Radiation management of bilateral retinoblastoma: Theneed to preservation

Inr J. Rodiorion Oncoology Bio/ 8 Pergamon Pres Ltd.. 1980

Phys.. Vol 6. pp. 669-673 Prinwd m thc U.S.A.

03bO-3016/80/060669-05SOZ.o0/0

??Orìgìnal Contrìbutìon RADIATION

MANAGEMENT OF BILATERAL RETINOBLASTOMA: THE NEED TO PRESERVE VISION

JAMES D. GAGNON,

M.D.*, CARRIE M. WARE**,

WILLIAM T. Mos, and KENNETH R. STEVENS, M.D.****

M.D.***,

University of Oregon Health Sciences Center, Portland, Oregon Thirty-four patients with retinoblastoma were treated in the Radiation Therapy Department of the Univarsity of Oregon Health Sciences Center from 1944 to 1978. Twenty-five of these patients had bilderal disease. Most patients were treated with megavoltage equipment and received doses of 5000 rad in 5 weeks. According to the lifetable method, five year survival was 67.6 % ; it increased to 85.7 % if patients who were treated with orthovoltage equipment were excluded. Seventy-one percent of evaluable patients had useful vision at 5 years; an additianal two pitients had useful vision for two years after radiation therapy. The value of even limited vision during this critical time of sensorimotor and psychological development is discussed. Ortbovoltage equipment should not be used to irradiate patients with retinoblastoma. Bilateral

retinoblastoma,

Heredity,

Second tumors, Vision preservation.

INTRODUCTION

METHODS AND MATERIALS

Recent data show an apparent increase in the incidence of retinoblastoma; this highly malignant tumor affects approximately 1/20,000 children at this time. The increase might be a result of higher survival rates; modern therapies may increase the population at risk for developing this hereditary disease. The majority of patients who present for radiation Those patients with therapy have bilateral disease. limited unilateral retinoblastoma can be treated with cryotherapy or photocoagulation when vision can be maintained in the affected eye. Enucleation is easily accomplished for patients who have lesions that are large or where useful vision is unlikely. The treatment for patients with bilateral involvement must be tailored more to the preservation of useful vision; although enucleation is performed routinely on the more-affected eye, great effort is made to preserve vision in the other eye. Many of these children are irradiated for this reason. Our purpose is to review our experience with radiation management of children with bilateral retinoblastoma, and to discuss the consequences of vision loss for patients who are usually stricken during the early period of growth and development.

Thirty-four patients with retinoblastoma were treated in the Radiation Therapy Department at the University of Oregon Health Sciences Center between 1944 and 1978. All cases were histologically verified or had typical clinical manifestations. Methods of treatment during this 35 year period evolved from the orthovoltage era of the 1940’s and 1950’s to our current method of treatment which has utilized the 2 mev photon beam from our Van de Graaf generator since 1958. The patients’ ages at the time of diagnosis varied from newborn to 6’/2 years: 97%’ of the patients were under one year of age at diagnosis (Fig. 1). Twenty-one males and thirteen females were treated with radiation (M:F ratio of 1.5). However, among the 25 patients with bilateral tumors the male:female ratio was more equal (14:11 or 1.2). The latter figure is similar to that recently reported by GaitanYanguas in a much larger series.” The nine patients with unilateral retinoblastoma wil1 not be discussed further. We classified retinoblastoma according to the staging system evolved by Reese.” (Table 1). A total of 50 eyes were affected in the twenty-five patients. Twenty-two eyes were enucleated primarily, al1 in groups IV and V. Twenty-eight eyes were irradiated. staged as shown in

*Assistant Professor. Department of Radiation Therapy. **Sophomore medical student and recipient of American Cancer Society Fellowship. ***Professor and Chairman. Department of Radiation TheraPY. ****Associate Professor, Department of Radiation Therapy.

Reprint requests to: James D. Gagnon. M.D.. Assistant Professor, Department of Radiation Therapy. Liniversity of Oregon Health Sciences Center, 3181 S.W. Sam Jackson Park Road. Portland. Oregon, 97201. Accepted for publication 8 February 1980.

