Therapy of Acquired Immunodeficiency Syndrome-Related Kaposi's Sarcoma of the Eyelids and Conjunctiva Radiation
Rafat
Ghabrial, MD; Jeanne
M.
Quivey, MD; James
\s=b\ We
retrospectively studied 42 acquired immunodeficiency syndrome-related Kaposi's sarcoma of the conjunctiva or eyelids who were treated with radiation. Forty-nine sites were treated, 35 (71%) of which involved the eyelids, 12 (24%) the conjunctiva, and two (4%) both the eyelids and conjunctiva. Group 1 consisted of 31 sites treated with a single dose of 800 cGy and group 2 men
with
consisted of 18 sites treated with a multiple-fraction regimen and total doses between 1500 and 3600 cGy. The response and recurrence rates in the two groups were similar. One patient from group 2 died within 1 month of treatment and was not included in the analysis. The lesions improved in all cases. A complete response was obtained in 10 (32%) of the 31 lesions in group 1, compared with four (22%) of 18 lesions in group 2. A partial response was obtained in 21 (68%) of 31 lesions in group 1, compared with 13 (72%) of 18 lesions in group 2. Expected minor reactions in the treatment field, primarily loss of cilia, were comparable in the two groups. No serious complications were noted. Recurrence occurred in seven (22%) of the 31 sites in group 1 (six patients) and seven (39%) of the 18 sites in group 2 (six patients). The results subgest that a single treatment of 800 cGy is a safe and effective palliative therapy for
ophthalmic acquired immunodeficiency syndrome-related Kaposi's sarcoma. (Arch Ophthalmol. 1992;110:1423-1426) Accepted
for publication March 9, 1992. From the Francis I. Proctor Foundation (Drs Ghabrial, Dunn, and Char), the Ocular Oncology Unit, Department of Ophthalmology (Dr Char), and the Department of Radiation Oncology (Drs Quivey and Char), the University of California, San Francisco. Reprint requests to the Ocular Oncology Unit, 10 Kirkham St, PO Box 0730, UCSF San Francisco, CA 94143 (Dr Char).
P.
Dunn, Jr, MD; Devron H. Char,
MD
TZaposi's sarcoma, associated with the -"-*acquired immunodeficiency syn¬
drome (AIDS), is a multicentric vascu¬ lar neoplasm that affects the skin, mu¬ cous membranes, internal organs, and lymph nodes. It is the most common neoplasm in AIDS and involves 15% to 24% of patients.1'3 It is second only to Pneumocystis carinii as the presenting manifestation of AIDS.4 Ninety-five percent of cases of AIDS-related Kapo¬ si's sarcoma occur in homosexual males.5 The behavior of Kaposi's sar¬ coma is different in various groups. Ac¬
quired immunodeficiency syndrome-
related Kaposi's sarcoma follows a much more fulminant course and is less responsive to therapy in homosexual males, in contrast to elderly men of Mediterranean or Eastern European Jewish ancestry, young adult black Af¬ rican men, or immunosuppressed pa¬ tients who have undergone renal trans¬ plantation."' Treatment options in¬ clude radiation,610 chemotherapy,11·12 immunotherapy,12"14 cryotherapy,10 and excision.1" Local palliative radiation has become the most common treatment, since systemic chemotherapy and im¬ munotherapy usually do not alter the ultimate course,'5 and both cryotherapy and excision are often ineffective.10 Involvement of the eyelids or con¬ junctiva occurs in 20% to 24% of pa¬ tients with AIDS-related Kaposi's sarcoma.1-10 These lesions are usually slow growing and may be asymptomatic. Lesions that are cosmetically disturb¬ ing, cause discomfort, or obstruct vision should be treated. Several different ra¬ diation regimens have been used for treatment of ophthalmic AIDS-related Kaposi's sarcoma.810 In this report we summarize the response of 42 patients with ophthalmic AIDS-related Kaposi's sarcoma treated with radiation.
PATIENTS AND METHODS All patients who underwent radiation therapy for Kaposi's sarcoma of the eyelids or conjunctiva between February 1984 and February 1991 were identified from the computerized record system at the Depart¬ ment of Radiation Oncology, University of California, San Francisco, and hospital records were reviewed to confirm the diag¬ nosis and treatment. The diagnosis of Kapo¬
si's sarcoma was based on the characteristic appearance of the eyelid or conjunctival lesion and biopsy diagnosis of Kaposi's sar¬ coma elsewhere on the body. Follow-up data were obtained from our medical records, community physicians, or other institutions when appropriate. Medical records were retrospectively re¬ viewed for ocular site, size, and associated symptoms of the lesion; the site(s) of nonocular Kaposi's sarcoma at the time of treat¬ ment; and the general condition of the pa¬ tient at the time of treatment, based on the Karnofsky Performance Status Index.16 Treatment information included previous therapies, radiation source, dosage, fractionation, and field size. Response to radiation
therapy
was
objectively assessed,
as
de¬
scribed below. All patients were homosexual or bisexual men. The mean age at the time of treatment was 37 years (range, 28 to 55 years). Twentysix (62%) of the 42 patients had a history of prior opportunistic infection. All but one pa¬ tient had a diagnosis of AIDS established prior to ophthalmic involvement of the Ka¬ posi's sarcoma; the remaining patient was known to be seropositive for the human im¬ munodeficiency virus and had both night sweats and lymphadenopathy. The Kaposi's sarcoma involved multiple sites in 41 patients (98%). In six patients (14%), the initial lesion involved the eyelids or conjunctiva. A common site of concurrent nonocular Kaposi's sarcoma was the oral cavity; 25 patients (60%) had involvement of the hard palate. Previous treatment of the ophthalmic lesions had been attempted in seven patients (17%); three of these (7%) had undergone systemic chemotherapy, two
