- Email: [email protected]
The Meningioma Controversy: Postoperative radiation therapy
In!. .I. Rodkuion Oncology No/. Pkys.. Vol. Printed in the U.S.A. All rights reserved.
0360-3016/88 $3.00 + .OO Copyright 0 1988 Pergamon Press plc
15. pp. 299-304
0 Original Contribution THE MENINGIOMA CONTROVERSY: POSTOPERATIVE RADIATION THERAPY BERNARD W. TAYLOR JR., M.D.,* ROBERT B. MARCUS JR., M.D.,* WILLIAM A. FRIEDMAN, M.D.,? WILLIAM E. BALLINGER JR., M.D.* AND RODNEY R. MILLION, M.D.* University of Florida, Gainesville, Florida Total surgical excision is the main goal of therapy for intracranial meningiomas. The controversy today involves the efficacy of postoperative radiation therapy. To evaluate this question, 132 patients with benign intracranial meningiomas, treated between October 1964 and April 1985, were evaluated. All patients had a minimum 2-year follow-up. The actuarial local control rates at 10 years for the three treatment groups were as follows: subtotal excision alone, 18%; subtotal excision plus postoperative radiation therapy, 822, and total excision alone, 77%. The actuarial determinate survival rates at 10 years were 49%, 81%, and 93%, respectively. Postoperative radiation therapy was also effective for patients treated at the time of the first recurrence, with an actuarial local control rate at 10 years after salvage treatment of 30% for patients treated with surgery alone and 89% for patients receiving postoperative radiation therapy at the time of salvage. This analysis suggests that radiation therapy has a significant role in the treatment of subtotally excised and recurrent intracranial meningiomas. Meningioma (benign), Radiation therapy, Surgery.
One hundred ninety-seven patients with the diagnosis of meningioma were evaluated between October 1964 and April 1985 at the University of Florida Shands Hospital or the Gainesville VA Hospital. Sixty-five patients were excluded from this analysis for the following rea-
sons: 5 patients had neurofibromatosis and were genetically predisposed to develop meningiomas, 8 patients refused all forms of treatment, 23 patients received surgery or irradiation at another institution, 2 patients’ medical records were lost, and 10 patients were lost to follow-up immediately after treatment because they were referred from South America and never returned for follow-up, nor could they be located. Also excluded were 9 patients with spinal meningiomas and 8 patients with malignant histologies. The remaining 132 patients were analyzed in this study. All had a minimum 2-year follow-up, and approximately 60% of the patients had a minimum follow-up of 5 years. Since 1976, most patients have had a yearly CT scan for radiographic follow-up, including those patients treated prior to the era of CT scanning. The age and sex distribution is shown in Figure 1. Age at first surgery ranged from 1 to 79 years with a mean age of 5 1 years. Although meningioma is uncommon in children, 4 of these patients were diagnosed prior to age 20. The male to female ratio was 1: 1.4; there were 23 black and 109 white patients, for a black to white ratio of 1:4.7. Histological confirmation was obtained in all patients at the initial surgical resection. The histology was sub-
Presented at the 29th Annual Meeting ofthe American Society for Therapeutic Radiology and Oncology, October 18-23, 1987, Boston, MA. * Dept. of Radiation Oncology. t Dept. of Neurosurgery.
$ Dept. of Neuropathology. Reprint requests to: Dr. R. B. Marcus Jr., Radiation Oncology, Box J-385, J. Hillis Miller Health Center, Gainesville, FL 32610-0385. Accepted for publication 2 March 1988.
INTRODUCTION Meningiomas comprise approximately 15% of all primary intracranial neoplasms. They are slow growing and account for only 7% of all deaths from primary brain neoplasms. I3 The goal of therapy is total surgical excision. However, if bone invasion, involvement of major vascular structures, or large tumor volume is present, total surgical resection may be impossible. Treatment of these patients can be frustrating, as evidenced by Dr. Harvey Cushing, who reported one patient requiring 25 reoperations for control of his intracranial meningioma.8 The question is, can postoperative irradiation decrease the rate of local recurrence when only a subtotal resection is achieved? To answer this, we reviewed our experience at the University of Florida between 1964 and 1985. METHODS
AND MATERIALS
299
I. J. Radiation Oncology 0 Biology 0 Physics
300
F
NO. PTS.
M
August 1988, Volume 15, Number 2
20. 16. 12. 6. 4.
n=76
4. 6. 12. 16.
M VI)F - 1:1.4 B VI w - 1:4.7
20 24
26J
-
lo-19
o-9
W=109
B=23
20-29
30-39
40-49 AGE
50-59
60-69
70-79
60-69
1
(YEARS)
Fig. 1. Age and sex distribution ( 132 patients).
classified according to the predominant cell type and pattern using the classification system proposed by Courville’ and adopted by Burger and Vogel.3 Of the 132 meningiomas, 64 (48%) were classified as meningotheliomatous (syncytial), 40 (30%) transitional (psammomatous), 22 (17%) fibroblastic, and 6 (5%) angiomatous. The sites were documented by X ray and/or the operative report and the distribution is shown in Table 1. The single most common site was the sphenoid ridge (19%) followed in order of frequency by the posterior fossa (17%), parasagittal (14%), convexity (12%), and falx (7%). These 5 sites comprised 70% of our series. Some of the sites were notorious for a higher rate of subtotal resection. Of the patients with a convexity meningioma, 100% had a total excision, while patients with a sphenoid ridge or posterior fossa meningioma had a total resection only 50% of the time. Twenty-three patients received irradiation at some phase in their treatment: 13 patients received postoperative irradiation after subtotal resection, and 10 patients
Table 1. Sites vs. initial treatment
Tumor site
No.of patients
Total excision %
Convexity Olfactory groove Miscellaneous* Parasagittal Parasellar Falx Sphenoid ridge Posterior fossa Total
16 14 8 19 14 9 27 25 132
100
0
0
86
14 13 26 14 33 22 40
0 13 0 14 0 26 12
75 74 72 67 52 48
SE %
SE+RT %
* Miscellaneous = optic nerve sheath, orbit, intraventricular, temporal fossa. SE = Subtotal excision; RT = Radiation therapy.
