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Prevention of Ocular Toxicity of Carmustine (BCNU) with Supraophthalmic Intracarotid Infusion
Prevention of Ocular Toxicity of Carmustine {BCNU) with Supraophthalmic Intracarotid Infusion GEORGIA ANTONAKOU CHROUSOS, MD,* EDWARD H. OLDFIELD, MD,t JOHN L. DOPPMAN, MD,t DAVID G. COGAN, MD§
Abstract: lntracarotid administration of carmustine (BCNU) is an increasingly accepted therapeutic modality for primary brain tumors. Its beneficial effect on prolonging survival, however, is countered by its frequent delayed complication of retinal toxicity and severe visual loss, which reportedly occurs in approximately 70% of the patients. Since this complication probably results from increased flow of the drug into the ophthalmic artery, the authors have attempted to infuse BCNU via a small intracarotid catheter advanced beyond the origin of the ophthalmic artery. In a series of nine patients (average follow-ups, 10.7 months), the authors were successful in treating six patients with exclusively supraophthalmic infusions. None of these patients developed any ocular toxicity. From the remaining three patients, two patients received one infraophthalmic infusion with no retinal toxicity. The third patient, however, who received three infraophthalmic infusions, developed ipsilateral retinopathy. These results suggest that retinopathic complications of intracarotid BCNU can be avoided if the infusion catheter is advanced beyond the origin of the ophthalmic artery. [Key words: brain tumors, chemotherapy, ocular toxicity.] Ophthalmology 93:1471-
1475, 1986
Grade III and IV malignant astrocytomas (glioblastomas multiforme) and uniformly rapidly fatal with current medical treatment. After surgery of histologically proven malignant astrocytomas, treatment with radiation therapy and systemic chemotherapy extends the median survival to only 1 year. '-3 The localized nature of these tumors and their relatively isolated arterial supply (the majority of tumors are perFrom the Center for Sight, Georgetown University, Department of Ophthalmology,* Washington, DC, the Surgical Neurology Branch,t and the Department of Diagnostic Radiology,:j: National Institutes of Health, and the Neuro-ophthalmology Section,§ NEI, National Institutes of Health, Bethesda. Presented at an Annual Meeting of the American Academy of Ophthalmology. Reprint requests to Georgia Antonakou Chrousos, MD, Center for Sight, Georgetown University Department of Ophthalmology, Kober-Gogan Building, 5th Floor, 3800 Reservoir Road, Washington, DC 20007.
fused by one carotid artery) make intracarotid chemotherapy with a suitable drug seem attractive. Intracarotid infusion of carmustine (BCNU)-a nitrosourea-is being used in several centers in the United States to increase the delivery of this chemotherapeutic agent to brain tumors while minimizing systemic effects-4-6 Although the demonstrated antineoplastic effect ofBCNU has been significant in early clinical trials, the delayed ocular toxicity ipsilaterally to the infusion restricts its use. Shingleton et al reported severe ipsilateral visual loss in seven of ten patients treated with intracarotid BCNU (3 of the 7 affected patients progressed to no light perception after the therapy). 7 Other investigators describe a similar experience.6·8 The toxicity is apparently due to the flow of the drug into the ophthalmic artery, which causes retinitis or, in some instances, neuroretinitis. 6-9 In addition to ocular toxicity, orbital toxicity ipsilateral to the infusion site has been reported, consisting of increased orbital vascularity, vasodilation, and occasional arteriovenous shunting. 10•11
1471
OPHTHALMOLOGY •
NOVEMBER 1986 •
VOLUME 93 •
NUMBER 11
Table 1. Clinical Profile of Patients Receiving lntracarotid BCNU
Patient
AgejSex
Site and Type of Tumor
62/F
2
30/F
3 4
16/F 32/M
Right temporoparietal glioblastoma grade Ill Right parietal glioblastoma grade IV Left frontal glioblastoma grade IV Left frontal glioblastoma grade Ill
5 6
39/F 15/M
Left frontal glioblastoma grade IV Left parietal glioblastoma grade Ill
7 8
42/F 58/F
Left frontal glioblastoma grade Ill Right frontal glioblastoma grade IV
9
30/F
Left frontal glioblastoma grade Ill
Previous Radiation Therapy
Cumulative BCNU dosage (mg)
Number of BCNU Infusions
Follow-up (months)
+
885
2
13
+
1530
4
24
+
1493 1031
4 3
17 10
374 804
1 2 (1 infraophthalmic) 2 1 (infraophthalmic) 3 (all infraophthalmic)
3 7
(6000 rad) (5000 rad) (6900 rad)
680 264
+
(5200 rad)
1098
Retinal Toxicity
3 3 17
+
BCNU = intracarotid administration of carmustine; F = female; M = male.
