J.

Brian

David

Goldsmith,

A. Larson,

Optic of

MD #{149}Seth MD, PhD

A Rosenthal,

Neuropathy ni’

Radiation-induced optic neuropathy (RON) is a rare and catastrophic cornplication of currently employed radiation therapy regimens for meningiomas that have been partially resected and sampled for biopsy. Between 1972 and 1989, 49 patients received postoperative irradiation for partially resected or biopsy sampled meningiomas, with the optic nerve within the treatment field. One patient experienced RON. The latency period for this case was 23 months. A review of the literature disclosed few cases of RON after treatment for meningioma; however, 42 cases of RON have been reported after radiation therapy for other lesions. The authors constructed two approaches to predict optic nerve radiation tolerance. The first is modeled on a previous proposal for a neural tissue nominal standard dose term and enabled accurate prediction of safe treatment regimens and risk of RON. This approach compared favorably with previously employed nominal standard dose terms. The second approach, based on the linear-quadratic model, proved unsuccessful due to its failure to achieve statistical significance. Index

of irradiation on, optic, 144.47 #{149} Radiations, exposure to patients and personnel, 22.893 #{149} Radiations, injurious effects, complications of therapeutic radiology, 22.893 22.893,

Radiology

terms:

Eye, effects

224.47

1992;

#{149} Nerves,

185:71-76

I From the Department of Radiation Oncology, University of California, San Francisco, 505 Parnassus Aye, Rm L-08, San Francisco, CA 94143-0226. Received February 14, 1992; revision requested April 13; revision received June 5; accepted June 22. Address reprint requests to B.J.G. 0 RSNA, 1992

MD

after

I,

William

#{149}

M. Wara,

MD

Irradiation

optic neuropa(RON) is a dreaded complication of parasellar irradiation. Parlially resected meningiomas are common in the sphenoid and parasellar areas, and if postoperative radialion therapy is not administered, approximately two-thirds of patients experience local recurrence (1,2). Postoperative radiation therapy has been shown to reduce the recurrence rate in these patients (1,2), although concerns regarding the potential morbidity of postoperative radiation therapy may limit appropriate referral and treatment. The dose-limiting structures for the treatment of meningiomas are often the optic nerves and chiasm. Appropriate assessment of the risk of optic tract complications is essential for optimal treatment planning and patient selection. Experience in the treatment of

1%

ADIATION-INDUCED

thy

meningiomas

at our

institution

has

been

previously reported (1). Until this year, we have not seen any cases of RON. However, after RON was diagnosed in one of our patients this year, we reviewed the records of all patients with meningioma treated at the University of California, San Francisco (UCSF), whose optic nerves or chiasm were included in the treatment volume. In addition, we reviewed the reported cases of RON in the literature. On the basis of our analysis of the data and review of the literature, we have constructed two models to predirt optic nerve tolerance. The first is based on the nominal standard dose (NSD) and the second on the linearquadratic model (3,4).

PATIENTS

AND

METHODS

Between 1972 and 1990, 75 patients underwent a course of external beam megavoltage photon radiation therapy at the UCSF Department of Radiation Oncology, with the optic nerve within the treatment field, for partially resected or biopsied

Patients who received ion particle therapy or brachytherapy as a component of their treatment were not included in this study. Forty-nine of the 75 patients had been followed up for at least 18 months (median follow-up, 46 months; range, 18-213 months); none of the remaining 26 patients had evidence of RON. Details of doses and fractionation schemes are presented in Table 1 . Treatment plans for the patients were reviewed in detail. Follow-up information was obtained from patient charts, with supplemental informarion obtained from referring physicians and telephone contacts with patients and family members. In addition, analysis of the reported cases of RON in the literature was performed by using two isoeffect formulalions (NSD and linear-quadratic models) in an effort to determine threshold and tolerance levels for RON. Although, to our meningiomas.

knowledge,

there

has

been

only

one

pre-

reported case of RON after treatment for meningioma (5), there is a substantial amount of literature in which RON is associated with cranial irradiation for other lesions, such as pituitary adenoma, craniopharyngioma, acromegaly, carcinoma of the paranasal sinuses and nasopharynx, and retinoblastoma, as well as prophylactic cranial irradiation for acute lymphocytic leukemia and pituitary ablation for breast cancer. In the absence of a series of meningioma-RON cases, characterization of the radiation tolerance of the optic nerve was based on findings from those reports. viously

Review

of the literature

disclosed

42 pa-

who developed RON after megavoltage external beam irradiation for a variety of cranial lesions (6-16). Reported latency of onset of RON ranged from 6 to 192 months (mean, 27 months; median, 12 months). Details of dose, fractionation, and duration of radiation therapy from our patient and those reported in the literature are presented in Table 2. Of note, there was some variabifity and uncertainty in the reporting of dose reference points. tients

Abbreviations: dose, RON thy, UCSF cisco.