received irradiation, in combination with surgery or alone, for salvage. There were no patients treated with radiation therapy prior to 1973 at this institution. The mean follow-up for these patients was 6 years for the postoperative patients and 8 years for the patients who received radiation therapy for salvage. Indications for irradiation were not always clear but appeared to be based on the surgeon’s beliefs about the use of postoperative radiation therapy. Patients who were referred for postop erative irradiation had larger residual masses than those receiving subtotal excision alone. All 23 patients received megavoltage irradiation, 5 treatments per week, 180-200 cGy per fraction. Treatment portals were determined by tumor location and encompassed the tumor bed with a 2-4 cm margin. The tumor dose ranged from 5000 to 6300 cGy. Treatment results (local control and survival) were evaluated actuarially, measured from the time of initial treatment (date of first surgery). For the survival curves, patients were counted as “dead” in the actuarial analysis only if they died of meningioma; those patients who died of intercurrent disease with the meningioma controlled for at least 2 years were withdrawn from the analysis “alive” (i.e., controlled) as of a follow-up period ending at the time of death (determinate survival analysis). Recurrence after a total resection was defined as the appearance of a new mass in the previous surgical bed as demonstrated by CT scan or, before the era of CT scans, by angiogram. Recurrence after subtotal resection was defined as an increase in the residual mass, demonstrated by CT scan and/or angiogram. Statistical methods included the Gehan method” for the significance of the difference between 2 curves and a l-tailed test based on the normal approximation of the binomial distribution6 or Fisher’s exact testI for the difference between 2 ratios. The Cutler and Ederer modification of the Berkson-Gage method was used to compute actuarial curves.’
Meningioma controversy 0 B. W. TAYLORJR. et al.
a
g
loo90.
SE + RT (n=13)
80. 70. 80. 40. 50-
$
8 2
! E
T.E.
(n=66)
3020-
2
Fig. 2.
301
4
8
8
10 12 14 TIME (YEARS)
16
18
20
22
Actuarial local control (128 patients). SE, subtotal excision; RT, radiation therapy; TE, total excision. RESULTS
better survival in patients receiving postoperative irradiation. However, the difference was not statistically significant, because of the small number of patients at risk after 6 years in the postoperative irradiation group. The apparent trend developing after 6 years may prove to be significant with further follow-up. Of 30 patients who developed recurrent disease after their initial treatment, 15 received surgery alone, 10 received surgery plus irradiation or irradiation alone, and 5 either refused treatment or were considered inoperable (and did not receive irradiation for various reasons). The actuarial local control and determinate survival curves after salvage are shown in Figures 4 and 5, respectively. Those patients who received irradiation alone or postop eratively for salvage had local control and survival rates that were statistically improved (a = .Ol). The results of salvage treatment in each of the three study categories are reported in Table 2. The salvage rate for patients treated initially with total excision was 7/8 (88%), and surgery alone appeared to be adequate for 5 patients (5/6). For patients treated initially with subtotal excision alone, the salvage rate was 9/20 (45%) overall. However, for patients treated initially with subtotal excision alone and then salvaged with surgery plus postoperative irradiation or irradiation alone, the salvage rate was 7/8 (88%). There was no correlation between histologic subtype
Of the 132 patients, 90 patients underwent a total surgical resection initially and had no adjuvant therapy. The actuarial local control and survival curves for these patients are demonstrated in Figures 2 and 3. The local control curve reflects 8 patients with recurrence. The recurrence rate after total resection was 8/86 (9%), excluding 4 patients who died postoperatively. The remaining 42 patients received a subtotal surgical resection for their initial treatment. Thirteen patients were given postoperative irradiation and 29 patients had no further therapy. To date, 20/29 (69%) of the patients undergoing subtotal excision alone have demonstrated a local recurrence as compared with only 2/l 3 ( 15%) of patients treated with subtotal excision followed by postoperative irradiation. The actuarial local control rates for these patients are also shown in Figure 2. Those patients who received postoperative irradiation had a significantly higher rate of local control compared with those who had subtotal resection alone (p = .Ol). The actuarial determinate survival curves are shown in Figure 3. The determinate survival of patients with subtotal excision alone was similar to that of patients with subtotal excision plus postoperative irradiation until about 6 years. After 6 years the curves diverge, with a trend towards
$ 1 g 2 +
TE MOUE
109 90 80 70 60 50
(n=66)
40 30 20 10
t t t t 2
4
6
6
10
12
14
16
18
26
TlME (YEARS) Fig. 3. Actuarial detenninat
survival (132 patients). TE, total excision; SE, subtotal excision; RT, radiation
302
I. J. Radiation Oncology 0 Biology 0 Physics
loo90. 80. 2 5 70. 00 60. a 50. 8 40. a 30. 20s lo,
August 1988, Volume 15, Number 2
SURGERY + RT (n=lO)
d
0 I2
4
6 TIME
8
10
12
14
(YEARS)
Fig. 4. Actuarial local control after treatment of first recurrence (25 patients).