We attempted to diminish the ocular damage of intracarotid administration of BCNU by infusing the medication via a small intracarotid catheter that is advanced beyond the origin of the ophthalmic artery. The results are described in this report.
MATERIALS AND METHODS Nine patients (2 men and 7 women), with ages ranging from 15 to 62 years, were treated with intracarotid BCNU
at the Clinical Center of the National Institutes of Health between 1983 and 1984. All patients had malignant astrocytomas (grade III or IV) and had undergone subtotal excision of the tumor before treatment with intra-arterial chemotherapy. Four patients had previously received radiation therapy to the whole brain with an additional dose to the tumor site. None had received any previous chemotherapy (Table 1). Complete ophthalmologic examinations and fundus photographs were obtained in all patients before and after treatment. Fluorescein angiography was done as needed. Patients were followed for an average of 10.7 months (range, 3-24 months). For BCNU administration, transfemoral catherization of the internal carotid artery was performed with a 5-F toposcopic catheter. This instrument is a 3-F flexible polyurethane catheter attached to a 5-F introducing catheter. The lead catheter advances by continously turning itself inside out to negotiate complex vascular curves. The toposcopic catheter was advanced through the carotid siphon, and its tip was positioned distal to the ophthalmic artery, between the origin of the posterior communicating artery and the intracranial bifurcation of the internal carotid artery, into the middle cerebral and arterior cerebral arteries. (Fig 1) BCNU, 220 mg/m2 body surface area, was then infused into the distal intracranial internal carotid artery over a 45-minute period with a syringe infusion pump at a rate of 2 to 3 ml/min. The BCNU solution contained 4% ethanol.
RESULTS
Fig 1. The infusion catheter (black arrows) is shown inside the carotid artery and beyond the origin of the ophthalmic artery (white arrow).
1472
In three patients, an infraopthalmic infusion was performed because of inability to advance the catheter tip beyond the origin of the ophthalmic artery. Patient 6 received one infraophthalmic infusion (ofatotal of2); pa-
CHROUSOS, et al •
BCNU TOXICITY
Fig 2. Fundus picture of the left eye of case 9 before intracarotid chemotherapy, left, and a few weeks after the third infraophthalmic infusion, right. Note cotton wool exudates and hemorrhages of the posterior pole.
tient 8, one (of 1); and patient 9, three (of 3) infusions (Table 1). Minor complications of conjunctival hyperemia, flushing of the skin, and pain in the side of the infusion occurred during all infraophthalmic infusions and only occasionally and to a lesser degree during supraophthalmic infusions. The conjunctival hyperemia usually resolved within several hours of the infusion, but in a few cases it lasted up to two days. Hemiparesis was noted in two patients immediately after an infusion. In one patient, it was transient and lasted only 30 minutes, and in the other patient it was permanent. Delayed ocular complications of retinitis or neuroretinitis were not observed in any of the patients who received supraophthalmic infusions, or in those patients who received only one infraophthalmic infusion (patients 6 and 8). In contrast, patient 9, who received three infraophthalmic infusions, developed retinal complications ipsilateral to the side of infusion. A delayed complication of focal cerebral necrosis was noted in three patients (by computerized tomography). CASE REPORT Patient 9 was a 30-year-old oriental woman who underwent a subtotal resection of a left frontal glioblastoma grade III in December 1982. After surgery, she received radiation therapy to the site of the tumor (5200 rad over six weeks). In May 1983, she developed aphasia and hemiparesis from tumor regrowth. Her preinfusion ophthalmologic examination revealed 20/20 visual acuity in each eye with her myopic correction on. A myopic conus and tilt of the optic nerve head was noted in both eyes. The rest ofthe examination was normal. She then received
monthly infraophthalmic infusions ofBCNU (cumulative dosage, 1098 mg) over three months. She experienced pain in the left eye and flushing of the periorbital skin during each infusion. Conjunctival hyperemia also occurred during the infusions and lasting from a few hours to one day after each infusion. The patient was monitored for late ocular complications. She had no ocular complaints and her examinations were unchanged until three weeks after her third infusion, when she complained of distortion and micropsia with her left eye. Visual acuity in that eye was 20/30. There were cotton wool spots and hemorrhages of the posterior pole and along the superior arcade of that eye (Fig 2). The macula was minimally involved. Fluorescein angiography, however, revealed some dye leakage. Her visual loss progressed to 20/40 over the next few weeks and has remained stable since. No further BCNU infusions were given. At her last clinic visit in November 1984, her ocular conditions were stable.
