Journal of Radiosurgery, Vol. 1, No. 1, 1998

Stereotactic Radiosurgery for Human Glioma: TreatmentParameters and Outcome for Low vs. High Grade

Jeffery Williams, M.D.1,2,4 Randa Zakhary, A.B.,3 Mark Watts, M.D.,2 and MoodyWharara, M.D.1

Stereotactic radiosurgery (SRS) offers the precise, local delivery of radiation for the treatment ofrecurrent gliomas. We examined the comparative characteristics, treatments, and outcome in apopulation having with low- and high-grade gliomas. Between September 1991 and December1995, 20 patients (13 males, 7 females) had SRS for low-grade [9 patients: World Health Organ-ization (WHO) grade II] vs. high-grade (11 patients: 9 WHO grade IV and 2 WHO grade III)gliomas. The patients with low-grade gliomas were younger (mean age ± SE, 39.6 ± 5.4 years;range, 11.4-61.0 years) than those with high-grade gliomas (51.3 ± 13.9 years; range, 32.9-78.5years) (P = 0.09). Tumor locations were similar in the two groups: lobar for 7 of 9 low-grade vs.9 of 11 high-grade gliomas (P = NS) and diencephalic or cerebellar for the remainder. The initialsurgical treatments were biopsy, subtotal resection, and total resection for three, three, and threepatients with low-grade gliomas, vs. three, seven, and one patients with high-grade gliomas, re-spectively (P = NS). Except for three patients with low-grade gliomas, all patients had conven-tional postoperative fractionated external-beam radiotherapy. The doses were 5583 ± 342 vs. 5345± 261 cGy (P = NS) for low- vs. high-grade gliomas, respectively. Intervals from surgery andconventional radiation (if given) to progression and SRS tended to be longer for low-grade gliomas:37.5 ± 9.5 vs. 30.6 ± 11.1 months (P = NS) for low- vs. high-grade gliomas, respectively. High-grade gliomas were larger. The diameters of the collimators that allowed enclosure of the enhancingtumor volume within the specified treatment isodoses were 22.4 ± 2.0 mm for low-grade vs. 29.8± 2.8 mm for high-grade gliomas (P = 0.02, ANOVA). SRS doses and isodose percentiles weresimilar, however, for the two groups: 1650 ± 191 cGy and 79 ± 4.0% vs. 1932 ± 182 cGy and75 ± 3.5% for low- vs. high-grade gliomas, respectively (P = NS, dose and isodose). All patientswith high-grade gliomas were followed until death. The mean survival after SRS was 11.6 ± 1.5months (42 ± 12 months after surgery). Five of nine patients with low-grade gliomas expired31.6 ± 6.0 months after SRS (P < 0.001, Kaplan-Meier log rank) (74.0 ± 16.0 months aftersurgery). The four survivors have been followed for 8, 13, 35, and 38 months after SRS, respec-tively. Multivariate analysis shows that the category of histologic grade correlates significantlywith survival after radiosurgery (P = 0.01). SRS may be an important therapeutic option forpatients with recurrent gliomas, regardless of their grade.

INTRODUCTION

For gliomas, the histologic grade defines the clini-cal natural history and is central to predicting the out-

1 Division of Radiation Oncology, Department of Oncology, The JohnsHopkins University School of Medicine, Baltimore, Maryland 21287.

2 Department of Neurosurgery, The Johns Hopkins University Schoolof Medicine, Baltimore, Maryland 21287.

3 The Johns Hopkins University School of Medicine, 600 North WolfeStreet, Baltimore, Maryland 21287-5001.

4 To whom correspondence should be addressed.

come of treatments. Low-grade gliomas typically ariseearlier in life and have been called "benign." Most pa-tients with low-grade gliomas, however, eventually die,and only approximately 15% of patients have a long-term survival (1). In the absence of prospective random-ized trials, the most effective treatment for low-gradegliomas remains controversial. The 5-year survival ofpatients with low-grade gliomas who have surgery aloneis only approximately 20% (1). Postoperative external-beam radiotherapy appears to prolong survival. For pa-

KEY WORDS: Stereotactic radiosurgery; malignant glioma; low-grade glioma; radiotherapy.

3I096-4053/98/0300-0003$15.00/0 C 1998 Plenum Publishing Corporation

Williams, Zakhary, Watts, and Wharam

tients who receive postoperative radiotherapy the sur-vival is approximately 50% (2). At the time ofrecurrence after initial surgery with or without radio-therapy, the best treatment for low-grade gliomas is evenless well defined. For these tumors, stereotactic radio-surgery (SRS) for recurrence remains largely unex-plored.

