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Intramedullary Low-Grade Astrocytomas: Long-Term Outcome Following Radical Surgery

George I Jallo MD, Shabbar Danish BA, Linda Velasquez MS and Fred Epstein

MD

Key Words: astrocytoma, intramedullary, radiotherapy, spinal cord tumor Summary: The management of low-grade intramedullary astrocytomas is controversial. Unlike ependymomas, which have a distinct cleavage plane, astrocytomas are diffuse infiltrative tumors. The intramedullary tumor database at NYU Medical Center was searched to identify all patients with intramedullary astrocytoma from 1988 to 1994. Seventeen patients presented with a low-grade diffuse astrocytoma. The medical, surgical and office records were reviewed retrospectively and statistically analyzed. All patients underwent a radical resection of the intramedullary tumor; 12 patients had gross total removal and 5 had subtotal removal. Nine patients received adjuvant radiotherapy. The median follow-up period was 7.4 years. Fourteen patients are alive and have stable disease. Eleven patients (79%) are functionally independent at last follow-up. The remaining patients are at functional Grade III. The 5-year overall survival was 82% for this group. These results indicate that aggressive surgery is associated with a prolonged survival for patients with intramedullary astrocytomas. Radiation therapy should only be reserved for patients who have radiographic progression or inoperable disease.

Correspondence/Reprint Author: George I Jallo MD, Division of Pediatric Neurosurgery, Johns Hopkins Hospital, 600 North Wolfe Street, Harvey 811, Baltimore, MD, 21287 410 955-7851, 410 955-7862 gjallo1@jhmi.edu

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INTRODUCTION

Intramedullary spinal cord tumors are rare central nervous system

neoplasms which affect individuals of all ages. Intramedullary low-grade

astrocytomas are the most frequent histologic type of intramedullary tumor in

children, however the majority of intramedullary neoplasms in adults are

ependymomas. Intramedullary spinal cord low-grade astrocytomas represent

only 5 to 15% of all adult spinal cord tumors [1], thus the literature is sparse

concerning the prognostic factors and long-term treatment results for adult

patients with low-grade intramedullary astrocytomas.

At most centers, a laminectomy and biopsy is typically performed for the

majority of intramedullary neoplasms. Following biopsy and histological

confirmation of an astrocytoma, the patient is then referred for adjuvant

radiotherapy. However, the efficacy of this treatment modality is controversial.

There are only few reports which substantiate the long-term benefits of

radiotherapy for intramedullary tumors [2-5]. This number is even smaller for

intramedullary astrocytomas [2,3,6-11]. In contrast, we have previously reported

our surgical approach and avoidance of radiation therapy for intramedullary

astrocytomas [12-15]. This review consists of a detailed analysis and long-term

follow-up of 17 adult patients, with histologically confirmed and characterized

low-grade intramedullary astrocytomas, who were treated with radical surgery.

Some of our patients have been previously included in other publications [13]

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CLINICAL MATERIAL and METHODS

Patient Population

The intramedullary tumor database at New York University Medical

Center was searched to identify all patients with histologically verified diffuse

low-grade astrocytoma. The search identified 17 adult patients with

intramedullary low-grade astrocytoma operated upon by the senior author from

April 1988 to April 1994. Intramedullary tumors other than low-grade

astrocytoma were excluded from this study. The medical, radiological, surgical,

pathological and office records from these 17 patients were reviewed

retrospectively. Data pertaining to clinical presentation, management and

outcomes were collected. The medical information analyzed for each patient

included age at presentation, symptoms at presentation, duration of symptoms,

previous treatment, adjuvant therapy and immediate and late functional status.

All patients were called and interviewed according to a carefully designed

questionnaire.