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Table 1.—Treatment and
Opportunistic Patient No. 17
18
Infection No Yes
19 20 21
Yes No Yes
22 23 24 25 26 27
Yes Yes No No Yes No Yes No No Yes Yes No Yes Yes Yes No No Yes
28 29 30 31 32 33 34 35 36 37 38 39
Yes No
40
42
*CR Indicates
Yes
Response Data of 26 Patients Treated for 31 Lesions by Single-Fraction Radiation Field
Response*
Energy 100 kV(p) 100 kV(p)
Dose 800 cGy 800 cGy
Size,
2.5x2.5 2.5X2.5
CR CR
kV(p) 100kV(p)
800 cGy 800 cGy 800 cGy 800 cGy 800 cGy 800 cGy 800 cGy 800 cGy 800 cGy 800 cGy 800 cGy 800 cGy 800 cGy 800 cGy 800 cGy 800 cGy 800 cGy 800 cGy 800 cGy 800 cGy 800 cGy 800 cGy 800 cGy 800 cGy 800 cGy 800 cGy 800 cGy 800 cGy 800 cGy
3.6x3.6 2.5x2.5 3X6
PR PR PR
6x6 10X10 5X5 6x6 2.5X2.5 6X6
PR CR PR PR PR PR PR PR PR PR CR CR PR CR PR CR PR PR CR PR PR PR CR PR CR PR
100
6 MeV 6 MeV 9 MeV 100 kV(p) 6 MeV 100 kV(p) 6 MeV 6 MeV 6 MeV 4 MV 6 MeV
100kV(p) 6 MeV Cobalt 60
100kV(p) 100kV(p) 100kV(p) 100 kV(p) 100kV(p) 100 kV(p) 6 MeV 6 MeV 6 MeV 4MV
100kV(p) 100kV(p) 100kV(p)
cm
3x6 6x6 5x2.5 3x3 5X5 15X15 5X5 5X5 7X7 5x5 5X5
3.5X3.5 3.5x3.5 6X6 6x6 6X6 5x5 2.5X2.5 2.5X2.5 7X7
Recurrence,
Survival,
mo
mo
4
>6 Unavailable for
follow-up at 5 wk
>4 16 >3 10 10
>2 14 >36 12
33
>3 >4 >2 13 13 13
42 42 >17
complete response; and PR, partial response.
Response Data of 16 Patients Treated for 18 Lesions With Multiple-Fraction Regimens of Radiation Therapy (in Increasing Order of Dosage)
Table 2.—Treatment and Patient No.
Opportunistic Infection Yes Yes Yes Yes
Energy 6 MeV 100 kV(p) 6 MeV 100 kV(p) 100
10 12
13 14 15 16 *PR indicates
No No No Yes Yes Yes Yes Yes No Yes Yes No
kV(p)
6 MeV Cobalt 60
Cobalt 60 6 MeV
100 kV(p) 6 MeV 6 MeV 6 MeV 6 MeV 6 MeV 6 MeV 6 MeV 6 MeV
Dose,
cGy
1500
1500 1500 1700
1700 2000 2000 2000 2000 2600 2800 2800 3000 3000 3000 3000 3000 3600
partial response; CR, complete response; and N/A,
No. of Fractions 10 10 10
Field Size, cm
Response*
10x10 3.5X3.5 10x10 3.5x3.5
PR PR PR PR
3.5X3.5
PR CR PR CR PR N/A PR CR PR PR CR PR PR PR
10
6X6 7X12
10 10
5X5 6X6
13 13
2.5X2.5 6X6 20X20 2x2 2X2
15 15 15 17
10x10 6X12 6X6 4X4
14 14
not available.
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Recurrence,
Survival,
mo
mo
14
14
27
12 12 >4
19
Table
3.—Complications of Therapy
Table
No. of
Complications Complication
I-1 Group 1 Group 2
(n=31)
(n=18)
Loss of cilia
3
Conjunctivitis Occipital hair
0
2 1
loss
Edema
Hyperpigmentatlon
(5%) had been treated with intralesional vinblastine sulfate, and two (5%) had
undergone both systemic and intralesional chemotherapy. Forty-nine ocular lesions were treated. Thirty-five (71%) of the lesions involved the eyelids and 12 (24%) involved the conjunc¬ tiva (six bulbar and six palpebrai). The remaining two lesions (4%) were diffuse, in¬ volving more than one periocular structure. All patients complained of cosmetic dis¬ turbance from the ophthalmic lesion. Eyelid swelling occurred in 23 lesions (47%), fre¬ quently limiting eyelid mobility and occa¬ sionally visual acuity. Pain and irritation were infrequently noted. Bleeding (two cases), epiphora (two cases), and pruritus (one case) were rare. No patient complained
of marked visual distortion or visual de¬ crease or had a diagnosis of active cytomegalovirus retinitis. Radiation doses ranged from 800 to 3600 cGy, administered in one to 17 fractions. Pa¬ tients were retrospectively divided into two groups, based on whether radiation was de¬ livered as a single large dose or in multiple smaller fractions. The most common regimen (31 sites in 26 patients [group 1]) was 800 cGy administered as a single dose, as shown in Table 1. The remaining 18 sites in 16 patients were treated with a multiple-fraction regi¬ men (group 2), as shown in Table 2. Superficial skin lesions smaller than 5 cm in maximum dimension were treated with orthovoltage radiation or electrons with ap¬ propriate lead shaping to encompass the le¬ sion with a 1-cm margin. A bolus was used with electron energies of 6 MeV, along with an internal eye shield unless the conjunctiva was involved. Superficial lesions larger than 5 cm were treated with either electron or di¬ rect photon fields. When facial edema was limited to the periorbital area, small perior¬ bital fields were treated with orthovoltage or electron energies. Conjunctival lesions were treated with a direct 6-MeV electron field with the eye open and with an external lens bar. The treatment parameters reflected the treating physician's bias and evolved as ex¬ perience was gained. Patients were not randomized to different treatment regimens. In general, patients treated early in the study received multiple-fraction regimens, while patients treated later received a single 800-cGy dose. A complete response was defined as a le¬ sion that completely flattened and faded in color. A partial response was defined as a le¬ sion that partially flattened and faded. Re¬ sponse rates did not appear to be related to
4.—Comparison of Patients With Lesions Treated With Single-Fraction Radiation (Group 1) With Those Treated With Multiple-Fraction Radiation (Group 2)
Group 2_ _Group 1 No. of patients_26_16_ Mean (range) age, y_37.5 (28-55)_37.3 (31-59) Mean (range) Karnofsky scores, %_78 (60-90)_76 (50-90)_ Prior opportunistic infections, No. (%) of patients_15 (58)_12 (75)_ No. of Lesion size (maximum diameter), No. of sites 2.5 cm_11_6_ Response, No. of sites 21 Partial 13 10 4* Complete 5 4 Complications 7 7 Recurrences, No. of sites Mean (range) time, mo after treatment 7.7 (2-33) 6.2 (2-14) "One patient's condition was not assessable.