In contrast, malignant gliomas have remained par-ticularly refractory to intensive treatments, despite con-tinued attempts to improve therapy (3-7). Althoughmalignant gliomas are relatively uncommon, totaling ap-proximately 40% of the 17,000 annual new cases of cen-tral nervous system malignancies diagnosed in theUnited States each year, the interest in their treatment isheightened by their resultant high mortality. Malignantgliomas rarely metastasize and the high mortality resultsfrom local failure of treatments.

Prospective trials have shown that postoperative ra-diotherapy for malignant gliomas improves survival (6),and escalation of the radiation dose [>60 Gy (1 Gy =100 rad)] may result in a further improvement in sur-vival (3, 5). For recurrent malignant gliomas, additionallocal radiotherapy via 125I implant (8) and SRS havebeen explored (9-11).

For the treatment of recurrent gliomas, regardlessof grade, SRS offers the precise, noninvasive deliveryof focal radiation while sparing the surrounding normalbrain (9, 10). Within a single institutional population,we compared the patient characteristics, treatments, andoutcome in patients having radiosurgery for recurrentlow- vs. high-grade gliomas.

MATERIALS AND METHODS

Patients. Between November 1991 and December1995, 20 patients (13 males, 7 females) had SRS forrecurrent low-grade [9 patients: World Health Organi-zation (WHO) grade II] vs. high-grade (11 patients: 9WHO grade IV and 2 WHO grade III) gliomas (TableI). The low-grade gliomas had no major oligodendroglialcomponent. All patients had had prior surgery. The ex-tent (biopsy, subtotal, or total resection) is collated be-low.

External-Beam Radiotherapy. Except for three pa-tients who had low-grade gliomas, all patients had con-ventional postoperative radiotherapy. Patients received54 to 60 Gy in 1.8- to 2.0-Gy fractions via 4-, 6-, or 10-MeV photons to the volume enclosing the presurgicalenhancing tumor, the surrounding edema, and a 3- to4-cm margin. Multiple fields were typically used to in-

crease the homogeneity of the dose within the treatmentvolume.

Chemotherapy. No patients received chemother-apy.

Recurrence. Recurrence prior to SRS was con-firmed radiographically. Patients having recurrence afterprior surgery and radiotherapy (if given) for low- orhigh-grade gliomas did not undergo biopsy or resectionof the recurrent tumor prior to SRS. To qualify for ra-diosurgery, patients had to meet the following eligibilitycriteria: (a) a tumor >1 cm from the optic nerves orchiasm and (b) a tumor size not >4 cm in greatest di-ameter in any axis.

Radiosurgery. After placement of the BRW(Brown-Roberts-Wells) frame, a contrast-enhancedcomputed tomography (CT) scan of the brain was ob-tained. The CT images containing the BRW fiducialswere analyzed using a computer program. The bordersof the enhancing tumors were defined, and the optimalposition of the isocenter(s) and diameter of the colli-mator(s) were selected. Multiple, noncoplanar arcs weresequentially selected and tested for the best coverage ofthe target. Both differential weighting and modificationof size of arcs helped provide conformal shaping of thedose to enclose the target and exclude surrounding nor-mal structures. The analysis of the dose-volume histo-gram allowed critical evaluation of the treatment plan.Most plans enclosed the target with the 80th percentileisodose line. Radiosurgery was delivered using a modi-fied 10-MeV linear accelerator.

Follow-up. Follow-up included both physicianevaluation and imaging studies. Imaging was done ap-proximately 1 month after radiosurgery and approxi-mately every 3-6 months thereafter. We collated thecharacteristics of the patients (sex, age, primary histol-ogy), tumors (size and site), external-beam radiotherapy(dose), SRS (collimator diameter, isodose percentile, and

Table I. Recurrent Low- vs. High-Grade Glioma Patients:Distributions of the Variables Between the Two Populations —

Histologic Grade, Age, Extent of Surgery, and Dose of PostoperativeExternal-Beam Irradiation

GradeAge (yr)SurgeryPostoperative

radiation (cGy)

Low grade

939.6 ± 5.4

3/3/3

5583 ± 342s

High grade

1151.3 ± 13.9

3/7/1

5345 ± 261

P

0.930.090.20

0.59

• Numbers of patients having total resection/subtotal resection/biopsyof the tumor.

* Three patients with low-grade gliomas had no postoperative radiation.

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Stereotactic Radiosurgery for Human Glioma

dose), and intervals (from diagnosis, external-beam ra-diotherapy, SRS, and death).

Statistics. Unless stated otherwise, data are themean ± SE. Differences in treatments between the twogroups (type of surgery, doses of external-beam radia-tion, and characteristics of SRS) were analyzed usinganalysis of variance (ANOVA; Wilcoxon rank sum test)(12). Survival curves were calculated using the Kap-lan-Meier product-limit method (13). Differences in sur-vival between subgroups were tested using the log ranktest (14).

