of cranial irradiation, particularly in well-resected low-grade tumors, has a survival or tumor control advantage. A review of 259 patients from 14 publications revealed a 5.8% incidence of intracraniai relapse (Table 3) which is similar to our findings. Garrett and Simpson ~ found no statistically significant survival advantage for a larger irradiated CNS volume and recommended localized radiation therapy up to 50 Gy except for high-grade lesions with a definite risk of the spinal ependymoma being a seedling from an occult infratentorial primary tumor. Chemotherapy
The number of patients receiving adjuvant chemotherapy with vincristine and CCNU was too small to demonstrate any benefit for either progression-free or cause-specific survival. When these drugs were used in patients with local progression of tumor, some patients showed symptomatic improvement (reduced local pain) but only one had a sustained objective response. Reoperation followed by chemotherapy and re-irradiation did not halt the progression of tumor at a previously
TABLE 3 Incidence of intracranial relapse in patients with primary spinal ependymoma Authors & Year Sagerman, el al., 1965 Fokes & Earle, 1969 Scott, 1974 Salazar, et al., 1975 Shuman, et al., 1975 Schwade, el al., 1978 Fischer& Mansuy, 1980 Kopelson, et al., 1980 Marks & Adler, 1982 Garrett & Simpson, 1983 Read, 1984 Shaw, et al., 1986 Linstadt, et al., 1989 diffuse disease localizeddisease Whitaker, et al., 1991 total cases
No. of Intracranial Relapses 1 2 0 0 0 0 1 1 1 3 I 1 1 0 3 15
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Total Cases 3 4 3 19 7 12 16 12 15 41 26 22 3 18 58 259
irradiated site. This concurs with reported experience, although Kopelson, et al.,13 described successful salvage in one patient with a recurrence at 3 months postoperatively who was treated with radiotherapy and chemotherapy, and tumor control for 11 years in a further patient with tumor progression. Conclusions The survival rate of patients with totally resected low-grade ependymomas is excellent. Postoperative radiation therapy in patients with incompletely resected tumors is associated with good long-term survival times without late radiation damage to the spinal cord with doses of 45 to 55 G y in fractions of 1.2 to 1.5 Gy. Although the exact role for radiation therapy remains undefined, the low morbidity and long-term survival rates in patients with residual tumor suggest its value for these patients. Acknowledgments We are grateful for the cooperation from our neurosurgical colleagues at Atkinson Morley's Hospital and The National Hospital for Nervous Diseases who have referred patients for further treatment. We gratefully acknowledge the help of the medical records departments of both hospitals and Miss Lindsay Pegus of the Medical Art Department, Royal Marsden Hospital. References 1. Ayres WW: Ependymoma of the cauda equina. A report of the clinicopathologic aspects and follow-up studies of 18 cases. Milit Med 122:10-35, 1958 2. Barone BM, Elvidge AR: Ependymomas. A clinical survey. J Neurosurg 33:428-438, 1970 3. Bloom HJG: Intracranial tumors: response and resistance to therapeutic endeavors, 1970-1980. Int J Radiat Oncol Biol Phys 8:1083-1113, 1982 4. Cooper PR, Epstein F: Radical resection of intramedullary spinal cord tumors in adults. Recent experience in 29 patients. J Neurosurg 63:492-499, 1985 5. Cox DR: Regression models and life tables (with discussion). J R Stat Soc (B) 34:187-220, 1972 6. Fischer G, Mansuy L: Total removal of intramedullary ependymomas: follow-up study of 16 cases. Surg Neurol 14:243-249, 1980 7. Fokes EC Jr, Earle KM: Ependymomas: clinical and pathological aspects. J Neurosurg 30:585-594, 1969 8. Garcia DM: Primary spinal cord tumors treated with surgery and postoperative irradiation. Int J Radiat Oncol Biol Phys ll:1133-1139, 1985 9. Garrett PG, Simpson WJK: Ependymomas: results of radiation treatment. Int J Radiat Oncol Biol Phys 9: 1121-1124, 1983 10. Greenwood J Jr: lntramedullary tumors of the spinal cord. A follow-up study after total surgical removal. J Neurosurg 20:665-668, 1963 11. Guidetti B, Mercuri S, Vagnozzi R: Long-term results of the surgical treatment of 129 intramedullary spinal gliomas. J Neurosurg 54:323-330, 1981 12. llgren EM, Stiller CA, Hughes JT, et al: Ependymomas: a clinical and pathologic study. Part 11- - survival features. Clin Neuropathol 3:122-127, 1984 727