and survival or local control. The angiomatous subtype should not be confused with the hemangiopericytic variant, which we term angioblastic, which has been reported to have a higher rate of recurrence.12 There were no angioblastic subtypes observed. There was no correlation between dose and tumor control (Table 3). However, all patients who had a recurrence after doses greater than 6000 cGy had large tumor volumes at the time of radiation treatment. For smaller residual masses, 5000-5500 cGy produced an excellent local control rate ( 15117). It is important to note that 17 patients experienced some type of neurological deficit postoperatively. Eight patients had only transient symptoms, but 9 patients had persistent hemiparesis or cranial nerve III palsy. The remaining non-neurological complications included postoperative deaths (7), cerebrospinal fluid leak (3), and postoperative hemorrhage (2). Seven patients required a second procedure for bone flap infection (3), VP shunt (2), tracheostomy (l), or frontal lobe lobectomy for edema (1). Acutely, radiation therapy complications included the usual temporary alopecia, headache, nausea, and vomiting. There was 1 death during treatment of a patient who was in poor health prior to radiation ther-
a g 3* s
loo90. 80. 7060so40. 30. 20-
apy. No major complications such as brain necrosis or pituitary or hypothalamic dysfunction were detected, nor was significant intellectual dysfunction reported by any patient or family member. However, no objective tests were used to detect these deficits. DISCUSSION Historically, meningiomas have been believed to be relatively radioresistant. King et ~1.‘~reported little therapeutic effect from radiation, as did Simpson” and Yamashita et ~1.~’In the past few decades there have been several articles to the contrary.2q4’5.20The purpose of this study was to evaluate our experience in the treatment of meningiomas as well as try to define those situations in which postoperative radiation is of benefit. Initial total excision The prognosis of patients with benign intracranial meningiomas is multifactorial. The completeness of surgical resection, which is influenced by size and location, is probably one of the most important prognostic factors. There is abundant evidence that a total surgical resection without further adjunctive therapy produces excellent results. Wara et al. found a control rate approaching
SURGERY + RT (n=lO)
0 SURGERY ALONE (n=15)
10r
T
2
4
6 TIME
8
10
12
14
(YEARS)
Fig. 5. Actuarial survival after first recurrence (25 patients).
Meningioma controversy 0 B. W. TAYLOR JR. et al. Table 2. Meningioma:
Ultimate results* of salvage treatment vs. initial treatment (no. controlled/no. Total excision
Initial treatment Salvage treatment Surgery alone Surgery + RT RT alone Refused treatment Postop death Total salvage
303
SE
treated)
SE+RT
Total
781867
9129
11/13
981128
516
217 212 516 O/3 O/2 9120 (45%)
0 0 0 O/2 0 O/2 (0%)
7/13 (54%) 2/2 ( 100%) 7/8 (88%) o/5 (0%) o/2 (0%) 16130 (53%)
2;2 0 0 718 (88%)
* Patient may have had more than 1 recurrence. t 4 patients who died postoperatively after total excision not included. SE = Subtotal excision; RT = Radiation therapy. 100% when the meningioma was thought to be totally resected.20 Most recently, Barbaro et al., updating Wara’s
results, found the risk of recurrence to be 4% with no deaths in this group of patients2 In this series, our recurrence rate for patients with a total surgical excision was 9% (8/86), although there were also 4 postoperative deaths. Seven of these 8 patients with local failures have been salvaged to date with either additional surgery or radiation therapy, producing an ultimate local control of over 98% (85/86).
Initial subtotal excision There is substantial evidence that anything less than a total surgical resection increases the rate of recurrence. Adegbite et al. concluded that the only significant factor influencing recurrences was the completeness of surgery, reporting a 52% relapse rate at 5 years for 18 patients with partially resected disease.’ Other authors reported a recurrence rate ranging from 37% to 60% after a subtotal excision (Table 4). In this series, those patients who received a subtotal resection alone had a recurrence rate of 57% at 5 years and 69% overall. Several recent analyses support the use of postoperative radiation therapy. Wara et al. found an incidence of recurrence of 29% in patients receiving postoperative radiation therapy vs. 74% when no radiation therapy was added after subtotal excision.20 Half of these patients had follow-up for more than 6 years. Carella et al. reported a recurrence rate of only 2/43 after subtotal resection and postoperative radiation therapy, although half of these patients had less than 3 years of follow-up.4 Most recently, Barbaro et al. showed that 60% of nonirradiated patients had a recurrence compared with 32% of those who received radiation therapy.2 Table 3. Results by radiation dose (all patients) Dose (cGy) 5000-5499 5500-5999 6000-6300 Total
No. with disease (controlled/treated) 819 718 516 20123
In this analysis, patients who received postoperative radiation therapy after subtotal excision had a recurrence rate of 15% (2/ 13) vs. 69% (20/29) in the nonirradi-
ated group. Ten-year survival rates were 8 1% for those who received postoperative radiation therapy compared with 49% for those in the nonirradiated group. With respect to follow-up data, 83% of the patients who died of meningioma received subtotal excision alone for their initial therapy.
Treatment of recurrence The mean interval to clinical recurrence is approxiMirimanoff et al. reported that the mately 4 years. ‘4q’5~18 probability of a third operation after the first salvage operation was 42% at 5 years and 56% at 10 years.” Despite these results, meningiomas are considered to be slow growing and relatively benign, and radiation therapy is often not used for the treatment of recurrences. Yamashita et al. reported that radiation therapy was of little value for recurrent meningiomas in his analysis of 336 cases of intracranial meningiomas, except occasionally in atypical or malignant meningiomas.2’ Carella et al. reported that the treatment of recurrent tumors was not satisfactory, with 5 of 14 patients in this category dying of their disease.4 Forbes and Goldberg also reported no difference in relapse-free survival rates for patients treated with or without radiation at salvage.” However, Table 4. Reported 5-year recurrence rates (initial treatment) SE alone Mirimanoff et al.” (MGH) Melamed et al.” (Israel) Barbaro et aL2 (UCSF) Forbes and Goldberg” (JCRT) Taylor et al. (UF)
SE+RT
37%
n.d.
33%
n.d.
60%
32%
n.d.
2%
57%
15%
* Update of study by Wara et al.” SE = Subtotal excision; RT = Radiation therapy; n.d. = No data.