Radiation

670

Oncology 0 Biology 0 Physics

June 1980. Volume 6. Number 6

Age at Diagnosis

0-6

6-12

12-18

18-24

24-30

Stage of Disease

78

30-36

1

Months Fig. 1. Age of patient unilateral or bilateral.

at initial

m

IJL

P

Stage

diagnosis of retinoblastoma,

Fig. 2. This represents twenty-five patients, three of whom had bilateral irradiation. The delay between probable onset of tumor and the diagnosis of retinoblastoma varied from no or minima1 delay in four patients to almost a year in five patients (Fig. 3). This information was obtainable for 18 of the twenty-five patients. The most commonly recorded first sign of disease was the “cat’s eye” phenomenon, noted by the child’s parents in twenty-one patients. Two asymptomatic patients were off’spring of an affected parent; they were diagnosed via routine examination under anesthesia. The mean delay of diagnosis after first symptom was four months. The interval between first symptom and diagnosis could not be determined for one patient. Six patients were treated with orthovoltage equipment. These patients, were treated with two, three or four circular treatment cones measuring 2-3 cm. directed to the eye or orbital contents. Dose to the volume of interest _ Table 1. Staging classification (Reese)” Group 1: Very favorable 1. Solitary tumor, less than 4 disc diameters in size. at or behind equator. 2. Multiple tumors, none over 4 disc diameters in size. al1 at or behind equator. Group 11: Favorable 1. Solitary tumor, 4 to 10 disc diameters in size, at or behind uator. 2. 3 ultiple tumors, 4 to 10 disc diameters in size, at or behind equator. Group 111: Doubtful 1. Any lesion anterior to equator. 2. Solitary tumors larger than 10 disc diameters equator.

II

Fig. 2. Number and stage of irradiated eyes. AH of these patients had initial bilateral involvement. three patients receiving bilateral irradiation.

ranged from 4600-7500 rad. Since 1958 al1 patients have been treated with a beam produced by our 2 mev Van de Graaf generator. The children were treated most often with an ipsilateral horizontal beam that measured 3.5 to 5 cm square. If both eyes were treated the beams were angled live degrees posteriorly to aid in lens sparing. A split-beam was also used to reduce divergente and to help spare the lens of one patient. Only one patient needed an adjunctive anterior beam because of anterior tumor extent. We immobilized the patients with occasional sedation and used an evacuated air bag and swaddling for al1 patients. Only two patients needed genera1 anesthesia, one for the entire treatment program (three fractions per week) and the other for the first treatment only. Our philosophy and technique of immobilization is similar to that described by Tapley.” Tumor dose measured at 2-3 cm. depth varied from 4500-5000 rad, 5 fractions per week. 200 rad per fraction. The source to skin distance was frequently less than 100 cm. to increase output and decrease treatment time. RESULTS Eighteen of twenty-five patients who had bilateral retinoblastoma were alive without evidente of disease after one year; twelve of 25 patients had no evidente of

Delay Onset to Diagnosis of Retinoblastoma 10l-

behind

Group IV: Unfavorabie 1. Multiple tumors, some larger than 10 disc diameters. 2. Any lesion extending anteriorly to ora serrata. Group V: Very unfavorable 1. Massive tumors involving over half the retina. 2. Vitreous seeding.

Months Fig. 3. Eighteen patients with bilateral for delay in diagnosis.

disease were evaluable

Bilatcral

retinoblastoma

disease 5 years after treatment. Eight of these 18 patients needed additional cryotherapy or photocoagulation after their irradiation for disease control. Optic nerve involvement was suspected in another patient who was receiving cyclophosphamide and vincristine at the time of this writing. One patient was lost to followup and the remaining six patients (24% of the study group) died of metastatic retinoblastoma. Four patients died of intracranial disease, and two developed distant metastases. Actuarial survival for the entire group of patients who had bilateral disease is shown in Fig. 4. Only 67.6% of patients survived disease-free at both 5 and 10 year intervals; however, if children who were treated with orthovoltage are excluded from the analysis 85.7% of patients survived. Complications of treatment could be assessed for 22 patients. Seventeen had no treatment-related complications. Three patients developed cataracts following irradiation; two of these were treated with a three-field orthovoltage technique to a tumor dose in excess of 7000 rad. These two patients had poor vision-one had 20/300 eyesight and the other became totally blind nine years after radiation treatment. The third patient who developed cataracts was treated with lateral and anterior 2 mev photon beams and received a dose of 4500 rad. She had a group 111 tumor and had good vision (20/70) despite the cataract. One patient developed a benign skin lesion and drainage problem which later required reconstructive surgery. This patient was treated by a threefield approach with orthovoltage to a total tumor dose of 4871 rad. This patient had continued tumor growth