NSD = =

nominal

=

radiation-induced

University

standard optic

of California,

neuropa-

San Fran-

71

Although

one

group

of investigators

(15)

Table

calculated the dose at the optic nerve, most reported the dose to the pituitary gl and. For the purposes of our subsequent analysis, we assumed that the dose received by the optic nerve was approximately equal to the dose to the pituitary gland reported by the authors. Eight of the 42 patients in the literature were excluded from our analysis: Four patients received extremely high doses compared with today’s standards (two received 8,000 rad in eight fractions; one received 12,500 rad in 10 fractions; and one received 13,000 rad in 20 fractions, respectively) (8,16), one had empty sella syndrome (12), one had tumor recurrence involving

the optic

underwent

nerve

(12), and

concomittant

Dose

1 Fractionation

Partially

and

Biopsy

to the

ated

with

number

lowest

optic

reported

optic

doses

on

a log-log

plot.

From

Dose

(cGy)

4,500-5,940

No. of fractions Dose per fraction Days of treatment Neuret

Optic ret Follow-up

(mo)

the

null

regression

Ret

optic

neuropathy

fractions

(N)

doses

these

hypothesis

Radiology

#{149}

coefficient

I

p

0.001


.10), rendering this model

Volume

No. of

Plan

Midplane

Excluded

per Fraction

Dose

2,400 4,240 4,240 4,250 4,250 4,250 4,250

from from from from

the UCSF

Treatment

10* 7 7 11 11 11

threshold ratio

and the Case from

Radiation Dose

(cGy)

Note-Data able. * Excluded t Excluded t Excluded

plot

in the Literature

No.

11

I

of RON Radiation Dose

ret. and

Treatment three-field,

plans included as well as arc,

twotech-

logic examination ingoendotheliomatous

niques. At a median follow-up of 46 months, 48 of the 49 patients (98%) had not experienced RON, and one

demonstrated meningioma.

The immediate postoperative course was notable because tient developed right cranial

. . .

men-

the panerve

.

.

developed RON 23 months after initiation of radiation therapy. The case is presented below. The patient who developed RON (a

palsy involving cranial nerves V, VII, VIII, IX, and X, which subsequently partially resolved. However, follow-up CT performed 37 months after

62-year-old woman) presented in October 1985 with a history of rightsided tinnitus and gait instability. Computed tomography (CT) demonstrated a petrous mass in the right side extending to the middle and posterior fossae. Embotization was per-

resection demonstrated an interval increase in the size of the petrous meningioma remnant. The patient was referred to the UCSF for radialion therapy in January 1989. Before initiation of radiation therapy, visual acuity was evaluated, and it was

formed,

and the mass

was partially

noted

that,

resected

in November

1985.

could

count

Patho-

with fingers

her right but

eye, she

could

not

Radiology

73

#{149}

5400 cOy in 30 fi

.

RON (Literatu,e

0

non-FiOt

and UCSF)

20 U C

U C

I.

U-

0 3

10

N

0 0.67 0.7

0.73 0.16 0.79 0.82 O.$S iC

O.I

0.94 0 0

neuret

ret x 1000

a.

I_I_I_1___________ 1

1.03 1.06 1.00 1.12 1.15 1.11 121

.24 1.21

x 1000

b.

Figure

2.

Frequency

of cases

with

and

without

RON

lure and the UCSF experience) after radiation therapy sected and biopsy sampled meningioma, as a function (1,), and optic ret (c).fx = fraction.

(from

the

litera-

for partially reof ret (a), neuret 20 C 0

.

RON (literature

0

non-RON

and UCSF)

(UCSF)

3 0 0

IL

read fine print. Acuity in her left eye was 20/30. A total of 5,400 cGy was administered with 6-MV photons in 30 x 180cGy fractions over 43 treatment days with a three-field technique (opposed laterals and vertex). This regimen corresponded to 965 neuret and 890 optic ret. The treatment plan has been subsequently

verified

(Fig

Radiology

#{149}

f-i 0.567 0.6 0.633 0.601

.i1J1_1i1_ lU

0.7 0.73 0.77

0.0

0.03

0.01

0.0

0.03

0.97

1

103

1.07

1.1

1.13

1.17

1.2

optic ret x 1000 C.