sites_31_18_ cm_20_12_
tumor size. Lack of response was defined
as
reduction in size and color density. Re¬ sponses were evaluated only in those pa¬ tients followed up for 1 month or longer. A recurrence was defined as the regrowth of a lesion or return of symptoms at a treated site following initial improvement. no
RESULTS
Response to therapy was assessable in 48 (98%) of 49 lesions; one patient died less than 1 month after treatment. All lesions responded to treatment. A complete response was obtained in 14 lesions (29%), and a partial response was obtained in 34 lesions (71%). One patient died prior to an evaluation of response. No serious complications of therapy occurred. Nine minor reactions were recorded, including loss of cilia, conjunctivitis, occipital hair loss at the exit site of high-energy photon beams, hyperpigmentation, and edema (Table 3). Fourteen recurrences (29%) oc¬ curred in 12 patients (Tables 1 and 2). The relative efficacies of various ra¬ diation doses and fractionation regi¬ mens are shown in Table 4. Patients treated with a single 800-cGy dose (group 1) and multiple fractions, con¬ sisting of a total dose of 1500 to 3600 cGy (group 2) were comparable for age and general medical condition (based on the Karnofsky Performance Status Index). A slightly greater percentage of pa¬ tients in group 2, however, had oppor¬ tunistic infections at the time of or prior to treatment. Complete response was obtained in 10 (32%) of 31 lesions in group 1 and four (22%) of 18 lesions in group 2. Partial response was obtained in 21 lesions (68%) in group 1 and in 13 lesions (72%) in group 2. Group 1 had seven recur¬ rences (22%), occurring a mean of 7.7 months (range, 2 to 33 months) after treatment. Four of these lesions re-
curred within 4 months after treatment (Table 1). Group 2 had seven recur¬ rences (39%), occurring a mean of 6 months (range, 2 to 14 months) after treatment. Four of these lesions re¬ curred within 3 months after treatment (Table 2). The earlier recurrences usu¬ ally developed in association with wors¬ ening immune status (either Pneumocystis carinii pneumonia or central nervous system lymphoma). The length of follow-up was shorter in group 1, with seven (27%) of the 26 patients examined less than 6 months after treatment. Mi¬ nor reactions (most commonly a loss of cilia), occurred in five (16%) of 31 cases in group 1, and in four (22%) of 18 cases in group 2. Thirty-one (74%) of 42 patients died 1 to 36 months (mean, 9.2 months) after treatment. To date, 10 patients (24%) are alive 2 to 42 months (mean, 12 months) after treatment. There were no cases of cytomegalovirus retinitis acti¬ vation during or after radiation ther¬ apy. The status of one patient (2%) is unknown. COMMENT
Kaposi's sarcoma occurs in 15% to 24% of patients with AIDS,1'3 with the vast majority occurring in homosexual men.5 There is some evidence that the percentage of homosexual patients with AIDS with Kaposi's sarcoma is declining3; because of the continued in¬ crease in cases of AIDS, however, the absolute number of patients with AIDS-related Kaposi's sarcoma contin¬ ues to increase.3 Ophthalmic involvement in AIDSrelated Kaposi's sarcoma occurs in 20% to 24% of patients,110 more frequently on the eyelid than the conjunctiva.10
Conjunctival lesions are typically pain¬ less, discrete, highly vascularized
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that develop most commonly in the inferior fornix.10 Eyelid lesions usu¬ ally manifest as painless papules rang¬ ing in color from pink to deep purple to brown and frequently are associated with periorbital edema. A clinical diag¬ nosis of ophthalmic Kaposi's sarcoma may be made, especially if characteris¬ tic violaceous lesions are found else¬ where on the skin and oral mucosa, no¬ tably the hard palate. It is uncommon for ophthalmic in¬ volvement to be the first manifestation of AIDS-related Kaposi's sarcoma10; we have not seen a patient with ocular in¬ volvement who did not have known symptoms or signs of human immuno¬ deficiency virus infection. In our study, six patients (14%) had periocular man¬ ifestations of Kaposi's sarcoma prior to its detection elsewhere in the body. It is almost never necessary to do a biopsy of the periocular lesion, since almost all patients have had a previous biopsy of either the skin or mucosal Kaposi's sar¬ coma. In very atypical cases a periocu¬ lar biopsy may be performed. Therapeutic options for AIDSrelated Kaposi's sarcoma include sys¬ temic immunotherapy,1214 intralesional5 or systemic chemotherapy,11·12 exci¬ sion,15 cryotherapy," and radiation.6'10 The neoplasm is multicentric, and pa¬ tients with AIDS-related Kaposi's sar¬ coma usually die of opportunistic infec¬ tions. It is reasonable to observe slowly progressive, asymptomatic lesions. Systemic chemotherapy and immunotherapy do not appear to alter the ulti¬ mate course of the tumor,5·10 but may be necessary to control widespread, fulmi¬ nant disease."11 Chemotherapy may in¬ crease the risk of opportunistic infec¬ tions and must be used judiciously. Local therapy with excision or cryo¬ therapy has been ineffective, with rapid recurrence of the tumor.10 Numerous reports have documented the radiosensitivity of Kaposi's sar¬ coma. In the non-AIDS-related forms of the disease, Lo et al17 found that a single fraction of 800 to 1200 cGy was sufficient to control local cutaneous le¬ sions. Cooperls found that doses of 2750 cGy or more delivered in 10 fractions over 2 weeks were associated with bet¬ ter long-term control than were smaller doses. Other studies have confirmed the effectiveness of palliative radiation therapy in AIDS-related Kaposi's sarmasses