Survival (12) (8)

+o--o-0-0-0-0 (8)

(81

(7)

(61

(5)

0s 40 30 -

0

2 mev only

20 -

o

2 mev + orthovoltage

10 0

I

1

1

I

I

I

I

I

12345678

Yeors ofter

I

J

9

10

treotment

Fig. 4. Actuarial survival is determined by the life table method.4 Numbers in parentheses refer to patients at risk at each interval.

0 J. D. GAGNON

671

er al.

Table 2. Assessment of vision and treatment technique* Patient No.

Stage

Vision

Treatment

1

Good

2 MEV

2

Vision status unknown

2 MEV

3

I

Excellent

2 MEV

4

Poor

Orthovolt.

5 6 7 8 9 10

Excellent Blind Excellent Excellent Poor Blind

2 MEV Orthovolt. 2 MEV 2 MEV 2 MEV 2 MEV

Blind

Orthovolt.

Goed

2 MEV

11 12

11

111

13

Vision status unknown

2 MEV

14

Fair

2 MEV

15

IV

16 17 *Vision 20/ 100-200

V

Blind

2 MEV

Good

Orthovolt.

Blind

Orthovolt.

is quantified as follows: 20/ IS-50 excellent, fair, 20/200-300

20/50-

100 goed.

poer.

despite irradiation and his second eye was enucleated. One patient had good eyesight for 16 years post-irradiation and then developed a central retina1 artery occlusion which caused subsequent blindness. He was treated with orthovoltage and received a tumor dose of 5000 rad. All of our complications save one were related to the use of orthovoltage irradiation. Information concerning the patient’s ability to see following irradiation was available for 17 patients (Table 2). Five of these patients were treated with orthovoltage, generally to high doses (up to 8000 rad), and had poor vision results. Only one of these 5 patients maintained good vision at all followup intervals; another, previously mentioned, lost his sight 16 years post-irradiation. Vision results for children treated with the Van de Graaf generator are more encouraging. Two of 3 patients with group I tumors, 4 of 5 with group II, 1 of I with group 111, 1 of 3 with group IV. and none with group V had useful vision at the end of the followup period. Useful vision for a child means enough vision to assist the child in developing his skills, sensorimotor as wel1 as psychological. A child treated for a group 111 tumor that did not have vision at the end of our followup period had useful vision for 2 years following radiation therapy. One other patient had a similar 2 year period of useful vision following treatment before becoming essentially blind. Another patient had glaucoma and no vision at the start of irradiation; the eye was enucleated after 1700 rad had been delivered. Another failure received radiation treatment to both eyes; one eye was enucleated after recurrence of disease and the other eye was successfully treated and the patient retained 20/40 vision for 10 years post-irradiation. Overall, 12 of 17 children (7 1 Sc) had vision for at least 5 years

671

Radiation

Oncology

0 Biology

0 Physics

Vision

(41 (4) 2 z &q

50 4o

0 2 mev

30

0 2 mev + orthovoltage

only

IO-

0:

’

I

I

2345670

l

Years

I

I

after

I

I

I

1

1

9

10

treatment

Fig. 5. Actuarial curve developed using the life table method’ to equate vision with survival. Numbers in parentheses refer to patients at risk at each interval.

after radiation therapy. Another 2 children had vision for at least 2 years during this critical development period. Three patients had no vision because of glaucoma or continued tumor growth and subsequent enucleation. We developed an actuarial curve for al1 patients for whom data was available that equates useful vision with survival; a second curve excludes patients who were treated with orthovoltage (Fig. 5). Our data are similar to that of Egbert et al. who report 22 of 38 irradiated eyes (58%) saved. with al1 but three patients having functional vision.’ DEX3J!SSION