I. J. Radiation Oncology 0 Biology 0 Physics
304
Wara et al. stated that radiation therapy was of value in patients who had a recurrence following primary resection.20 They reported a higher salvage rate in those patients who received radiation (with or without reoperation). Our series concurs with that of Wara et al. For the 15 patients who received surgery alone for salvage, the actuarial local control rate at 10 years was 30%. In comparison, the 10 patients who received radiation (with or without resection) had an actuarial local control rate of 89%. Actuarial determinate survival was also significantly affected by the addition of radiation therapy for salvage: 43% at 10 years without salvage radiation therapy compared with 89% for those patients who received irradiation. Initial irradiation vs. irradiation for recurrence If irradiation is so effective with recurrence, why not wait until the tumor recurs or the patient shows signs of disease progression? It is reported that recurrence has an adverse effect on survival.5Y’9*2’ In our series, a trend toward improved survival was seen at 10 years for patients receiving subtotal excision and postoperative irradiation initially as compared with patients receiving subtotal excision only. It is important to note that this implies that many patients who have recurrences after subtotal excision alone were not salvaged. Of the patients with recurrence, several
August 1988, Volume 15,Number 2
died at the second procedure or were considered inoperable at the time of recurrence. Also, our data show that most of the patients who died of meningioma since 1964 at our institution were initially treated with a subtotal resection alone. Therefore, it is logical to assume that if irradiation used initially increases the local control rate and decreases the recurrence rate, fewer patients would have recurrences and be subjected to the risks of a second procedure or an inoperable lesion. CONCLUSION
Based on the data from this analysis, we have recommended the following guidelines for treatment of benign intracranial meningiomas: (a) If the meningioma is totally resected, no further therapy is usually required. However, careful and persistent follow-up is necessary, since most of the few recurrences that occur can be salvaged. (b) If the meningioma is subtotally resected, postoperative irradiation should be strongly considered to a dose of 5000-5500 cGy at 180 cGy a day. In certain medical situations, it may be prudent to reserve treatment until recurrence is diagnosed. (c) For recurrent meningioma without prior radiation treatment, we recommend surgical resection, if safe and technically possible, followed by postoperative irradiation. If surgery is not an option, then radiation therapy alone is recommended.
REFERENCES
1. Adegbite,A.B., Khan, M.I., Paine, K.W.E.,Tan, L.K.: The recurrence of intracranial meningiomas after surgical treatment. J. Neurosurg. 58: 5 l-56, 1983. 2. Barbaro, N.M., Gutin, P.H., Wilson, C.B., Sheline, G.E., Boldrey, E.B., Wara, W.M.: Radiation therapy in the treatment of partially resected meningiomas. Neurosurgery 20: 525-528,1987.
3. Burger, P.C., Vogel, F.S.: Surgical Pathology of the Nervous System and Its Coverings, 2nd edition. New York,
John Wiley &Sons. 1982, pp. 83-170. 4. Carella, R.J., Ransohoff, J., Newall, J.: Role of radiation therapy in the management of meningioma. Neurosurgery lo: 332-339,1982. 5. Chan, R.C., Thompson, G.B.: Morbidity, mortality, and
quality of life following surgery for intracranial meningiomas. A retrospective study in 257 cases. J. Neurosurg. 60:
52-60,1984. 6. Colton, T.: Statistics in Medicine. Boston, Little, Brown &
Co. 1974, pp. 163-167.
7. Courville, C.B.: Pathology of the Central Nervous System. A Study Based Upon a Survey of Lesions Found in a Series of Thirty Thousand Autopsies, 2nd edition. Mountain
View _ ! CA1-Pacific ~. Press? 1945. 8. Cushing, H., Eisenhardt, L.: Meningiomas, Their Classijcation, Regional Behavior, Life History, and Surgical End Results. New York, Hafner. 1962. _ DD. _ 669-7 19.734740. 9. Cutler, S.J., Ederer, F.: Maximum utilization of the life table method in analyzing survival. J. Chronic Dis. 8: 699712,1958. 10. Forbes, A.R., Goldberg, I.D.: Radiation therapy in the treatment of meningioma: the Joint Center for Radiation Therapy experience 1970-1982. J. Clin. Oncol. 2: 11391143, 1984.
11. Gehan, E.A.: A generalized Wilcoxan test for comparing arbitrarily singly-censored samples. Biometrika 52: 203223,1965. 12. Jellinger, K., Slowik, F.: Histologic subtypes and prognostic problems in meningiomas. J. Neural. 208: 279-298,
1975. 13. Kepes, J.J.: Meningiomas: Biology, Pathology, and Differential Diagnosis. New York, Masson Publishing
USA, 1982. 14. King, D.L., Chang, C.H., Pool, J.L.: Radiotherapy in the management of meningiomas. Acta Radiol. Ther. Phys. Biol. 5: 26-33, 1966. 15. Melamed, S., Sahar, A., Beller, A.J.: The recurrence of intracranial meningiomas. Neurochirurgia (Stuttg.) 22: 47-
51, 1979. 16. Mendenhall, W., Ott, L., Larson, R.F.: Statistics: A Tool for the Social Sciences. North Scituate, MA, Duxbury Press. 1974, pp. 333-336. 17. Mirimanoff, R.O., Dosoretz, D.E., Linggood, R.M., Ojemann, R.G., Martuza, R.L.: Meningioma: Analysis of recurrence and progression following neurosurgical resection. J. Neurosurg. 62: 18-24, 1985.
18. Petty, A.M., Kun, L.E., Meyer, G.A.: Radiation therapy for incompletely resected meningiomas. J. Neurosurg. 62: 502-507, 1985.
19. Simpson; D.: The recurrence of intracranial meningiomas after surgical treatment. J. Neural. Neurosurg. Psychiat. 20: 22-39,1957.
20. Wara, W.M., Sheline, G.E., Newman, H., Townsend, J.J., Boldrey, E.B.: Radiation therapy of meningiomas. Am. J. Roentgenol. 123: 453-458, 1975.