coma,0,7 with a satisfactory response in
than 90% of treated fields.6 The morbidity induced by different fractionation regimens is an important factor in selecting treatment. A single 800-cGy dose may be as effective as multiplefraction regimens of 1500 to 4000 cGy in treating nonocular AIDS-related Kaposi's sarcoma, with fewer adverse more
reactions.6
Previous reports of radiation therapy for ophthalmic AIDS-related Kaposi's sarcoma have reported good results with multiple-fraction regimens. Coo¬ per and Fried" first described success¬ ful radiation therapy of aggressive con¬
junctival Kaposi's sarcoma in a patient with AIDS, using 3000 cGy in 10 frac¬ tions
2 weeks. No side effects or noted after 4 months. Shuler et al10 described 12 patients with ophthalmic Kaposi's sarcoma treated with 2000 to 3000 cGy in 200- to 300-cGy fractions over 3 weeks. All patients re¬ sponded to therapy, with complete res¬ olution in 10 patients. Two patients de¬ veloped recurrence within 4 months and four patients developed recurrence af¬ ter 6 months. Side effects of treatment included local skin erythema in six pa¬ tients and hair loss at the beam exit site in one patient. A retrospective study cannot assess all therapeutic issues. In our analysis, cellular immunity and other factors that correlate with treatment response14 were not considered. While it is possible that a randomized trial would demon¬ strate significant differences in re¬ sponse rates or complications between the radiation groups, we did not observe this. Similarly, a higher total radiation dose, regardless of fractionation, might alter recurrence roles; however, this was not assessed in this study. Larger single fractions may provide longer control, but this was not as¬ sessed in this study. All patients re¬ sponded to therapy, and our findings were similar to those of Cooper and Fried8 and Shuler et al.10 Side effects were minor and equivalent in the two groups. The single-dose regimen we used has several practical advantages over multiple-fraction treatments. The control and complication rates were comparable between both regimens and the single-fraction approach is clearly more expeditious. It is less inconve¬ nient and time-consuming for the paover
recurrences were
tient, and is not interrupted if intercur¬ rent illnesses develop. This study was supported in part by NIH grant E YO by unrestricted grants from That Man May See and Research to Prevent Blindness Inc.
7504 and
References 1. Rutherford GW, Payne SF, Lemp GF. The epidemiology of AIDS-related Kaposi's sarcoma.J AIDS. 1990;3(suppl):924-931. 2. AIDS Weekly Surveillance Report. Atlanta, Ga: United States AIDS Program, Center for
Infectious Diseases, Centers for Disease Control;
August 1,
1988. 3. Haverkes HW, Friedman-Kien AE, Drotman DP, Morgan WM. The changing incidence of Kaposi sarcoma amongst patients with AIDS. J Am Acad Dermatol. 1990;22:1250-1253. 4. Centers for Disease Control. Update: acquired immunodeficiency syndrome and human immunodeficiency virus infection in the United States. MMWR. 1989;38:1-4. 5. Friedman-Kien AE, Saltzman BR. Clinical manifestations of classical, endemic African, and epidemic AIDS-related Kaposi's sarcoma. J Am Acad Dermatol. 1990:22:1237-1250. 6. Berson AM, Quivey JM, Harris JW, Wara WM. Radiation therapy for AIDS-related Kaposi's sarcoma. Int J Radiat Oncol Biol Phys. 1990;19: 569-575. 7. Cooper JS, Fried PR. Defining the role of radiation therapy in the management of epidemic Kaposi's sarcoma. Int J Radiat Oncol Biol Phys.
1987;3:35-39.
Cooper JS, Fried PR. Treatment of aggresepidemic Kaposi's sarcoma of the conjunctiva by radiotherapy. Arch Ophthalmol. 1988;106:20-21. 9. Cooper JS. Optimal treatment of epidemic Kaposi's sarcoma. Int J Radiat Oncol Biol Phys. 8. sive
1990;19:807-808.
10. Shuler JD, Holland GN, Miles SA, Miller BJ, Grossman I. Kaposi sarcoma of the conjunctiva and eyelids associated with the acquired immunodeficiency syndrome. Arch Ophthalmol. 1989;107:858\x=req-\ 862. 11. Volberding P. Therapy of Kaposi's sarcoma in AIDS. Semin Oncol. 1984;11:60-67. 12. Mitsuyuasu RT, Groopman JE. Biology and therapy of Kaposi's sarcoma. Semin Oncol. 1984; 11:54-59. 13. Krown SE, Real FX, Vadhan-Raj S, et al. Kaposi's sarcoma and the acquired immune deficiency syndrome: treatment with recombinant interferon alpha and analysis of prognostic factors. Cancer. 1986;57:1662-1665. 14. Mitsayasu RT, Taylor JMG, Glaspy J, Fahey JL. Heterogeneity of epidemic Kaposi's sarcoma: implications for therapy. Cancer. 1986;57:1657\x=req-\ 1661. 15. Macher AM, Palestine A, Masur H, et al. Multicentric Kaposi's sarcoma of the conjunctiva in a male homosexual with the acquired immunodefi-
ciency syndrome. Ophthalmology. 1983;90:879-884. 16. Schag CC, Heinrich RL, Ganz PA. Karnofsky performance status revisited: reliability, validity, and guidelines. J Clin Oncol. 1984;2:187-194. 17. Lo TCM, Salzman FA, Smedal MI, Wright KA. Radiotherapy for Kaposi's sarcoma. Cancer. 1980;45:684-687.
18. Cooper JS. The influence of dose on the long-term control of classic (non-AIDS associated) Kaposi's sarcoma by radiotherapy. Int J Radiat Oncol Biol Phys. 1988;15:1141-1146.