The patient’s functional status was assessed in accordance to the

previously published McCormick scale [16]. Grade I, neurologically normal,

with mild focal deficit not significantly affecting the function of the involved

limb, mild spasticity or reflex abnormality and normal gait; Grade II, the

presence of a sensorimotor deficit affecting the function of the involved limb,

mild to moderate gait difficulty, and severe pain or dysesthetic syndrome

impairing the patient’s quality of life, but with independent function and

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ambulation; Grade III, more severe neurological deficit, the requirement of a cane

or brace for ambulation, or significant bilateral upper extremity impairment,

with or without independent function; and Grade IV, a severe neurological

deficit, the requirement of a wheelchair or cane or brace due to bilateral upper

extremity impairment, and usually without independence of function. The pre-

and postoperative functional grade as well as the grade at follow-up of all

patients alive was recorded.

Surgical Approach

The senior author attempted gross-total removal (GTR) in all patients.

Gross total removal is defined as removal of more than 95% of the tumor as

evidenced by both the surgical report and post-operative imaging studies. Sub-

total resection is defined as 80 to 95% removal of the tumor. The surgical

technique has been described in detail in previous publications [13-15]. Briefly,

ultrasonography was routinely employed before and after resection for

localization and to assure the extent of the resection [17]. The ultrasonic

aspirator was used to excavate the tumor from the inside outward until the glial-

white matter interface was reached. Sensory and motor evoked potentials were

used routinely for all the operations. Sensory evoked potential were monitored

for all patients, and motor potentials were monitored in patients operated upon

after 1991.

Statistical Analysis

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Progression-free survival (PFS) and overall survival rates were measured

from the first operation performed by the senior author. Progression-free and

overall survival rates were estimated using the technique of Kaplan and Meier

[18]. The parameters investigated include age, sex, duration of symptoms,

location, extent of resection and radiation therapy.

RESULTS

Presentation

The patient population consisted of 7 men and 10 women ranging in age

from 22 and 61 years (mean, 33.0 yrs). At the time of diagnosis the location of

tumors was cervical (10 cases), cervicothoracic (2 cases) and thoracic (4 cases).

The duration of symptoms before medical attention ranged from 1 to 48

months, with mean of 20.0 months. Table 1 summarizes the characteristics for

this patient population. The most common indicators for radiographic imaging

were pain, sensory, motor difficulties or gait abnormalities. The most common

presenting symptoms were pain and sensory deficits with significant weakness

usually evolving much later. Pain was predominately along the spinal axis. The

mean preoperative functional status for the study group was 2.4. Prior to

surgery, 3 patients were classified as Grade I, 7 as Grade II, 3 as Grade III, and

4 as grade IV.

Seven patients had undergone prior surgery before being referred to the

senior author. All these patients had biopsies for histological diagnosis and 5

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patients then received adjuvant radiotherapy. These patients were referred for

further treatment because of clinical or radiographic progression.

Surgical Results

Complete removal was achieved in 12 patients and subtotal removal

performed in the remaining 5 patients. The histological diagnosis was low-grade

fibrillary astrocytoma in all cases. There were no cases of pilocytic astroctyoma

in this series. In several cases a peripheral rim of gliosis was present which

contained numerous Rosenthal fibers. Small biopsies of this gliotic tissue may

lead to the diagnosis of pilocytic astrocytoma, however with the large tumor

specimen a more definitive diagnosis of fibrillary astrocytoma was easily

confirmed.

Adjuvant therapy

A total of nine patients received additional therapy. Five patients received

adjuvant radiotherapy prior to referral. These patients received prior

radiotherapy after a laminectomy and biopsy of the intramedullary tumor was

performed. Four patients received postoperative radiotherapy after subtotal

removal at our institution. No patient received adjuvant chemotherapy. The

remaining patients were treated with surgery alone.

Outcome Analysis

All patients were available for follow-up review. There was no peri-

operative mortality, and the median long-term follow-up was 7.4 years (range

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33-158 months). There was only one complication, a cerebrospinal fluid leak

which required a wound revision.