DISCUSSION BCNU is a nitrosourea derivative with lipophilic properties, small molecular weight, and limited binding to plasma proteins. 12 These contribute to its ability to penetrate the blood-brain and blood-retina barrier. BCNU derives its activity by alkylation of nucleic acids and other cell constituents. 12 As with other alkylating agents, high peak concentrations ofBCNU may be more effective than chronic low levels of the drug. 13 Brain concentrations of BCNU can be increased fourfold when the same dose of the drug is administered into the carotid artery rather than intravenously. 14 The agent causing tumor cell death may be one or more of the metabolites of carmustine. These metabolites persist 1473
OPHTHALMOLOGY
•
NOVEMBER 1986
in the plasma for several days or weeksY This would explain the clinically observed findings of delayed toxicity. Multiple systemic toxicities of the nitrosoureas have been extensively reported. However, ocular side effects have been recognized only recently. In 1973, DeWys and Fowler reported a necrotizing ateriolitis of the internal carotid artery system on the side of infusion in dogs treated with intracarotid BCNU. 15 In addition, they noted retinal and corneal edema that produced blindness in the majority of the animals. Subsequently, McLennan and Taylor reported acute bilateral optic neuroretinitis and permanent visual loss in a patient who received BCNU, procarbazine, cyclophosphamide, and prednisone. 9 Grimson and associates reported another patient who developed neuroretinitis ipsilateral to the infusion side after treatment with intracarotid BNCU. 8 More recently, Shingleton and associates found a 70% incidence of severe ipsilateral visual loss in patients treated with intracarotid BCNU. 7 This toxicity became apparent 2 to 14 weeks after intracarotid administration of BCNU. Retinal hemorrhages and cotton wool exudates were the most prominent ophthalmoscopic abnormalities. The authors suggested that the BCNU-induced retinal injury was caused by damage to the retina vessels. The lesions consisted of segmental intraretinal vasculitis and/or obstruction. One patient had light and electromicroscopic confirmation of cilioretinal artery occlusion and choroidal fibrin thrombi. Gebarski and associates reported orbital changes after intracarotid BCNU injections. 10 They describe increased orbital vascularity and vasodilation, as well as arteriovenous shunting. No neuroretinallesions occurred in our patients with supraophthalmic infusion ofBCNU, even though the dose of BCNU administered was equal or greater than that used in most of the previous studies and the patient followup was sufficiently long to cover the period during which the toxicity becomes manifest_1- 9•11 In our series of nine patients with intracarotid BCNU therapy, one patient developed retinopathy. This patient had the drug administered by the intracarotid route three times and had also received radiation to the head. Two other patients who had had a single infusion by the infraophthalmic route and no radiation developed no retinopathy. Nor did retinopathy develop in any of the six patients who had had supraophthalmic infusions even though the number of infusions and amount of radiation
•
VOLUME 93
•
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in several cases exceeded that given to the affected patient of the infraophthalmic group. The evidence suggests, therefore, that retinopathic complications may be avoided by placing the canula above the exit site of the ophthalmic artery when multiple infusions are to be given.