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Rafat
Ghabrial, MD; Jeanne
M.
Quivey, MD; James
\s=b\ We
retrospectively studied 42 acquired immunodeficiency syndrome-related Kaposi's sarcoma of the conjunctiva or eyelids who were treated with radiation. Forty-nine sites were treated, 35 (71%) of which involved the eyelids, 12 (24%) the conjunctiva, and two (4%) both the eyelids and conjunctiva. Group 1 consisted of 31 sites treated with a single dose of 800 cGy and group 2 men
with
consisted of 18 sites treated with a multiple-fraction regimen and total doses between 1500 and 3600 cGy. The response and recurrence rates in the two groups were similar. One patient from group 2 died within 1 month of treatment and was not included in the analysis. The lesions improved in all cases. A complete response was obtained in 10 (32%) of the 31 lesions in group 1, compared with four (22%) of 18 lesions in group 2. A partial response was obtained in 21 (68%) of 31 lesions in group 1, compared with 13 (72%) of 18 lesions in group 2. Expected minor reactions in the treatment field, primarily loss of cilia, were comparable in the two groups. No serious complications were noted. Recurrence occurred in seven (22%) of the 31 sites in group 1 (six patients) and seven (39%) of the 18 sites in group 2 (six patients). The results subgest that a single treatment of 800 cGy is a safe and effective palliative therapy for
ophthalmic acquired immunodeficiency syndrome-related Kaposi's sarcoma. (Arch Ophthalmol. 1992;110:1423-1426) Accepted
for publication March 9, 1992. From the Francis I. Proctor Foundation (Drs Ghabrial, Dunn, and Char), the Ocular Oncology Unit, Department of Ophthalmology (Dr Char), and the Department of Radiation Oncology (Drs Quivey and Char), the University of California, San Francisco. Reprint requests to the Ocular Oncology Unit, 10 Kirkham St, PO Box 0730, UCSF San Francisco, CA 94143 (Dr Char).
P.
Dunn, Jr, MD; Devron H. Char,
MD
TZaposi's sarcoma, associated with the -"-*acquired immunodeficiency syn¬
drome (AIDS), is a multicentric vascu¬ lar neoplasm that affects the skin, mu¬ cous membranes, internal organs, and lymph nodes. It is the most common neoplasm in AIDS and involves 15% to 24% of patients.1'3 It is second only to Pneumocystis carinii as the presenting manifestation of AIDS.4 Ninety-five percent of cases of AIDS-related Kapo¬ si's sarcoma occur in homosexual males.5 The behavior of Kaposi's sar¬ coma is different in various groups. Ac¬
quired immunodeficiency syndrome-
related Kaposi's sarcoma follows a much more fulminant course and is less responsive to therapy in homosexual males, in contrast to elderly men of Mediterranean or Eastern European Jewish ancestry, young adult black Af¬ rican men, or immunosuppressed pa¬ tients who have undergone renal trans¬ plantation."' Treatment options in¬ clude radiation,610 chemotherapy,11·12 immunotherapy,12"14 cryotherapy,10 and excision.1" Local palliative radiation has become the most common treatment, since systemic chemotherapy and im¬ munotherapy usually do not alter the ultimate course,'5 and both cryotherapy and excision are often ineffective.10 Involvement of the eyelids or con¬ junctiva occurs in 20% to 24% of pa¬ tients with AIDS-related Kaposi's sarcoma.1-10 These lesions are usually slow growing and may be asymptomatic. Lesions that are cosmetically disturb¬ ing, cause discomfort, or obstruct vision should be treated. Several different ra¬ diation regimens have been used for treatment of ophthalmic AIDS-related Kaposi's sarcoma.810 In this report we summarize the response of 42 patients with ophthalmic AIDS-related Kaposi's sarcoma treated with radiation.
PATIENTS AND METHODS All patients who underwent radiation therapy for Kaposi's sarcoma of the eyelids or conjunctiva between February 1984 and February 1991 were identified from the computerized record system at the Depart¬ ment of Radiation Oncology, University of California, San Francisco, and hospital records were reviewed to confirm the diag¬ nosis and treatment. The diagnosis of Kapo¬
si's sarcoma was based on the characteristic appearance of the eyelid or conjunctival lesion and biopsy diagnosis of Kaposi's sar¬ coma elsewhere on the body. Follow-up data were obtained from our medical records, community physicians, or other institutions when appropriate. Medical records were retrospectively re¬ viewed for ocular site, size, and associated symptoms of the lesion; the site(s) of nonocular Kaposi's sarcoma at the time of treat¬ ment; and the general condition of the pa¬ tient at the time of treatment, based on the Karnofsky Performance Status Index.16 Treatment information included previous therapies, radiation source, dosage, fractionation, and field size. Response to radiation
therapy
was
objectively assessed,
as
de¬
scribed below. All patients were homosexual or bisexual men. The mean age at the time of treatment was 37 years (range, 28 to 55 years). Twentysix (62%) of the 42 patients had a history of prior opportunistic infection. All but one pa¬ tient had a diagnosis of AIDS established prior to ophthalmic involvement of the Ka¬ posi's sarcoma; the remaining patient was known to be seropositive for the human im¬ munodeficiency virus and had both night sweats and lymphadenopathy. The Kaposi's sarcoma involved multiple sites in 41 patients (98%). In six patients (14%), the initial lesion involved the eyelids or conjunctiva. A common site of concurrent nonocular Kaposi's sarcoma was the oral cavity; 25 patients (60%) had involvement of the hard palate. Previous treatment of the ophthalmic lesions had been attempted in seven patients (17%); three of these (7%) had undergone systemic chemotherapy, two