21. Yamashita, J., Handa, H., Iwaki, K., Abe, M.: Recurrence of intracranial meningiomas with special reference to radiotherapy. Surg. Neurol. 14: 33-40, 1980.
0360-3016/88 $3.00 + .OO Copyright 0 1988 Pergamon Press plc
15. pp. 299-304
0 Original Contribution THE MENINGIOMA CONTROVERSY: POSTOPERATIVE RADIATION THERAPY BERNARD W. TAYLOR JR., M.D.,* ROBERT B. MARCUS JR., M.D.,* WILLIAM A. FRIEDMAN, M.D.,? WILLIAM E. BALLINGER JR., M.D.* AND RODNEY R. MILLION, M.D.* University of Florida, Gainesville, Florida Total surgical excision is the main goal of therapy for intracranial meningiomas. The controversy today involves the efficacy of postoperative radiation therapy. To evaluate this question, 132 patients with benign intracranial meningiomas, treated between October 1964 and April 1985, were evaluated. All patients had a minimum 2-year follow-up. The actuarial local control rates at 10 years for the three treatment groups were as follows: subtotal excision alone, 18%; subtotal excision plus postoperative radiation therapy, 822, and total excision alone, 77%. The actuarial determinate survival rates at 10 years were 49%, 81%, and 93%, respectively. Postoperative radiation therapy was also effective for patients treated at the time of the first recurrence, with an actuarial local control rate at 10 years after salvage treatment of 30% for patients treated with surgery alone and 89% for patients receiving postoperative radiation therapy at the time of salvage. This analysis suggests that radiation therapy has a significant role in the treatment of subtotally excised and recurrent intracranial meningiomas. Meningioma (benign), Radiation therapy, Surgery.
One hundred ninety-seven patients with the diagnosis of meningioma were evaluated between October 1964 and April 1985 at the University of Florida Shands Hospital or the Gainesville VA Hospital. Sixty-five patients were excluded from this analysis for the following rea-
sons: 5 patients had neurofibromatosis and were genetically predisposed to develop meningiomas, 8 patients refused all forms of treatment, 23 patients received surgery or irradiation at another institution, 2 patients’ medical records were lost, and 10 patients were lost to follow-up immediately after treatment because they were referred from South America and never returned for follow-up, nor could they be located. Also excluded were 9 patients with spinal meningiomas and 8 patients with malignant histologies. The remaining 132 patients were analyzed in this study. All had a minimum 2-year follow-up, and approximately 60% of the patients had a minimum follow-up of 5 years. Since 1976, most patients have had a yearly CT scan for radiographic follow-up, including those patients treated prior to the era of CT scanning. The age and sex distribution is shown in Figure 1. Age at first surgery ranged from 1 to 79 years with a mean age of 5 1 years. Although meningioma is uncommon in children, 4 of these patients were diagnosed prior to age 20. The male to female ratio was 1: 1.4; there were 23 black and 109 white patients, for a black to white ratio of 1:4.7. Histological confirmation was obtained in all patients at the initial surgical resection. The histology was sub-
Presented at the 29th Annual Meeting ofthe American Society for Therapeutic Radiology and Oncology, October 18-23, 1987, Boston, MA. * Dept. of Radiation Oncology. t Dept. of Neurosurgery.
$ Dept. of Neuropathology. Reprint requests to: Dr. R. B. Marcus Jr., Radiation Oncology, Box J-385, J. Hillis Miller Health Center, Gainesville, FL 32610-0385. Accepted for publication 2 March 1988.
INTRODUCTION Meningiomas comprise approximately 15% of all primary intracranial neoplasms. They are slow growing and account for only 7% of all deaths from primary brain neoplasms. I3 The goal of therapy is total surgical excision. However, if bone invasion, involvement of major vascular structures, or large tumor volume is present, total surgical resection may be impossible. Treatment of these patients can be frustrating, as evidenced by Dr. Harvey Cushing, who reported one patient requiring 25 reoperations for control of his intracranial meningioma.8 The question is, can postoperative irradiation decrease the rate of local recurrence when only a subtotal resection is achieved? To answer this, we reviewed our experience at the University of Florida between 1964 and 1985. METHODS
AND MATERIALS
299
I. J. Radiation Oncology 0 Biology 0 Physics
300
F
NO. PTS.
M
August 1988, Volume 15, Number 2
20. 16. 12. 6. 4.
n=76
4. 6. 12. 16.
M VI)F - 1:1.4 B VI w - 1:4.7
20 24
26J
-
lo-19
o-9
W=109
B=23
20-29
30-39
40-49 AGE
50-59
60-69
70-79
60-69
1
(YEARS)
Fig. 1. Age and sex distribution ( 132 patients).
classified according to the predominant cell type and pattern using the classification system proposed by Courville’ and adopted by Burger and Vogel.3 Of the 132 meningiomas, 64 (48%) were classified as meningotheliomatous (syncytial), 40 (30%) transitional (psammomatous), 22 (17%) fibroblastic, and 6 (5%) angiomatous. The sites were documented by X ray and/or the operative report and the distribution is shown in Table 1. The single most common site was the sphenoid ridge (19%) followed in order of frequency by the posterior fossa (17%), parasagittal (14%), convexity (12%), and falx (7%). These 5 sites comprised 70% of our series. Some of the sites were notorious for a higher rate of subtotal resection. Of the patients with a convexity meningioma, 100% had a total excision, while patients with a sphenoid ridge or posterior fossa meningioma had a total resection only 50% of the time. Twenty-three patients received irradiation at some phase in their treatment: 13 patients received postoperative irradiation after subtotal resection, and 10 patients
Table 1. Sites vs. initial treatment
Tumor site
No.of patients
Total excision %
Convexity Olfactory groove Miscellaneous* Parasagittal Parasellar Falx Sphenoid ridge Posterior fossa Total
16 14 8 19 14 9 27 25 132
100
0
0
86
14 13 26 14 33 22 40
0 13 0 14 0 26 12
75 74 72 67 52 48
SE %
SE+RT %
* Miscellaneous = optic nerve sheath, orbit, intraventricular, temporal fossa. SE = Subtotal excision; RT = Radiation therapy.