Three patients died from tumor progression. The mean survival of these 3

patients was 33.3 months (range, 24-36 months). At the time of death, all 3

showed evidence of progressive local disease. The mean age of these three

patients was 38.7 years, compared with a mean of 34.7 years in patients who are

still alive. Fourteen patients are alive for analysis. In this group, 9 patients show

no evidence of tumor as evaluated by MRI. Five patients have evidence of

residual but stable disease. No patient currently alive has active disease.

The survival rate for all patients with spinal cord low-grade astrocytoma

was 82% at 5-years and 82% at 10-years. Patient survival and progression-

free rate was not correlated with age, prior treatment, tumor span, or location.

Patients who did not receive radiation therapy did not have a poorer survival

rate than patients who did.

Functional Status of Patients

The mean functional status of the 14 surviving patients is 1.7. Twelve

(86%) patients have improved or remained the same as compared to the

preoperative status. Only two (14%) patients have worsened as compared to

their preoperative function. Eleven patients are functionally independent (Grade

I or II) and the remaining patients are functional Grade III.

DISCUSSION

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Intramedullary astrocytomas are much less frequent than ependymomas

in adults [1]. The potential for inflicting neurological injury by radical surgery

in patients with intramedullary neoplasms is significant and the optimum

treatment for these neoplasms remains controversial. In particular, the role of

surgery and radiation therapy in the treatment of these lesions is the center of

debate. The survival of adult low-grade astrocytomas of the spinal cord is

generally long in comparison with the high-grade astrocytomas. There have

been many studies investigating the role of radiotherapy for these tumors [2,3,6-

11], however the results have been inconclusive. Radiation therapy achieves a 5-

year survival rate in the range of 50-90% (see Table 2). There is a high incidence

of local failure, range 22-56%, usually occurring in the first 36 months, and there

does not appear to be a dose response relationship suggesting that better control

can be achieved with doses higher than 5040 cGy. The major concern with

radiation therapy is that the target organ and the structure most at risk for

normal tissue damage are the same [19].

We, like some authors[19-21], advocate aggressive surgery and avoidance

of radiation therapy for these low-grade tumors. Other surgeons believe that the

infiltrating nature of astrocytomas, in contrast to ependymomas, does not

portend to a radical resection [22,23]. These authors recommend a more

conservative approach for these tumors. We previously reported our favorable

experience with intramedullary astrocytomas in adults [13]. In this report, with a

longer follow-up period, we investigated the role of aggressive surgery and

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avoidance of radiation therapy for these low-grade tumors. This group of

patients was operated upon between the years 1988 to 1994 and the mean follow-

up period was 7.2 years.

In our series we were able to achieve a gross total resection in 71% of

patients. The remaining patients had a subtotal resection that was 80-95% tumor

removal. A biopsy was not performed in any patient. We believe, with

intraoperative neurophysiological monitoring of somatosensory and motor

potentials, that a radical resection of these infiltrative lesions is safely possible.

This surgical adjunct allows the surgeon to remove these infiltrative tumors and

selectively monitor the corticospinal tracts in a precise manner. Intraoperative

motor evoked potentials (MEPs) are an essential surgical adjunct to making

decisions about when to stop surgery for these infiltrative tumors. There is an

incremental decrease in the motor potentials, which guides the extent of tumor

resection [24]. If the MEPs remain present during tumor removal, the surgery

can be safely continued to allow for a total or near total resection, and radiation

therapy can be avoided.

At last follow-up the mean functional grade of all patients alive was 1.7 as

compared to the preoperative grade of 2.4. These results are similar to our

experience with children[12,25] and although there may be immediate worsening

of functional status following surgery, most patients improve or remain the same

as the preoperative status. No patient undergoing surgery deteriorated by more

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than one grade. These long-term results encourage us to continue with our

surgical strategy to these intramedullary tumors.