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Table 1.—Treatment and
Opportunistic Patient No. 17
18
Infection No Yes
19 20 21
Yes No Yes
22 23 24 25 26 27
Yes Yes No No Yes No Yes No No Yes Yes No Yes Yes Yes No No Yes
28 29 30 31 32 33 34 35 36 37 38 39
Yes No
40
42
*CR Indicates
Yes
Response Data of 26 Patients Treated for 31 Lesions by Single-Fraction Radiation Field
Response*
Energy 100 kV(p) 100 kV(p)
Dose 800 cGy 800 cGy
Size,
2.5x2.5 2.5X2.5
CR CR
kV(p) 100kV(p)
800 cGy 800 cGy 800 cGy 800 cGy 800 cGy 800 cGy 800 cGy 800 cGy 800 cGy 800 cGy 800 cGy 800 cGy 800 cGy 800 cGy 800 cGy 800 cGy 800 cGy 800 cGy 800 cGy 800 cGy 800 cGy 800 cGy 800 cGy 800 cGy 800 cGy 800 cGy 800 cGy 800 cGy 800 cGy
3.6x3.6 2.5x2.5 3X6
PR PR PR
6x6 10X10 5X5 6x6 2.5X2.5 6X6
PR CR PR PR PR PR PR PR PR PR CR CR PR CR PR CR PR PR CR PR PR PR CR PR CR PR
100
6 MeV 6 MeV 9 MeV 100 kV(p) 6 MeV 100 kV(p) 6 MeV 6 MeV 6 MeV 4 MV 6 MeV
100kV(p) 6 MeV Cobalt 60
100kV(p) 100kV(p) 100kV(p) 100 kV(p) 100kV(p) 100 kV(p) 6 MeV 6 MeV 6 MeV 4MV
100kV(p) 100kV(p) 100kV(p)
cm
3x6 6x6 5x2.5 3x3 5X5 15X15 5X5 5X5 7X7 5x5 5X5
3.5X3.5 3.5x3.5 6X6 6x6 6X6 5x5 2.5X2.5 2.5X2.5 7X7
Recurrence,
Survival,
mo
mo
4
>6 Unavailable for
follow-up at 5 wk
>4 16 >3 10 10
>2 14 >36 12
33
>3 >4 >2 13 13 13
42 42 >17
complete response; and PR, partial response.
Response Data of 16 Patients Treated for 18 Lesions With Multiple-Fraction Regimens of Radiation Therapy (in Increasing Order of Dosage)
Table 2.—Treatment and Patient No.
Opportunistic Infection Yes Yes Yes Yes
Energy 6 MeV 100 kV(p) 6 MeV 100 kV(p) 100
10 12
13 14 15 16 *PR indicates
No No No Yes Yes Yes Yes Yes No Yes Yes No
kV(p)
6 MeV Cobalt 60
Cobalt 60 6 MeV
100 kV(p) 6 MeV 6 MeV 6 MeV 6 MeV 6 MeV 6 MeV 6 MeV 6 MeV
Dose,
cGy
1500
1500 1500 1700
1700 2000 2000 2000 2000 2600 2800 2800 3000 3000 3000 3000 3000 3600
partial response; CR, complete response; and N/A,
No. of Fractions 10 10 10
Field Size, cm
Response*
10x10 3.5X3.5 10x10 3.5x3.5
PR PR PR PR
3.5X3.5
PR CR PR CR PR N/A PR CR PR PR CR PR PR PR
10
6X6 7X12
10 10
5X5 6X6
13 13
2.5X2.5 6X6 20X20 2x2 2X2
15 15 15 17
10x10 6X12 6X6 4X4
14 14
not available.
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Recurrence,
Survival,
mo
mo
14
14
27
12 12 >4
19
Table
3.—Complications of Therapy
Table
No. of
Complications Complication
I-1 Group 1 Group 2
(n=31)
(n=18)
Loss of cilia
3
Conjunctivitis Occipital hair
0
2 1
loss
Edema
Hyperpigmentatlon
(5%) had been treated with intralesional vinblastine sulfate, and two (5%) had
undergone both systemic and intralesional chemotherapy. Forty-nine ocular lesions were treated. Thirty-five (71%) of the lesions involved the eyelids and 12 (24%) involved the conjunc¬ tiva (six bulbar and six palpebrai). The remaining two lesions (4%) were diffuse, in¬ volving more than one periocular structure. All patients complained of cosmetic dis¬ turbance from the ophthalmic lesion. Eyelid swelling occurred in 23 lesions (47%), fre¬ quently limiting eyelid mobility and occa¬ sionally visual acuity. Pain and irritation were infrequently noted. Bleeding (two cases), epiphora (two cases), and pruritus (one case) were rare. No patient complained
of marked visual distortion or visual de¬ crease or had a diagnosis of active cytomegalovirus retinitis. Radiation doses ranged from 800 to 3600 cGy, administered in one to 17 fractions. Pa¬ tients were retrospectively divided into two groups, based on whether radiation was de¬ livered as a single large dose or in multiple smaller fractions. The most common regimen (31 sites in 26 patients [group 1]) was 800 cGy administered as a single dose, as shown in Table 1. The remaining 18 sites in 16 patients were treated with a multiple-fraction regi¬ men (group 2), as shown in Table 2. Superficial skin lesions smaller than 5 cm in maximum dimension were treated with orthovoltage radiation or electrons with ap¬ propriate lead shaping to encompass the le¬ sion with a 1-cm margin. A bolus was used with electron energies of 6 MeV, along with an internal eye shield unless the conjunctiva was involved. Superficial lesions larger than 5 cm were treated with either electron or di¬ rect photon fields. When facial edema was limited to the periorbital area, small perior¬ bital fields were treated with orthovoltage or electron energies. Conjunctival lesions were treated with a direct 6-MeV electron field with the eye open and with an external lens bar. The treatment parameters reflected the treating physician's bias and evolved as ex¬ perience was gained. Patients were not randomized to different treatment regimens. In general, patients treated early in the study received multiple-fraction regimens, while patients treated later received a single 800-cGy dose. A complete response was defined as a le¬ sion that completely flattened and faded in color. A partial response was defined as a le¬ sion that partially flattened and faded. Re¬ sponse rates did not appear to be related to
4.—Comparison of Patients With Lesions Treated With Single-Fraction Radiation (Group 1) With Those Treated With Multiple-Fraction Radiation (Group 2)
Group 2_ _Group 1 No. of patients_26_16_ Mean (range) age, y_37.5 (28-55)_37.3 (31-59) Mean (range) Karnofsky scores, %_78 (60-90)_76 (50-90)_ Prior opportunistic infections, No. (%) of patients_15 (58)_12 (75)_ No. of Lesion size (maximum diameter), No. of sites 2.5 cm_11_6_ Response, No. of sites 21 Partial 13 10 4* Complete 5 4 Complications 7 7 Recurrences, No. of sites Mean (range) time, mo after treatment 7.7 (2-33) 6.2 (2-14) "One patient's condition was not assessable.