received irradiation, in combination with surgery or alone, for salvage. There were no patients treated with radiation therapy prior to 1973 at this institution. The mean follow-up for these patients was 6 years for the postoperative patients and 8 years for the patients who received radiation therapy for salvage. Indications for irradiation were not always clear but appeared to be based on the surgeon’s beliefs about the use of postoperative radiation therapy. Patients who were referred for postop erative irradiation had larger residual masses than those receiving subtotal excision alone. All 23 patients received megavoltage irradiation, 5 treatments per week, 180-200 cGy per fraction. Treatment portals were determined by tumor location and encompassed the tumor bed with a 2-4 cm margin. The tumor dose ranged from 5000 to 6300 cGy. Treatment results (local control and survival) were evaluated actuarially, measured from the time of initial treatment (date of first surgery). For the survival curves, patients were counted as “dead” in the actuarial analysis only if they died of meningioma; those patients who died of intercurrent disease with the meningioma controlled for at least 2 years were withdrawn from the analysis “alive” (i.e., controlled) as of a follow-up period ending at the time of death (determinate survival analysis). Recurrence after a total resection was defined as the appearance of a new mass in the previous surgical bed as demonstrated by CT scan or, before the era of CT scans, by angiogram. Recurrence after subtotal resection was defined as an increase in the residual mass, demonstrated by CT scan and/or angiogram. Statistical methods included the Gehan method” for the significance of the difference between 2 curves and a l-tailed test based on the normal approximation of the binomial distribution6 or Fisher’s exact testI for the difference between 2 ratios. The Cutler and Ederer modification of the Berkson-Gage method was used to compute actuarial curves.’
Meningioma controversy 0 B. W. TAYLORJR. et al.
a
g
loo90.
SE + RT (n=13)
80. 70. 80. 40. 50-
$
8 2
! E
T.E.
(n=66)
3020-
2
Fig. 2.
301
4
8
8
10 12 14 TIME (YEARS)
16
18
20
22
Actuarial local control (128 patients). SE, subtotal excision; RT, radiation therapy; TE, total excision. RESULTS
better survival in patients receiving postoperative irradiation. However, the difference was not statistically significant, because of the small number of patients at risk after 6 years in the postoperative irradiation group. The apparent trend developing after 6 years may prove to be significant with further follow-up. Of 30 patients who developed recurrent disease after their initial treatment, 15 received surgery alone, 10 received surgery plus irradiation or irradiation alone, and 5 either refused treatment or were considered inoperable (and did not receive irradiation for various reasons). The actuarial local control and determinate survival curves after salvage are shown in Figures 4 and 5, respectively. Those patients who received irradiation alone or postop eratively for salvage had local control and survival rates that were statistically improved (a = .Ol). The results of salvage treatment in each of the three study categories are reported in Table 2. The salvage rate for patients treated initially with total excision was 7/8 (88%), and surgery alone appeared to be adequate for 5 patients (5/6). For patients treated initially with subtotal excision alone, the salvage rate was 9/20 (45%) overall. However, for patients treated initially with subtotal excision alone and then salvaged with surgery plus postoperative irradiation or irradiation alone, the salvage rate was 7/8 (88%). There was no correlation between histologic subtype
Of the 132 patients, 90 patients underwent a total surgical resection initially and had no adjuvant therapy. The actuarial local control and survival curves for these patients are demonstrated in Figures 2 and 3. The local control curve reflects 8 patients with recurrence. The recurrence rate after total resection was 8/86 (9%), excluding 4 patients who died postoperatively. The remaining 42 patients received a subtotal surgical resection for their initial treatment. Thirteen patients were given postoperative irradiation and 29 patients had no further therapy. To date, 20/29 (69%) of the patients undergoing subtotal excision alone have demonstrated a local recurrence as compared with only 2/l 3 ( 15%) of patients treated with subtotal excision followed by postoperative irradiation. The actuarial local control rates for these patients are also shown in Figure 2. Those patients who received postoperative irradiation had a significantly higher rate of local control compared with those who had subtotal resection alone (p = .Ol). The actuarial determinate survival curves are shown in Figure 3. The determinate survival of patients with subtotal excision alone was similar to that of patients with subtotal excision plus postoperative irradiation until about 6 years. After 6 years the curves diverge, with a trend towards
$ 1 g 2 +
TE MOUE
109 90 80 70 60 50
(n=66)
40 30 20 10
t t t t 2
4
6
6
10
12
14
16
18
26
TlME (YEARS) Fig. 3. Actuarial detenninat
survival (132 patients). TE, total excision; SE, subtotal excision; RT, radiation
302
I. J. Radiation Oncology 0 Biology 0 Physics
loo90. 80. 2 5 70. 00 60. a 50. 8 40. a 30. 20s lo,
August 1988, Volume 15, Number 2
SURGERY + RT (n=lO)
d
0 I2
4
6 TIME
8
10
12
14
(YEARS)
Fig. 4. Actuarial local control after treatment of first recurrence (25 patients).