Heredity

Retinoblastoma may be caused by a somatic mutation, a germinal mutation or a deletion of the long arm of chromosome 13 (13q).’ The germinal mutations are hereditary; they occur in 100% of patients who have bilateral retinoblastoma and lO-15% of the patients who have unilateral lesions. Thirty-fìve to forty per cent of retinoblastoma patients have a hereditary form of the disease, since bilateral retinoblastoma occurs in 30% of all retinoblastoma patients, and 15% of unilateral retinoblastoma patients have a germinal mutation. In its hereditary form, retinoblastoma is transmitted as an autosomal dominant trait with incomplete penetrante. The penetrante of the gene is estimated at 70-90%. The association of retinoblastoma and an abnormality in the long arm of chromosome 13 suggests that the lotus for

June 1980. Volume

6. Number

6

the retinoblastoma gene may involve this area. A malformation syndrome that is associated with partial deletion of the long arm of chromosome 13 is characterized by mental retardation, microcephaly, skeletal malformation, eye defects and congenital heart disease. The severity of the syndrome depends on the extent and location of the deletion. It is possible that ah retinoblastomas may be associated with a chromosomal deletion ‘and that in many cases this deletion may be too smal1 to be detected by current chromosomal banding techniques. In our series. one patient had congenital mental defìciency of an unspecified type, and was institutionalized. A second patient was also mentally retarded but had normal chromosomes. Another patient became psychotic, but this evolved over a 10 year period after a centra1 retina1 artery thrombosis caused total blindness 16 years after treatment. The incidence of retinoblastoma is increasing with improved therapeutic techniques.‘* More patients who have the hereditary form of this disease are surviving. including those with bilateral disease ( 17 of 25 patients in our series). We think that genetic counseling should be made available to the parents of these patients as wel1 as to the patients themselves when they approach childbearing age. Two patients in our series had a parent who was previously treated for bilateral retinoblastoma. Second tumors

The patient with bilateral retinoblastoma is at a high risk for developing a second primary tumor which may be life-threatening at a later period. Second primary tumors of different histologie type develop almost exclusively in patients who have bilateral disease.’ The most frequent secondary neoplasm is osteogenic sarcoma. There is a latent period after the completion of irradiation (or onset of retinoblastoma) before symptoms of the second malignancy appear. This latent period ranges from 4 to 30 years, with an average of 1 I years, according to a study by Sagerman, et. al.” In the past. these second primary malignancies were presumed to be radiation-induced since many of the tumors appeared in the treatment field that received high radiation doses and after long latent periods. More recently. a study by Abramson et. al.* has shown the incidence of second primary tumors to be similar in patients with bilateral retinoblastoma whether or not they received radiation treatments. The incidence of second tumors was 14% in the non-irradiated group in Abramson, et. al.‘s study; the Armed Forces Institute of Pathology reported a 12.6% incidence of development of a second tumor in al1 bilateral retinoblastoma survivors.’ Thus. the role of radiation treatment as an inducer of these second malignancies requires further clarification. The tendency to develop second tumors may be linked only to the germinal mutation in bilatera! retinoblastoma patients which enhances development -of the initial tumor. One patient in our study developed a malignant

Bilateral retinoblastoma 0 J. D. GAGNON cr UI.

tumor within the radiation field 19 years after the completion of her radiation therapy. The tumor involved her nasal fossa and ethmoid bone, tumor type unknown. She had been irradiated with orthovoltage equipment to a 7000 rad tumor dose. Because of the long latent period before the development of second tumors, other tumors may yet develop in our patients who have been followed for shorter periods of time. Vision The justification for the administration of irradiation to children with retinoblastoma lies in its promise of preserving vision. Vision, even limited vision, is obviously important, but its value can be difficult to quantify objectively. It is known, however, that children who become blind shortly after birth suffer from marked delays in locomotor achievements. Not al1 activities are so affected as Adelson and Fraiberg pointed out in their study of 10 infants who were blind since birth.3 They noted that the postural achievements of the blind infants, such as sitting alone momentarily or steadily, or taking stepping motions when their hands were held, was very close chronologically to those of children with sight. However, for those activities that required self-initiated mobility, such as pulling to stand (by furniture), taking steps and walking alone, there was a significant delay for the blind children beyond the sighted age range. The blind infant also must rely on auditory stimuli, and is very slow to grasp the concept that he/she can come into contact with an object by moving toward its sound. What the blind child cannot fee1 ceases to exist until he/she comes into contact with it once again. Perhaps the most devastating effect of blindness on these young children is the marked delay in acquiring the concept of “Ir*.’ A sighted child’s hand moves in front of