sites_31_18_ cm_20_12_
tumor size. Lack of response was defined
as
reduction in size and color density. Re¬ sponses were evaluated only in those pa¬ tients followed up for 1 month or longer. A recurrence was defined as the regrowth of a lesion or return of symptoms at a treated site following initial improvement. no
RESULTS
Response to therapy was assessable in 48 (98%) of 49 lesions; one patient died less than 1 month after treatment. All lesions responded to treatment. A complete response was obtained in 14 lesions (29%), and a partial response was obtained in 34 lesions (71%). One patient died prior to an evaluation of response. No serious complications of therapy occurred. Nine minor reactions were recorded, including loss of cilia, conjunctivitis, occipital hair loss at the exit site of high-energy photon beams, hyperpigmentation, and edema (Table 3). Fourteen recurrences (29%) oc¬ curred in 12 patients (Tables 1 and 2). The relative efficacies of various ra¬ diation doses and fractionation regi¬ mens are shown in Table 4. Patients treated with a single 800-cGy dose (group 1) and multiple fractions, con¬ sisting of a total dose of 1500 to 3600 cGy (group 2) were comparable for age and general medical condition (based on the Karnofsky Performance Status Index). A slightly greater percentage of pa¬ tients in group 2, however, had oppor¬ tunistic infections at the time of or prior to treatment. Complete response was obtained in 10 (32%) of 31 lesions in group 1 and four (22%) of 18 lesions in group 2. Partial response was obtained in 21 lesions (68%) in group 1 and in 13 lesions (72%) in group 2. Group 1 had seven recur¬ rences (22%), occurring a mean of 7.7 months (range, 2 to 33 months) after treatment. Four of these lesions re-
curred within 4 months after treatment (Table 1). Group 2 had seven recur¬ rences (39%), occurring a mean of 6 months (range, 2 to 14 months) after treatment. Four of these lesions re¬ curred within 3 months after treatment (Table 2). The earlier recurrences usu¬ ally developed in association with wors¬ ening immune status (either Pneumocystis carinii pneumonia or central nervous system lymphoma). The length of follow-up was shorter in group 1, with seven (27%) of the 26 patients examined less than 6 months after treatment. Mi¬ nor reactions (most commonly a loss of cilia), occurred in five (16%) of 31 cases in group 1, and in four (22%) of 18 cases in group 2. Thirty-one (74%) of 42 patients died 1 to 36 months (mean, 9.2 months) after treatment. To date, 10 patients (24%) are alive 2 to 42 months (mean, 12 months) after treatment. There were no cases of cytomegalovirus retinitis acti¬ vation during or after radiation ther¬ apy. The status of one patient (2%) is unknown. COMMENT
Kaposi's sarcoma occurs in 15% to 24% of patients with AIDS,1'3 with the vast majority occurring in homosexual men.5 There is some evidence that the percentage of homosexual patients with AIDS with Kaposi's sarcoma is declining3; because of the continued in¬ crease in cases of AIDS, however, the absolute number of patients with AIDS-related Kaposi's sarcoma contin¬ ues to increase.3 Ophthalmic involvement in AIDSrelated Kaposi's sarcoma occurs in 20% to 24% of patients,110 more frequently on the eyelid than the conjunctiva.10
Conjunctival lesions are typically pain¬ less, discrete, highly vascularized
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that develop most commonly in the inferior fornix.10 Eyelid lesions usu¬ ally manifest as painless papules rang¬ ing in color from pink to deep purple to brown and frequently are associated with periorbital edema. A clinical diag¬ nosis of ophthalmic Kaposi's sarcoma may be made, especially if characteris¬ tic violaceous lesions are found else¬ where on the skin and oral mucosa, no¬ tably the hard palate. It is uncommon for ophthalmic in¬ volvement to be the first manifestation of AIDS-related Kaposi's sarcoma10; we have not seen a patient with ocular in¬ volvement who did not have known symptoms or signs of human immuno¬ deficiency virus infection. In our study, six patients (14%) had periocular man¬ ifestations of Kaposi's sarcoma prior to its detection elsewhere in the body. It is almost never necessary to do a biopsy of the periocular lesion, since almost all patients have had a previous biopsy of either the skin or mucosal Kaposi's sar¬ coma. In very atypical cases a periocu¬ lar biopsy may be performed. Therapeutic options for AIDSrelated Kaposi's sarcoma include sys¬ temic immunotherapy,1214 intralesional5 or systemic chemotherapy,11·12 exci¬ sion,15 cryotherapy," and radiation.6'10 The neoplasm is multicentric, and pa¬ tients with AIDS-related Kaposi's sar¬ coma usually die of opportunistic infec¬ tions. It is reasonable to observe slowly progressive, asymptomatic lesions. Systemic chemotherapy and immunotherapy do not appear to alter the ulti¬ mate course of the tumor,5·10 but may be necessary to control widespread, fulmi¬ nant disease."11 Chemotherapy may in¬ crease the risk of opportunistic infec¬ tions and must be used judiciously. Local therapy with excision or cryo¬ therapy has been ineffective, with rapid recurrence of the tumor.10 Numerous reports have documented the radiosensitivity of Kaposi's sar¬ coma. In the non-AIDS-related forms of the disease, Lo et al17 found that a single fraction of 800 to 1200 cGy was sufficient to control local cutaneous le¬ sions. Cooperls found that doses of 2750 cGy or more delivered in 10 fractions over 2 weeks were associated with bet¬ ter long-term control than were smaller doses. Other studies have confirmed the effectiveness of palliative radiation therapy in AIDS-related Kaposi's sarmasses