RESULTS

The patients with low-grade gliomas were younger(mean age ± SE, 39.6 ± 5.4 years; range, 11.4-61.0years) than those with high-grade gliomas (51.3 ± 13.9years; range, 32.9-78.5 years) (P = 0.09, ANOVA) (Ta-ble I). Tumor locations were similar in the two groups:lobar for 7 of 9 low-grade vs. 9 of 11 high-grade gliomas(P = 0.83, x2) and diencephalic or cerebellar for theremainder. The initial surgical treatments were biopsy,subtotal, resection, and total resection for three, three,and three patients with low-grade gliomas, vs. three,seven, and one patients with high-grade gliomas, re-spectively (P = 0.20, ANOVA). Except for three pa-tients with low-grade gliomas, all patients hadconventional postoperative fractionated external-beamradiotherapy. The doses (cGy) were 5583 ± 342 vs.5345 ± 261 (P = 0.59, ANOVA) for low- vs. high-'grade gliomas, respectively. The intervals from surgeryand conventional radiation (if given) to progression andSRS tended to be longer for low-grade gliomas: 37.5 ±9.5 vs. 30.6 ± 11.1 months (P = 0.65) for low- vs.high-grade gliomas, respectively (Table II). High-gradegliomas were larger. Thus, the diameters of the colli-mators that allowed enclosure of the enhancing tumorvolumes within the specified treatment isodoses were22.4 ± 2.0 mm for low-grade vs. 29.8 ± 2.8 mm (P= 0.02, ANOVA) for high-grade gliomas. SRS doses(cGy) and isodose percentiles were similar for the twogroups: 1650 ± 191 cGy and 79 ± 4.0% vs. 1932 ±182 cGy and 75 ± 3% for low- vs. high-grade gliomas,respectively (P = 0.30, dose, P = 0.5, isodose). Twolow-grade vs. seven high-grade gliomas had fractiona-tion of SRS.

Follow-up. All patients with high-grade gliomaswere followed until death. The mean survival after SRSwas 11.6 ± 1.5 months (42 ± 12 months after surgery)for high-grade gliomas (Fig. 1). Five of nine patientswith low-grade gliomas expired 31.6 ± 6.0 months after

Fig. 1. Kaplan-Meier survival measured from the date of radiosurgeryfor patients with recurrence of low- vs. high-grade gliomas. Abscissa,time (months); ordinate, survival (proportion). (+) Censored obser-vation.

SRS (P < 0.001, Kaplan-Meier log rank, vs. high-gradegliomas) (74.0 ± 16 months after surgery). The foursurvivors have been followed for 8, 13, 35, and 38months, respectively, after SRS. Multivariate analysisshows that the category of histologic grade correlatessignificantly with the survival after radiosurgery (P =0.01).

DISCUSSION

Low-Grade Gliomas. The optimal treatment forlow-grade gliomas remains controversial in the absenceof prospective randomized trials. Most patients with fi-brillary low-grade astrocytomas eventually die, and onlyapproximately 15% of patients have a long-term survival

Table II. Characteristics of Radiosurgery Patients: Low- vs. High-Grade Gliomas

Interval (mo)A

Collimator (mm)b

Isodose (%)Radiosurgery dose (cGy)Survival (mo)c

Low grade

37.5 ± 9.522.4 ± 2.0

79 ± 4.01650 ± 1913.16 ± 6.0

(37.3 ± 9.8)

High grade

30.6 ± 11.129.8 ± 2.8

75 ± 3.51932 ± 18211.6 ± 1.5

(10.3 ± 1.4)

P

0.650.02*0.500.300.005**

° Interval from initial surgical procedure and postoperative radiother-apy (if given) to recurrence and radiosurgery.

* Diameter of the collimator allowing enclosure of the enhancing tumorwith the prescribed isodose.

'Kaplan-Meier mean survival after SRS. The median survival isshown in parentheses.

Williams, Zakhary, Watts, and Wharam

(1). Postoperative external-beam radiotherapy appears toprolong survival (2). In a study of 35 consecutive adultpatients with nonanaplastic, nonpilocytic astrocytomas,the median survival was 9.8 years after surgery and ex-ternal-beam irradiation. Other studies of radiotherapy forlow-grade gliomas also show an improved survival (1,15, 16). However, postradiotherapy recurrence and pro-gression are common. The role of SRS for recurrence oflow-grade gliomas, however, has remained undefined.