Our series shows that long-term progression-free and overall survival can

be achieved in patients with low-grade astrocytomas through aggressive surgery

alone (see Figure 1). Patients who did not receive radiation therapy faired as

well as those who did. The mean time to death for the three patients was 33.3

months. This progression rate is similar to the patients treated with radiation

therapy alone. Thus patients with low-grade astrocytomas should be followed

closely in the postoperative period for progression, and if no progression occurs

in this initial period the overall survival tends to be excellent. The extent of

resection, both gross total and subtotal resections, was equally efficacious for this

long-term survival. We cannot comment about the role of biopsy for these

tumors since only radical resections were performed. This supports our

aggressive approach for the management of these indolent tumors.

Our study shows a 5-year survival of 82% for patients with low-grade

astrocytoma (see Figure 2). These results are better than the majority of

published papers that advocate a conservative approach with biopsy and

adjuvant radiation therapy. These low-grade tumors possess very little potential

to transform spontaneously into high-grade malignant tumor. Irradiation may

induce a second malignant tumor or radiation myelopathy. Since a radical

resection yields a survival and functional outcome that is comparable to or better

than that achieved with biopsy and radiotherapy, this may be a treatment

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alternative to these tumors. We reserve radiotherapy for patients with

significant residual disease in the conus or when a second reoperation is unlikely

to be attempted.

CONCLUSION

Our experience reinforces our previous results for intramedullary low-

grade astrocytomas. These tumors tend to be indolent and have a favorable

long-term prognosis. Radical surgery alone results in long-term survival for

patients with intramedullary astrocytomas. Intraoperative electrophysiological

monitoring allows for the radical resection of these tumors, which obviates the

need for postoperative radiotherapy. Radiotherapy should be reserved for

progressive disease and tumors which are deemed inoperable.

ACKNOWLEDGEMENTS

This clinical study was supported by a research grant from Medtronic

Sofamar Danek.

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Table 1: Analysis of Patients with Low-Grade Intramedullary Astrocytoma

Age, Sex Symptom Duration (months)

Location PreOp FunctionalGrade

Last Functional Grade

Radiation Therapy Follow-up (months)

32,F 48 C3-T1 4 Dead Yes 3325,F

11 C1-C5 3 1 Yes 6830,F 24 C3-6 3 2 Yes 4829,F 18 T8-T11 2 1 No 15831,M 28 T8-T9 3 1 No 11038,F 6 C1-C3 2 1 No 8523,M 38 C0-C2 1 Dead Yes 4861,M 5 C6-C7 2 Dead Yes 5431,M 8 C1-C6 2 2 No 7731,M 24 C1-C5 1 1 No 9329,M 27 C2-C3 2 1 No 10831,M 12 T8-T12 4 1 Yes 7633,F 13 C2-C5 2 2 Yes 9922,F 11 C5-T3 4 3 No 8929,F 48 C2-C4 2 3 Yes 13642,F 1 C4-C5 1 2 No 9646,F 18 T5-T9 4 3 Yes 98

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Table 2: Previous Studies Treating Low-Grade Astrocytomas with Radiation Therapy

Series, Year Patients Survival Rate (%) 5-year 10-year

Kopelson and Linnggood, 1982 9 89 89 Garcia et al, 1985 14 60 50 Lindstadt et al, 1989 12 91 91 Chun et al, 1990 16 60 40 Shirato et al, 1995 6 50 50 McLaughlin et al, 1998

8 86 57

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FIGURE LEGEND Figure 1: Survival curve analyzing the role of radiotherapy in patients with low-

grade intramedullary astrocytoma

Figure 2: Kaplan-Meier survival curve for 17 patients with intramedullary

astrocytoma

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Figure 1: Survival Curve Comparing Surgery Alone versus Radiotherapy and Surgery

0.10.20.30.40.50.60.70.80.91.0

Sur

vivi

ng

0 10 20 30 40 50 60 70 80 90 100 110 120Months

Surgery Alone

Surgery + Radiation Therapy

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Figure 2: Kaplan-Meier Survival Curve for 17 Patients with Intramedullary Astrocytoma

0.1

0.2

0.3

0.4

0.5

0.6

0.7

0.8

0.9

1.0

Sur

vivi

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0 10 20 30 40 50 60 70 80 90 100 110 120Months

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