4). Maxi-

mum inhomogeneity was ±5%, with the maximum treatment volume dose 5,670 cGy, 1,013 neuret, and 937 optic ret (see below). Twenty-three months after initiation of radiation therapy, the patient had a rapid, irreversible loss of visual acuity in her left eye. She could not detect hand motion at 30 cm; this did not improve with refraction. The visual fields in her left eye were constricted, with vision in only the inferonasal quadrant. Visual acuity in the patient’s right eye was 5/200, with full visual fields. Subsequent Ti-weighted magnetic resonance (MR) imaging with gadopentetate dimeglumine showed increased signal intensity in the left optic nerve adjacent to the chiasm, demonstrating radiation-induced disruption of the blood-brain barrier and accumulation of contrast material within the optic nerve, consistent with acute inflammation of the optic nerve. There was no evidence of interval tumor growth or encroachment on the left optic nerve (Fig 5). The MR imaging findings were strongly suggestive of RON (20-22). There is no obvious reason why this patient experienced RON after undergoing postoperative radiation therapy; many other patients treated with a similar regimen at this institution have not. This patient does not have 74

10

known

peripheral

vascular

disease

or

any of its risk factors. It is conceivable that embolization and surgery may have played a contributory role. Certainly

interpatient

of radiosensitivity was a probable

variability

in terms

of normal contributing

tissues factor.

DISCUSSION Radiation therapy is safe and efficacious in the treatment of partially resected memngiomas. In a series of 84 patients who underwent partial reseclion of memngioma, Barbaro et al (1)

reported lion

that recurrence

after

irradia-

(4,950-7,000 cGy in 180 cGy fraclions) was significantly reduced from 60% to 32% (P < .05). No cases of RON or other radiation-associated complications were noted after a mean follow-up of 78 months (range, 5-i5 years). Glahohn et al (2) reviewed the Royal Marsden Hospital experience of i86 patients who underwent radialion therapy (5,000-5,500 cGy in 30-33 fractions over 6-6.5 weeks with 4-8-MV linear accelerators or cobalt60) and reported similar recurrence rates to those of Barbaro et al. However, Glaholm et al noted four patients (2%) with late neurologic Sequelae, but no cases of RON, at 80-

month

median follow-up (range, 0.2months). The development of RON after treatment for meningioma is rare; it is certainly less common than damage to the anterior visual pathway from 26i

progressive

or recurrent

tumor.

To

our knowledge, only one definite case of RON developing after radiation therapy for meningioma has been previously reported. In the study by Guy and Schatz (5), a 59-year-old woman received 6,000 rad to the postenor fossa for a right petrous apex meningioma. Fractionation and duralion of therapy were not reported. Twelve months after completion of therapy, visual acuity in the right eye diminished to 20/40, which progressed to counting fingers 6 weeks later. Visual loss subsequently developed in her left eye, and, 18 months after therapy, she could count fingers at 1 foot (30 cm) with her right eye and 4 feet (i20 cm) with her left. Optic atrophy was prominent in both eyes. CT showed a decrease in the size of the meningioma. The patient’s vision ultimately stabilized at counting fingers at 2 feet (60 cm) with her right eye and hand movements at 3 feet (90 cm) with her left eye. The pathogenesis of RON is unclear, with several authors suggesting October1992

Table 3 Sample Fractionation Regimens Corresponding to Approximately 890 Optic Ret Radiation Dose

Dose per Fraction

(cGy)

(cGy)

3,000 3,750 4,800 5,400 6,080 6,600

300 250 200 180 160 150

No. of Fractions 10 15 24 30 38 43

Optic Ret 885 893 891 890 884 888

0.04

i.

0.03

Linear

alpha/beta

0

Threshold RON

Literature

U

c5

Regression

Data

for Threshold

3.06 Gy

=

0

0.02

#{149}sloO.OO37GY

0

> C -

0.01

intercept

=

0.011

Gy-1

i4 regression

0.0c

coefficient

p

>

0.10

.

0

1

2

dose

4

3

Ix

fx (Gy)

per

Figure 3. Reciprocal dose plot for threshold-RON data (from the literature and the UCSF experience).

fraction.