S. J. Whitaker, et al. 13. Kopelson G, Linggood RM, Kleinman GM, et al: Management of intramedallary spinal cord tumors. Radiology 135:473-479, 1980 14. Linstadt DE, Wara WM, Leibel SA, et al: Postoperative radiotherapy of spinal cord tumors. Int J Radiat Oneol Biol Phys 16:1397-1403, 1989 15. Mabon RF, Svien HJ, Kernohan JW, et al: Ependymomas. Proc Staff Meet Mayo Clin 24:65-71, 1949 16. Marks JE, Adler SJ: A comparative study of ependymomas by site of origin, lnt J Radiat Oneol Biol Phys 8: 73-83, 1982 17. McCormick PC, Torres R, Post KD, et al: lntramedullary ependymoma of the spinal cord. J Neurosurg 72: 523-532, 1990 18. M0rk SJ, LOken AC: Ependymoma. A follow-up study of 101 cases. Cancer 40:907-915, 1977 19. Peschel RE, Kapp DS, Cardinale F, et al: Ependymomas of the spinal cord. Int J Radiat Oncol Biol Phys 9: 1093-1096, 1983 20. Peto R, Pike MC, Armitage P, et al: Design and analysis of randomised clinical trials requiring prolonged observation of each patient. 2: Analysis and examples. Br J Cancer 35:1-39, 1977 21. Read G: The treatment of ependymoma of the brain or spinal canal with radiotherapy: a report of 79 cases. Clin Radiol 35:163-166, 1984 22. Sagerman RH, Bagshaw MA, Hanbery J: Considerations in the treatment of ependymoma. Radiology 84: 401-408, 1965 23. Salazar OM: A better understanding of CNS seeding and a brighter outlook for post-operatively irradiated patients with ependymomas. Int J Radiat Oncol Biol Phys 9: 1231-1234, 1983 24. Salazar OM, Rubin R, Bassano D, et al: Improved survival of patients with intracranial ependymomas by irradiation: dose selection and field extension. Cancer 35: 1563-1573, 1975
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25. Schwade JG, Wara WM, Sheline GE, et al: Management of primary spinal cord tumors. Int d Radiat Oneoi Biol Phys 4:389-393, 1978 26. Scott M: Infiltrating ependymomas of the cauda equina. Treatment by conservative surgery plus radiotherapy. J Neurosurg 41:446-448, 1974 27. Shaw EG, Evans RG, Scheithauer BW, et al: Radiotherapeutic management of adult intraspinal ependymomas. Int J Radial Oncol Biol Phys 12:323-327, 1986 28. Sheline GE, Wara WM, Smith V: Therapeutic irradiation and brain injury. Int J Radiat Oncol Biol Phys 6: 1215-1228, 1980 29. Shuman RM, Alvord EC, Leech RW: The biology of childhood ependymomas. Arch Neurol 32:731-739, 1975 30. SloolT JL, Kernohan JW, MacCarty CS: Primary lntramedullary Tumors of the Spinal Cord and Filum Terminale. Philadelphia: WB Saunders, 1964 31. Sonneland PRL, Scheithauer BW, Onofrio BM: Myxopapillary ependymoma. A clinical and immunocytochemical study of 77 cases. Cancer 56:883-893, 1985 32. Wood EH, Berne AS, Taveras JM: The value of radiation therapy in the management of intrinsic tumors of the spinal cord. Radiology 63:11-24, 1954 Manuscript received June 27, 1990. Accepted in final form October 23, 1990. This work was supported by the Cancer Research Campaign and the Royal Marsden Hospital. Professor H. J. G. Bloom died on December 21, 1988. Present address for Dr. Bessell: Department of Clinical Oncology, Nottingham General Hospital, Park Row, Nottingham, England. Address reprint requests to: Michael Brada, M.R.C.P., F.R.C.R., Academic Unit of Radiotherapy and Oncology, Royal Marsden Hospital, Downs Road, Sutton, Surrey SM2 5PT, England.
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