Other focal therapies for low-grade gliomas havebeen explored. Permanent and temporary 125I seed im-plantation for WHO grade II astrocytoma has been de-scribed (17). For this technique, temporary seeds wereimplanted for 20 to 30 days, resulting in a median totaldose of 60 Gy. The permanent 125I seeds resulted in amedian total dose of 100 Gy. The 5- and 10-year sur-vival rates for patients with WHO grade II astrocytomas(250 patients) were 61 and 51%, respectively. For pa-tients receiving implantation for the initial treatment vs.that following recurrence after surgery and radiation, the5-year survival was 61 vs. 40%. In a second study forthe treatment of insular low-grade gliomas with 125I seedimplantation alone, the 5- and 10-year survival rateswere 54 and 47% (18). Hence, for low-grade fibrillaryastrocytomas, local irradiation via radioactive seed im-plantation may result in a survivorship similar to thatwith large-field cranial external-beam irradiation. Con-trolled trials are necessary to address this issue.

In contrast to the surgical implantation of radioac-tive seeds, SRS allows the noninvasive, precise deliveryof focal radiation. Studies of radiosurgery for low-gradegliomas are both uncontrolled and limited by the smallnumbers of patients. In a study of 10 patients withlow-grade gliomas who received radiosurgery, 1 patientexpired 66 months after treatment, and 9 were alive22-82 months after treatment (19). In a study of 16 pa-tients with low-grade gliomas, 6 received conventionalexternal fractionated radiotherapy, 6 received fraction-ated stereotactic radiotherapy, and 4 received no priorradiation (20). In that study, tumors disappeared in eightcases and significantly decreased in size or ceasedgrowth in five cases. The survival was not reported,however.

In the current study, the mean survival for patientswith low-grade gliomas having radiosurgery at the timeof recurrence was approximately 32 months. Because thepatients did not undergo biopsy at the time of recurrence,the possibility of progression of the histologic grade ex-ists. In one study, 11 patients had additional tissue ob-tained following suspected progression of disease; tumorwas found in 10 patients, 4 of whom had histologic pro-gression to high-grade gliomas (1). Thus, it is possible

that the patients treated in our series had progression ofgrade prior to treatment.

The results of radiosurgery for low-grade gliomasare comparable to those following external-beam radio-therapy or 125I seed implantation. However, comparisonof these treatments is limited by the small numbers ofpatients and the uncontrolled distributions of importantprognostic features. Compared to implantation, however,SRS offers a noninvasive means for the precise, localadministration of radiation and may represent an impor-tant treatment option for these patients.

High-Grade Gliomas. The role of radiosurgery inthe initial postoperative treatment of malignant gliomascontinues to be defined. The addition of radiosurgery toconventional treatment (surgery and external-beam ra-diotherapy) in the initial management of malignantgliomas appears to result in only a modest improvementin survival compared to that in historical reports. For 41patients with malignant gliomas enrolled in a prospectivestudy, radiosurgical doses of 1200 cGy after conven-tional radiotherapy resulted in a 76% survival with amedian follow-up of 19 months (21). Gannett et al. de-scribed a planned SRS boost as part of the primary man-agement of patients with malignant gliomas (22). In thatstudy the 1- and 2-year disease-specific survivorshipsmeasured from the date of diagnosis were 57 and 25%,respectively. Other studies show similar results. For 31patients receiving SRS after conventional radiotherapy,the median survival was 10.5 months (23). In 11 patientsreceiving planned external-beam radiotherapy and radio-surgery, the median survival was 17 months (24). Allpatients had progression of disease within 1 year of ra-diosurgery. In 31 patients receiving planned external-beam radiotherapy and radiosurgery, the median survivalwas 9.5 months (25) and peripheral recurrences were thedominant mode of failure.

Radiosurgery has also been explored for the treat-ment of recurrent malignant gliomas. The results oftreatment are similar to those published by others. In onestudy of 35 patients treated for recurrence of malignantgliomas, the survival after radiosurgery was 8 months(21 months after initial surgery) (10). For 22 patientswith recurrent malignant gliomas receiving fractionatedstereotactic radiotherapy (30 to 50 Gy in 6 to 10 frac-tions), the median survival after radiotherapy was againsimilar: 9.8 months (9). Finally, in a study of 86 patientshaving radiosurgery for recurrent malignant gliomas, themedian survival was 10.2 months, and the survival after12 and 24 months was 45 and 19%, respectively (11).In the current study, the survival after radiosurgery (11.6months) compares favorably with the results of pub-lished studies describing the radiosurgical management

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Stereotactic Radiosurgery for Human Glioma

of recurrent malignant gliomas. In the absence of rig-orous analyses of important tumor (size) and nontumor(age and performance status) variables among the re-ported series, conclusions regarding differences in out-come are difficult to draw. However, it appears thatradiosurgery alone for recurrent malignant gliomas maynot be a satisfactory treatment option.

Summary. For patients with recurrent gliomas SRSoffers a precise, local administration of radiotherapy thatmay result in both rumor control and prolongation ofsurvival. Further assessment of this modality for thetreatment of recurrent gliomas requires a prospective,randomized clinical evaluation.

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