=

the prevalence of RON was considered as a function of fraction size, totat dose, age, field size, and associated illness, the only significant association was with fraction size, which, in turn, was

a function

of the

number

of frac-

tions. They also found that increasing the magnitude of the N exponent of the NSD formula improved the differentiation of patients RON. Because the

tation mous ing

3 Figure

4.

three-field

Coronal

6-MV

pho-

ton isodose plan used in the patient with RON from the UCSF

experience.

with initial

and NSD

without formu-

was based on data from squacell carcinoma, it is not surpristhat

it was

not

equally

applicable

to the optic nerve. This issue was appreciated by Sheline et al (4) who subsequently modifled the NSD formula to define a new equation,

neuret

=

D . N#{176}

. T#{176}#{176},

to better describe isoeffects on neural tissues. The N exponent was derived from their review of 80 cases of brain necrosis after therapeutic irradiation, demonstrating

that

a line

of slope

0.44

fitted welt within the log-log scattergram of total dose versus number of fractions (4). The selection of 0.44 as the N exponent for neural tissue was subsequently supported by studies of rat spinal cord radiation tolerance (25,26). In addition, it was found that spinal

either direct injury to nervous tissue, ischemic injury secondary to vascular changes, or damage by means of an autoimmune mechanism (5,8,9,14, 20,22). Historically, the NSD formulation developed by Ellis (19) has been used to describe radiation isoeffects for dissimilar treatment regimens (6,23). The NSD is expressed in units of ret = D N#{176} . T#{176}, where T = total time in days, N = number of fractions, and D = dose in centigrays. Ellis derived the N exponent (0.24) from the slope of curative doses for squamous cell carcinoma as a function of number of fractions on a log-log graph. The N exponent term is believed to correlate Volume

185

Number

#{149}

I

with

the

impact of repair of sublethal (which is dependent on the number of fractions and their magnitude), whereas the T exponent term models the effect of repopulalion by damage

proliferation

and

redistribution

and

hence is dependent on time (24). Although previous reports suggested that the ret was a satisfactory predictor of RON toxicity (6,23), Harris and Levene (12) subsequently reviewed 55 patients who underwent irradiation for pituitary adenoma or craniopharyngioma

and

reported

that

the ret did not enable good prediction of RON, noting considerable overlap of the ret distributions of patients with and without RON. In fact, when

cord

tolerance

was

substantially by prolonging lion of treatment, leading clusion that the T exponent 0.05

theory,

or less.

In terms

altered

the durato the conshould be

of radiobiologic

recovery in cellturnover rate, such as skin, depends on both repair of sublethal damage and repopulation, whereas recovery in neural tissues with a low cell-turnover rate should be expected to depend primarily on repair of sublethal damage (24). This theory is in agreement with observations made by Sheline et al and van der Kogel. Sheline et al (4) found the prevalence of brain necrosis to be very low with doses of about 1,000 neuret (4). However, to our knowledge, eight tissues

radiation

not

with

damage

a relatively

high

Radiology

#{149} 75

patients with RON in the literature underwent treatment with less than 990 neuret (6,9,11-13) (Table 2); this is worrisome because the therapeutic regimen commonly employed for parlially resected meningioma (5,400 cGy in 30 180-cGy fractions over 6 weeks) corresponds to 966 neuret. The degree to which the neuret model overlaps the RON distribution in the literature with this very safely employed regimen brings into question its value as a discriminant for RON. Ideally, an isotoxicity formulation for optic neuropathy should be based on clinical data to maximize its applicability to the human optic nerve. Therefore, we used an approach similar to that of Sheline et at (4) in the analysis of RON,

derived

a statistically

ret model, and found that ret helps differentiate RONregimens from non-RON

regimens

better

favorably

than

the

ret

with

the

neuret.

and

is a rare

and

3.

catastrophic

complication of radiation therapy for partially resected and biopsy sampled Analysis

meningiomas.

of RON

cases

from the literature has enabled us to define a new nominal standard dose term, the optic ret, which can help effectively differentiate between safely employed radiation therapy regimens and those with a risk for RON. In the absence of a statistically significant (18) linear-quadratic model for RON, we recommend that the optic ret formula be used when planning radiation therapy to a volume that includes the optic nerve. To minimize the probability of RON, we recommend that, whenever possible, this structure receive a maximum dose of 890

optic

ret.

Of

course,

neither

this

formula nor any other should preempt clinical judgment. When technically feasible, multiple field or arc techniques should be employed to minimize inhomogeneity of dose that could increase the irradiation of the nerve beyond this recommended optic ret ceiling. U

Barbaro Radiation

N, Gutin therapy

tially resected 1987;

76

20:525-528.

Radiology

#{149}

4.

5.

6.

7.

8.

9.

10.

1 1.

12.

13.

References 1.