REFERENCES 1. Walker MD, Alexander E Jr, Hunt WE, et al. Evaluation of BCNU and/ or radiotherapy in the treatment of anaplastic gliomas; a cooperative clinical trial. J Neurosurg 1978; 49:333-43. 2. Wilson CB. Current concepts in cancer; brain tumors. N Engl J Med 1979; 300:1469-71. 3. Walker MD, Green SB, Byar DP, et al. Randomized comparisons of radiotherapy and nitrosoureas for the treatment of malignant glioma after surgery. N Engl J Med 1980; 303:1323-9. 4. Greenberg HS, Ensminger WD, Seeger JF, et al. Intra-arterial BCNU chemotherapy for the treatment of malignant gliomas of the central nervous system: a preliminary report. Cancer Treat Rep 1981; 65: 803-10. 5. Yamada K, Bremer AM, West CR, et al. Intra-arterial BCNU therapy in the treatment of metastatic brain tumor from lung carcinoma: a preliminary report. Cancer 1979; 44:2000-7. 6. Greenberg HS, Ensminger WD, Chandler WF, et al. Intra-arterial BCNU chemotherapy for treatment of malignant gliomas of the central nervous system. J Neurosurg 1984; 61:423-9. 7. Shingleton BJ, Bienfang DC, Albert DM, et al. Ocular toxicity associated with high-dose carmustine. Arch Ophthalmol1982; 100:1766-72. 8. Grimson BS, Mahaley MS Jr, Dubey HD, Dudka L. Ophthalmic and central nervous system complications following intracarotid BCNU (Carmustine). J Clin Neuro-Ophthalmol1984; 1:261-4. 9. Mclennan R, Taylor HR. Optic neuroretinitis in association with BCNU and procarbazine therapy. Med Pediatr Oncol1978; 4:43-8. 10. Gebarski SS, Greenberg HS, Gabrielsen TO, Vine AK. Orbital angiegraphic changes after intracarotid BCNU chemotherapy. AJNR 1984; 5:55-8. 11. Miller DF, Bay JW, Lederman RJ, et al. Ocular and orbital toxicity following intracarotid injection of BCNU (Carmustine) and cisplatinum for malignant gliomas. Ophthalmology 1985; 92:402-6. 12. Oliverio VT. Toxicology and pharmacology of the nitrosoureas. Cancer Chemother Rep 1973; 4(Suppl):13-20. 13. Skipper HE. The effects of chemotherapy on the kinetics of leukemic cell behavior. Cancer Res 1965; 25:1544-50. 14. Crafts DC, Levin VA, Nielsen S. lntracarotid BCNU (NSC-409962): a toxicity study in six rhesus monkeys. Cancer Treat Rep 1976; 60: 541-5. 15. DeWys WD, Fowler EH. Report of vasculitis and blindness after intracarotid injection of 1,3-bis(2-chloroethyl)-1-nitrosourea (BCNU; NSC409962) in dogs. Cancer Chemother Rep 1973; 57:33-40.
Discussion
by
Andrew K. Vine, MD Dr. Chrousos and her colleagues have presented nine patients who underwent a total of 22 intracarotid infusions of carmustine (BCNU). Eighteen of these infusions were successfully given as supraophthalmic infusions. No retinal toxicity was seen in paFrom the Vitreo-Retina Service, The W.K. Kellogg Eye Center, The University of Michigan, Ann Arbor.