67)

his/her face countless times before the child comes to realize the “me-ness” of the hand. This process is significantly delayed in the blind child who has no sensory mode available which wil1 immediately replicate any of his/her own body parts. The realization of self comes slowly to most, and not at al1 to some; in the blind child population a large number of school age or even older children do not have “1” or any self-reference pronouns in their vocabularies. The value of this critical sense cannot be overestimated for the children in our group in whom vision was preserved during this crucial period of development. even if only partially or temporarily. Patterns of failure within the treated eyes do not indicate that geographic miss is a problem. For almost al1 patients, immobilization with the evacuated air bag and firm swaddling is satisfactory without using sedation or anesthesia. We currently treat children who have group V or extraocular tumors as participants in Children’s Cancer Study Grqup protocols (961, 962), so that many children receive chemotherapy in addition to surgery and irradiation. Cyclophosphamide and vincristine with or without doxorubicin are recommended; hopefully the results of these studies wil1 show that the numbers of patients with disease-free survival wil1 increase with this more aggressive approach. This is especially true for children with extraocular retinoblastoma for whom the prognosis is very dire. We therefore recommend the use of primary irradiation for every child in whom there is any promise of useful vision. 7 1% of these children might be expected to retain useful vision, and the complication rate is acceptable. Our data clearly show that megavoltage equipment should be used to irradiate these children: there is no place for the use of orthovoltage equipment in the modern therapy of retinoblastoma.

REFERENCES 1. Abramson,

2.

3.

4.

5.

6.

D.H., Ellsworth, R.M., Zimmerman. L.E.: Non-ocular tumors in retinoblastoma survivors. Trans. Am. Acad. Ophthalmol. 81: 457. 1976. Abramson, D.H.. Ronner, H.J., Ellsworth, R.M.: Second tumors in nonirradiated bilateral retinoblastoma. Amer. J. Ophthal. 87: 624-627. 1979. Adelson, E.. Fraiberg, S.: Gross motor development in infants blind since birth. Child Develop. 45: 114-126. 1974. American Joint Committee for Cancer Staging and End Results Reporting (AJCCS): Reporting of cancer survival and end results, 1977, Chicago. AJCCS. Egbert, P.R., Donaldson, S.S.. Moazed, K., Rosenthal. R.: Visual results and ocular complications following radiotherapy for retinoblastoma. Arch. Ophtholmol. 96: 18261830, 1978. Fraiberg. S., Adelson. E.: Self-representation in language and play: Observations of blind children. Psychoanal. Quart. 42: 559-561. 1973.

7. Francois, J.: Genetics of retinoblastoma. Mod. Proh. Ophthal. 18: 165-172, 1977. 8. Gaitan-Yanguas. M.: Retinoblastoma: Analysis of 235 cases. Int. J. Radiat. Oncol. Biol. Phrx. 4: 359-365, 1978. 9. Knudson. A.G.. Jr.: Retinoblastoma: A prototypic hereditary neoplasm. Sen?. in Oncol. 5: 57-60, 1978. 10. Reese. A.B.: Tumors o/ the Eye. Ne\i, Y’ork. Harper and Row. 1963. 11. Sagerman. R.H., Cassady, J.R.. Tretter. P., Ellsworth. R.M.: Radiation induced neoplasia following external beam therapy for children with retinoblastoma. Am. J. Roentgen. 105: 529-535. 1969. 12. Shidnia. H., Hornback. N.B.. Helveston. E.M.. Gettlefinger, T.. Biglan. A.W.: Treatment results of retinoblastoma at Indiana tiniversity Hospitals. Cu~c,er 40: 2917- 2922. 1977. 13. Tapley. N. duV.: External irradiation of retinoblastoma. In Textbook of RodiotherapJ,. ed. 2. G.H. Fletcher. (Ed.) Philadelphia. Lea and Febiger. 1973. pp. 436-437.