2.

com-

CONCLUSION RON

Figure of the

b. 5. left

Coronal intracranial

(a) and optic

axial (b) Ti-weighted nerve, consistent

with

MR images RON.

show

gadolinium

enhancement

significant

(18) optic the optic associated pares

a.

PH, Wilson CB, et al. in the treatment of parmemngiomas. Neurosurgery

Glaholm J, Bloom HJG, Crow JH. The role of radiotherapy in the management of intracranial meningiomas: the Royal Marsden Hospital experience with 186 patients. IntJ Radiat Oncol Biol Phys 1990; 18:755761. Fowler J. The linear-quadratic formula and progress in fractionated radiotherapy. BrJ Radiol 1989; 62:679-694. Sheline GE, Wara WM, Smith V. Therapeutic irradiation and brain injury. IntJ Radiat Oncol Biol Phys 1980; 6:1215-1228. GuyJ, Schatz NJ. Hyperbaric oxygen in the treatment of radiation-induced optic neuropathy. Opthalmology 1986; 93:10831088. Aristizabal 5, Caldwell WL, Avila J. The relationship of time-dose fractionation factors to complications in the treatment of pituitary tumors by irradiation. Int J Radiat Oncol Biol Phys 1977; 2:667-673.

Atkinson

Martins Delayed Neurosurg

16.

17.

18.

19.

20.

SD, et al.

Progressive visual failure in acromegaly following external pituitary irradiation. Clin Endocrinol 1979; 10:469-479. Buys N, Kerns TC Jr. Irradiation damage to the chiasm. Am J Opthalmol 1957; 44: 483-486. Di Lorenzo N, Nolletti A, Palma L. Late cerebral necrosis. Surg Neurol 1978; 10: 281-290. Fishman M, Bean SC, Cogan DG. Optic atrophy following prophylactic chemotherapy and cranial radiation for acute lymphocytic leukemia. Am J Opthalmol 1976; 82:571-576. Hammer HM. Optic chiasmal radionecrosis. Trans Opthalmol Soc U.K. 1983; 103: 208-211. Harris JR. Levene MB. Visual complications following irradiation for pituitary adenomas and craniopharyngiomas. Radiology 1976; 120:167-171. Kline L, Kim JY, Ceballos R. Radiation optic neuropathy. Opthalmology 1985; 92: 1118-1

14.

A, Allen IV, Gordon

15.

21.

22.

Parsonsj, Fitzgerald CR, Hood CI, et al. The effects of irradiation on the eye and optic nerve. IntJ Radiat Oncol Biol Phys 1983; 9:609-622. Urdaneta N, Chessin H, Fischer JJ. Pituitary adenomas and craniopharyngiomas: analysis of 99 cases with radiation therapy. IntJ Radiat Oncol Biol Phys 1976; 1:895902. Douglas B, FowlerJ. The effect of multipie small doses of x-rays on skin reactions in the mouse and a basic interpretation. Radiat Res 1976; 66:401-426. Matthews D, Farewell V. Linear regression models for medical data. In: Using and understanding medical statistics. 2nd ed. Basel: Karger, 1988; 124-130. Ellis F. Dose, time, and fractionation: a clinical hypothesis. Clin Radiol 1969; 20: 1-7. Guy J, Mancuso A, Quisling RG, et al. Gadolinium-DPTA-enhanced magnetic resonance imaging in optic neuropathies. Opthalmology 1990; 97:592-600. Guy J, Mancuso A, Beck R, et al. Radiation-induced optic neuropathy: a magnetic resonance imaging study. J Neurosurg 1991; 74:426-432. Zimmerman C, Schatz NJ, GlaserJS. Magnetic resonance imaging of radiation optic neuropathy. Am J Opthalmol 1990; 110: 389-394.

23.

24. 25.

26.

Shukovsky L, Fletcher GH. Retinal and optic nerve complications in a high dose irradiation technique of ethmoid sinus and nasal cavity. Ther Radiol 1972; 104:629-634. Hall E. Radiobiology for the radiologist. 3rd ed. Philadelphia: Lippincott, 1988. van der Kogel AJ, Barendsen GW. Late effects of spinal cord irradiation with 300 kV x rays and 15 MeV neutrons. BrJ Radiol 1974; 47:393-398. van der Kogel AJ. Radiation tolerance of the rat spinal cord: time-dose relationships. Radiology 1977; 122:505-509.

126.

A, Johnston JS, Henry JM, et al. radiation necrosis of the brain. 1977; 47:336-345.

October

1992