1474
tients who received only supraophthalmic injections or only one infraophthalmic injection. One patient who received three infraophthalmic injections developed retinal toxicity. The authors conclude that retinopathic complications may be avoided by supraophthalmic infusions. A variety of factors may contribute to BCNU-induced retinal toxicity. The authors have focused on one parameter, the intracarotid position of the catheter. Although no retinal toxicity
CHROUSOS, et al
occurred with supraophthalmic injections, significant neurologic complications, such as hemiparesis and cerebral necrosis, occurred. In this regard, it is noteworthy that one center with greater experience in supraophthalmic BCNU infusions (56 supraophthalmic infusions) subsequently discontinued this technique because of increased brain edema and leukoencephalopathy. 1 A second factor affecting both retinal and brain toxicity is the amount of BCNU injected into the carotid. As the ophthalmic artery receives a significant proportion of the flow of the internal carotid artery, the same dosage of BCNU injected above the ophthalmic artery will result in a significantly higher concentration reaching the brain, possibly causing toxic side effects. The dosage of BCNU may have to be adjusted depending on the actual intracarotid injection site. A third factor that may contribute to BCNU toxicity is its solubility and its solvent, ethanol. Several investigators have proposed that the recommended solvent (ethanol) may contribute to BCNU induced toxicity. 2 Although intracarotid injections of alcohol in dogs failed to show toxic effects, it is possible that alcohol, when combined with BCNU, does increase the potential toxicity. 3 Recent studies have shown that reducing the alcohol solvent dramatically decreaSes the amount of soluble BCNU that is available to the tissues. 4 To avoid possible ethanol induced
•
BCNU TOXICITY
toxicity, BCNU can be slowly dissolved in 4% dextrose and water. BCNU in 4% dextrose and water has the same degree of soluble BCNU available to the tissues as the ethanol preparation. A fourth parameter that may influence both retinal and brain toxicity is the rate of infusion of intracarotid BCNU. In summary, the authors have demonstrated decreased retinal toxicity with supraophthalmic BCNU injections. A concurrent increase in cerebral toxicity may have occurred. Many factors appear to contribute to the BCNU retinal toxicity. The intracarotid position of the catheter is only one part of the puzzle.
References 1. Hochberg FH. Personal Communication. 2. Greenberg HS, Ensminger WD, Chandler WF, et al. Intra-arterial BCNU chemotherapy for treatment of malignant gliomas of the central nervous system. J Neurosurg 1984; 61:423-9. 3. DeWys WD, Fowler EH. Report of vasculitis and blindness after intracarotid injection of 1,3·bis(2-chloroethyl)-1-nitrosourea (BCNU; NSC409962) in dogs. Cancer Chemother Rep 1973; 57:33-40. 4. Layton PB, Greenberg HS, Stetson PL, et al. BCNU solubility and toxicity in the treatment of malignant astrocytomas. J Neurosurg 1984; 60:1134-7.
1475
Abstract: lntracarotid administration of carmustine (BCNU) is an increasingly accepted therapeutic modality for primary brain tumors. Its beneficial effect on prolonging survival, however, is countered by its frequent delayed complication of retinal toxicity and severe visual loss, which reportedly occurs in approximately 70% of the patients. Since this complication probably results from increased flow of the drug into the ophthalmic artery, the authors have attempted to infuse BCNU via a small intracarotid catheter advanced beyond the origin of the ophthalmic artery. In a series of nine patients (average follow-ups, 10.7 months), the authors were successful in treating six patients with exclusively supraophthalmic infusions. None of these patients developed any ocular toxicity. From the remaining three patients, two patients received one infraophthalmic infusion with no retinal toxicity. The third patient, however, who received three infraophthalmic infusions, developed ipsilateral retinopathy. These results suggest that retinopathic complications of intracarotid BCNU can be avoided if the infusion catheter is advanced beyond the origin of the ophthalmic artery. [Key words: brain tumors, chemotherapy, ocular toxicity.] Ophthalmology 93:1471-
1475, 1986
Grade III and IV malignant astrocytomas (glioblastomas multiforme) and uniformly rapidly fatal with current medical treatment. After surgery of histologically proven malignant astrocytomas, treatment with radiation therapy and systemic chemotherapy extends the median survival to only 1 year. '-3 The localized nature of these tumors and their relatively isolated arterial supply (the majority of tumors are perFrom the Center for Sight, Georgetown University, Department of Ophthalmology,* Washington, DC, the Surgical Neurology Branch,t and the Department of Diagnostic Radiology,:j: National Institutes of Health, and the Neuro-ophthalmology Section,§ NEI, National Institutes of Health, Bethesda. Presented at an Annual Meeting of the American Academy of Ophthalmology. Reprint requests to Georgia Antonakou Chrousos, MD, Center for Sight, Georgetown University Department of Ophthalmology, Kober-Gogan Building, 5th Floor, 3800 Reservoir Road, Washington, DC 20007.