coma,0,7 with a satisfactory response in
than 90% of treated fields.6 The morbidity induced by different fractionation regimens is an important factor in selecting treatment. A single 800-cGy dose may be as effective as multiplefraction regimens of 1500 to 4000 cGy in treating nonocular AIDS-related Kaposi's sarcoma, with fewer adverse more
reactions.6
Previous reports of radiation therapy for ophthalmic AIDS-related Kaposi's sarcoma have reported good results with multiple-fraction regimens. Coo¬ per and Fried" first described success¬ ful radiation therapy of aggressive con¬
junctival Kaposi's sarcoma in a patient with AIDS, using 3000 cGy in 10 frac¬ tions
2 weeks. No side effects or noted after 4 months. Shuler et al10 described 12 patients with ophthalmic Kaposi's sarcoma treated with 2000 to 3000 cGy in 200- to 300-cGy fractions over 3 weeks. All patients re¬ sponded to therapy, with complete res¬ olution in 10 patients. Two patients de¬ veloped recurrence within 4 months and four patients developed recurrence af¬ ter 6 months. Side effects of treatment included local skin erythema in six pa¬ tients and hair loss at the beam exit site in one patient. A retrospective study cannot assess all therapeutic issues. In our analysis, cellular immunity and other factors that correlate with treatment response14 were not considered. While it is possible that a randomized trial would demon¬ strate significant differences in re¬ sponse rates or complications between the radiation groups, we did not observe this. Similarly, a higher total radiation dose, regardless of fractionation, might alter recurrence roles; however, this was not assessed in this study. Larger single fractions may provide longer control, but this was not as¬ sessed in this study. All patients re¬ sponded to therapy, and our findings were similar to those of Cooper and Fried8 and Shuler et al.10 Side effects were minor and equivalent in the two groups. The single-dose regimen we used has several practical advantages over multiple-fraction treatments. The control and complication rates were comparable between both regimens and the single-fraction approach is clearly more expeditious. It is less inconve¬ nient and time-consuming for the paover
recurrences were
tient, and is not interrupted if intercur¬ rent illnesses develop. This study was supported in part by NIH grant E YO by unrestricted grants from That Man May See and Research to Prevent Blindness Inc.
7504 and
References 1. Rutherford GW, Payne SF, Lemp GF. The epidemiology of AIDS-related Kaposi's sarcoma.J AIDS. 1990;3(suppl):924-931. 2. AIDS Weekly Surveillance Report. Atlanta, Ga: United States AIDS Program, Center for
Infectious Diseases, Centers for Disease Control;
August 1,
1988. 3. Haverkes HW, Friedman-Kien AE, Drotman DP, Morgan WM. The changing incidence of Kaposi sarcoma amongst patients with AIDS. J Am Acad Dermatol. 1990;22:1250-1253. 4. Centers for Disease Control. Update: acquired immunodeficiency syndrome and human immunodeficiency virus infection in the United States. MMWR. 1989;38:1-4. 5. Friedman-Kien AE, Saltzman BR. Clinical manifestations of classical, endemic African, and epidemic AIDS-related Kaposi's sarcoma. J Am Acad Dermatol. 1990:22:1237-1250. 6. Berson AM, Quivey JM, Harris JW, Wara WM. Radiation therapy for AIDS-related Kaposi's sarcoma. Int J Radiat Oncol Biol Phys. 1990;19: 569-575. 7. Cooper JS, Fried PR. Defining the role of radiation therapy in the management of epidemic Kaposi's sarcoma. Int J Radiat Oncol Biol Phys.
1987;3:35-39.
Cooper JS, Fried PR. Treatment of aggresepidemic Kaposi's sarcoma of the conjunctiva by radiotherapy. Arch Ophthalmol. 1988;106:20-21. 9. Cooper JS. Optimal treatment of epidemic Kaposi's sarcoma. Int J Radiat Oncol Biol Phys. 8. sive
1990;19:807-808.
10. Shuler JD, Holland GN, Miles SA, Miller BJ, Grossman I. Kaposi sarcoma of the conjunctiva and eyelids associated with the acquired immunodeficiency syndrome. Arch Ophthalmol. 1989;107:858\x=req-\ 862. 11. Volberding P. Therapy of Kaposi's sarcoma in AIDS. Semin Oncol. 1984;11:60-67. 12. Mitsuyuasu RT, Groopman JE. Biology and therapy of Kaposi's sarcoma. Semin Oncol. 1984; 11:54-59. 13. Krown SE, Real FX, Vadhan-Raj S, et al. Kaposi's sarcoma and the acquired immune deficiency syndrome: treatment with recombinant interferon alpha and analysis of prognostic factors. Cancer. 1986;57:1662-1665. 14. Mitsayasu RT, Taylor JMG, Glaspy J, Fahey JL. Heterogeneity of epidemic Kaposi's sarcoma: implications for therapy. Cancer. 1986;57:1657\x=req-\ 1661. 15. Macher AM, Palestine A, Masur H, et al. Multicentric Kaposi's sarcoma of the conjunctiva in a male homosexual with the acquired immunodefi-
ciency syndrome. Ophthalmology. 1983;90:879-884. 16. Schag CC, Heinrich RL, Ganz PA. Karnofsky performance status revisited: reliability, validity, and guidelines. J Clin Oncol. 1984;2:187-194. 17. Lo TCM, Salzman FA, Smedal MI, Wright KA. Radiotherapy for Kaposi's sarcoma. Cancer. 1980;45:684-687.
18. Cooper JS. The influence of dose on the long-term control of classic (non-AIDS associated) Kaposi's sarcoma by radiotherapy. Int J Radiat Oncol Biol Phys. 1988;15:1141-1146.
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