and survival or local control. The angiomatous subtype should not be confused with the hemangiopericytic variant, which we term angioblastic, which has been reported to have a higher rate of recurrence.12 There were no angioblastic subtypes observed. There was no correlation between dose and tumor control (Table 3). However, all patients who had a recurrence after doses greater than 6000 cGy had large tumor volumes at the time of radiation treatment. For smaller residual masses, 5000-5500 cGy produced an excellent local control rate ( 15117). It is important to note that 17 patients experienced some type of neurological deficit postoperatively. Eight patients had only transient symptoms, but 9 patients had persistent hemiparesis or cranial nerve III palsy. The remaining non-neurological complications included postoperative deaths (7), cerebrospinal fluid leak (3), and postoperative hemorrhage (2). Seven patients required a second procedure for bone flap infection (3), VP shunt (2), tracheostomy (l), or frontal lobe lobectomy for edema (1). Acutely, radiation therapy complications included the usual temporary alopecia, headache, nausea, and vomiting. There was 1 death during treatment of a patient who was in poor health prior to radiation ther-
a g 3* s
loo90. 80. 7060so40. 30. 20-
apy. No major complications such as brain necrosis or pituitary or hypothalamic dysfunction were detected, nor was significant intellectual dysfunction reported by any patient or family member. However, no objective tests were used to detect these deficits. DISCUSSION Historically, meningiomas have been believed to be relatively radioresistant. King et ~1.‘~reported little therapeutic effect from radiation, as did Simpson” and Yamashita et ~1.~’In the past few decades there have been several articles to the contrary.2q4’5.20The purpose of this study was to evaluate our experience in the treatment of meningiomas as well as try to define those situations in which postoperative radiation is of benefit. Initial total excision The prognosis of patients with benign intracranial meningiomas is multifactorial. The completeness of surgical resection, which is influenced by size and location, is probably one of the most important prognostic factors. There is abundant evidence that a total surgical resection without further adjunctive therapy produces excellent results. Wara et al. found a control rate approaching
SURGERY + RT (n=lO)
0 SURGERY ALONE (n=15)
10r
T
2
4
6 TIME
8
10
12
14
(YEARS)
Fig. 5. Actuarial survival after first recurrence (25 patients).
Meningioma controversy 0 B. W. TAYLOR JR. et al. Table 2. Meningioma:
Ultimate results* of salvage treatment vs. initial treatment (no. controlled/no. Total excision
Initial treatment Salvage treatment Surgery alone Surgery + RT RT alone Refused treatment Postop death Total salvage
303
SE
treated)
SE+RT
Total
781867
9129
11/13
981128
516
217 212 516 O/3 O/2 9120 (45%)
0 0 0 O/2 0 O/2 (0%)
7/13 (54%) 2/2 ( 100%) 7/8 (88%) o/5 (0%) o/2 (0%) 16130 (53%)
2;2 0 0 718 (88%)
* Patient may have had more than 1 recurrence. t 4 patients who died postoperatively after total excision not included. SE = Subtotal excision; RT = Radiation therapy. 100% when the meningioma was thought to be totally resected.20 Most recently, Barbaro et al., updating Wara’s
results, found the risk of recurrence to be 4% with no deaths in this group of patients2 In this series, our recurrence rate for patients with a total surgical excision was 9% (8/86), although there were also 4 postoperative deaths. Seven of these 8 patients with local failures have been salvaged to date with either additional surgery or radiation therapy, producing an ultimate local control of over 98% (85/86).
Initial subtotal excision There is substantial evidence that anything less than a total surgical resection increases the rate of recurrence. Adegbite et al. concluded that the only significant factor influencing recurrences was the completeness of surgery, reporting a 52% relapse rate at 5 years for 18 patients with partially resected disease.’ Other authors reported a recurrence rate ranging from 37% to 60% after a subtotal excision (Table 4). In this series, those patients who received a subtotal resection alone had a recurrence rate of 57% at 5 years and 69% overall. Several recent analyses support the use of postoperative radiation therapy. Wara et al. found an incidence of recurrence of 29% in patients receiving postoperative radiation therapy vs. 74% when no radiation therapy was added after subtotal excision.20 Half of these patients had follow-up for more than 6 years. Carella et al. reported a recurrence rate of only 2/43 after subtotal resection and postoperative radiation therapy, although half of these patients had less than 3 years of follow-up.4 Most recently, Barbaro et al. showed that 60% of nonirradiated patients had a recurrence compared with 32% of those who received radiation therapy.2 Table 3. Results by radiation dose (all patients) Dose (cGy) 5000-5499 5500-5999 6000-6300 Total
No. with disease (controlled/treated) 819 718 516 20123
In this analysis, patients who received postoperative radiation therapy after subtotal excision had a recurrence rate of 15% (2/ 13) vs. 69% (20/29) in the nonirradi-
ated group. Ten-year survival rates were 8 1% for those who received postoperative radiation therapy compared with 49% for those in the nonirradiated group. With respect to follow-up data, 83% of the patients who died of meningioma received subtotal excision alone for their initial therapy.
Treatment of recurrence The mean interval to clinical recurrence is approxiMirimanoff et al. reported that the mately 4 years. ‘4q’5~18 probability of a third operation after the first salvage operation was 42% at 5 years and 56% at 10 years.” Despite these results, meningiomas are considered to be slow growing and relatively benign, and radiation therapy is often not used for the treatment of recurrences. Yamashita et al. reported that radiation therapy was of little value for recurrent meningiomas in his analysis of 336 cases of intracranial meningiomas, except occasionally in atypical or malignant meningiomas.2’ Carella et al. reported that the treatment of recurrent tumors was not satisfactory, with 5 of 14 patients in this category dying of their disease.4 Forbes and Goldberg also reported no difference in relapse-free survival rates for patients treated with or without radiation at salvage.” However, Table 4. Reported 5-year recurrence rates (initial treatment) SE alone Mirimanoff et al.” (MGH) Melamed et al.” (Israel) Barbaro et aL2 (UCSF) Forbes and Goldberg” (JCRT) Taylor et al. (UF)
SE+RT
37%
n.d.
33%
n.d.
60%
32%
n.d.
2%
57%
15%
* Update of study by Wara et al.” SE = Subtotal excision; RT = Radiation therapy; n.d. = No data.
I. J. Radiation Oncology 0 Biology 0 Physics
304
Wara et al. stated that radiation therapy was of value in patients who had a recurrence following primary resection.20 They reported a higher salvage rate in those patients who received radiation (with or without reoperation). Our series concurs with that of Wara et al. For the 15 patients who received surgery alone for salvage, the actuarial local control rate at 10 years was 30%. In comparison, the 10 patients who received radiation (with or without resection) had an actuarial local control rate of 89%. Actuarial determinate survival was also significantly affected by the addition of radiation therapy for salvage: 43% at 10 years without salvage radiation therapy compared with 89% for those patients who received irradiation. Initial irradiation vs. irradiation for recurrence If irradiation is so effective with recurrence, why not wait until the tumor recurs or the patient shows signs of disease progression? It is reported that recurrence has an adverse effect on survival.5Y’9*2’ In our series, a trend toward improved survival was seen at 10 years for patients receiving subtotal excision and postoperative irradiation initially as compared with patients receiving subtotal excision only. It is important to note that this implies that many patients who have recurrences after subtotal excision alone were not salvaged. Of the patients with recurrence, several
August 1988, Volume 15,Number 2
died at the second procedure or were considered inoperable at the time of recurrence. Also, our data show that most of the patients who died of meningioma since 1964 at our institution were initially treated with a subtotal resection alone. Therefore, it is logical to assume that if irradiation used initially increases the local control rate and decreases the recurrence rate, fewer patients would have recurrences and be subjected to the risks of a second procedure or an inoperable lesion. CONCLUSION
Based on the data from this analysis, we have recommended the following guidelines for treatment of benign intracranial meningiomas: (a) If the meningioma is totally resected, no further therapy is usually required. However, careful and persistent follow-up is necessary, since most of the few recurrences that occur can be salvaged. (b) If the meningioma is subtotally resected, postoperative irradiation should be strongly considered to a dose of 5000-5500 cGy at 180 cGy a day. In certain medical situations, it may be prudent to reserve treatment until recurrence is diagnosed. (c) For recurrent meningioma without prior radiation treatment, we recommend surgical resection, if safe and technically possible, followed by postoperative irradiation. If surgery is not an option, then radiation therapy alone is recommended.
REFERENCES
1. Adegbite,A.B., Khan, M.I., Paine, K.W.E.,Tan, L.K.: The recurrence of intracranial meningiomas after surgical treatment. J. Neurosurg. 58: 5 l-56, 1983. 2. Barbaro, N.M., Gutin, P.H., Wilson, C.B., Sheline, G.E., Boldrey, E.B., Wara, W.M.: Radiation therapy in the treatment of partially resected meningiomas. Neurosurgery 20: 525-528,1987.
3. Burger, P.C., Vogel, F.S.: Surgical Pathology of the Nervous System and Its Coverings, 2nd edition. New York,
John Wiley &Sons. 1982, pp. 83-170. 4. Carella, R.J., Ransohoff, J., Newall, J.: Role of radiation therapy in the management of meningioma. Neurosurgery lo: 332-339,1982. 5. Chan, R.C., Thompson, G.B.: Morbidity, mortality, and
quality of life following surgery for intracranial meningiomas. A retrospective study in 257 cases. J. Neurosurg. 60:
52-60,1984. 6. Colton, T.: Statistics in Medicine. Boston, Little, Brown &
Co. 1974, pp. 163-167.
7. Courville, C.B.: Pathology of the Central Nervous System. A Study Based Upon a Survey of Lesions Found in a Series of Thirty Thousand Autopsies, 2nd edition. Mountain
View _ ! CA1-Pacific ~. Press? 1945. 8. Cushing, H., Eisenhardt, L.: Meningiomas, Their Classijcation, Regional Behavior, Life History, and Surgical End Results. New York, Hafner. 1962. _ DD. _ 669-7 19.734740. 9. Cutler, S.J., Ederer, F.: Maximum utilization of the life table method in analyzing survival. J. Chronic Dis. 8: 699712,1958. 10. Forbes, A.R., Goldberg, I.D.: Radiation therapy in the treatment of meningioma: the Joint Center for Radiation Therapy experience 1970-1982. J. Clin. Oncol. 2: 11391143, 1984.
11. Gehan, E.A.: A generalized Wilcoxan test for comparing arbitrarily singly-censored samples. Biometrika 52: 203223,1965. 12. Jellinger, K., Slowik, F.: Histologic subtypes and prognostic problems in meningiomas. J. Neural. 208: 279-298,
1975. 13. Kepes, J.J.: Meningiomas: Biology, Pathology, and Differential Diagnosis. New York, Masson Publishing
USA, 1982. 14. King, D.L., Chang, C.H., Pool, J.L.: Radiotherapy in the management of meningiomas. Acta Radiol. Ther. Phys. Biol. 5: 26-33, 1966. 15. Melamed, S., Sahar, A., Beller, A.J.: The recurrence of intracranial meningiomas. Neurochirurgia (Stuttg.) 22: 47-
51, 1979. 16. Mendenhall, W., Ott, L., Larson, R.F.: Statistics: A Tool for the Social Sciences. North Scituate, MA, Duxbury Press. 1974, pp. 333-336. 17. Mirimanoff, R.O., Dosoretz, D.E., Linggood, R.M., Ojemann, R.G., Martuza, R.L.: Meningioma: Analysis of recurrence and progression following neurosurgical resection. J. Neurosurg. 62: 18-24, 1985.
18. Petty, A.M., Kun, L.E., Meyer, G.A.: Radiation therapy for incompletely resected meningiomas. J. Neurosurg. 62: 502-507, 1985.
19. Simpson; D.: The recurrence of intracranial meningiomas after surgical treatment. J. Neural. Neurosurg. Psychiat. 20: 22-39,1957.
20. Wara, W.M., Sheline, G.E., Newman, H., Townsend, J.J., Boldrey, E.B.: Radiation therapy of meningiomas. Am. J. Roentgenol. 123: 453-458, 1975.
21. Yamashita, J., Handa, H., Iwaki, K., Abe, M.: Recurrence of intracranial meningiomas with special reference to radiotherapy. Surg. Neurol. 14: 33-40, 1980.