fused by one carotid artery) make intracarotid chemotherapy with a suitable drug seem attractive. Intracarotid infusion of carmustine (BCNU)-a nitrosourea-is being used in several centers in the United States to increase the delivery of this chemotherapeutic agent to brain tumors while minimizing systemic effects-4-6 Although the demonstrated antineoplastic effect ofBCNU has been significant in early clinical trials, the delayed ocular toxicity ipsilaterally to the infusion restricts its use. Shingleton et al reported severe ipsilateral visual loss in seven of ten patients treated with intracarotid BCNU (3 of the 7 affected patients progressed to no light perception after the therapy). 7 Other investigators describe a similar experience.6·8 The toxicity is apparently due to the flow of the drug into the ophthalmic artery, which causes retinitis or, in some instances, neuroretinitis. 6-9 In addition to ocular toxicity, orbital toxicity ipsilateral to the infusion site has been reported, consisting of increased orbital vascularity, vasodilation, and occasional arteriovenous shunting. 10•11
1471
OPHTHALMOLOGY •
NOVEMBER 1986 •
VOLUME 93 •
NUMBER 11
Table 1. Clinical Profile of Patients Receiving lntracarotid BCNU
Patient
AgejSex
Site and Type of Tumor
62/F
2
30/F
3 4
16/F 32/M
Right temporoparietal glioblastoma grade Ill Right parietal glioblastoma grade IV Left frontal glioblastoma grade IV Left frontal glioblastoma grade Ill
5 6
39/F 15/M
Left frontal glioblastoma grade IV Left parietal glioblastoma grade Ill
7 8
42/F 58/F
Left frontal glioblastoma grade Ill Right frontal glioblastoma grade IV
9
30/F
Left frontal glioblastoma grade Ill
Previous Radiation Therapy
Cumulative BCNU dosage (mg)
Number of BCNU Infusions
Follow-up (months)
+
885
2
13
+
1530
4
24
+
1493 1031
4 3
17 10
374 804
1 2 (1 infraophthalmic) 2 1 (infraophthalmic) 3 (all infraophthalmic)
3 7
(6000 rad) (5000 rad) (6900 rad)
680 264
+
(5200 rad)
1098
Retinal Toxicity
3 3 17
+
BCNU = intracarotid administration of carmustine; F = female; M = male.
We attempted to diminish the ocular damage of intracarotid administration of BCNU by infusing the medication via a small intracarotid catheter that is advanced beyond the origin of the ophthalmic artery. The results are described in this report.
MATERIALS AND METHODS Nine patients (2 men and 7 women), with ages ranging from 15 to 62 years, were treated with intracarotid BCNU
at the Clinical Center of the National Institutes of Health between 1983 and 1984. All patients had malignant astrocytomas (grade III or IV) and had undergone subtotal excision of the tumor before treatment with intra-arterial chemotherapy. Four patients had previously received radiation therapy to the whole brain with an additional dose to the tumor site. None had received any previous chemotherapy (Table 1). Complete ophthalmologic examinations and fundus photographs were obtained in all patients before and after treatment. Fluorescein angiography was done as needed. Patients were followed for an average of 10.7 months (range, 3-24 months). For BCNU administration, transfemoral catherization of the internal carotid artery was performed with a 5-F toposcopic catheter. This instrument is a 3-F flexible polyurethane catheter attached to a 5-F introducing catheter. The lead catheter advances by continously turning itself inside out to negotiate complex vascular curves. The toposcopic catheter was advanced through the carotid siphon, and its tip was positioned distal to the ophthalmic artery, between the origin of the posterior communicating artery and the intracranial bifurcation of the internal carotid artery, into the middle cerebral and arterior cerebral arteries. (Fig 1) BCNU, 220 mg/m2 body surface area, was then infused into the distal intracranial internal carotid artery over a 45-minute period with a syringe infusion pump at a rate of 2 to 3 ml/min. The BCNU solution contained 4% ethanol.
RESULTS
Fig 1. The infusion catheter (black arrows) is shown inside the carotid artery and beyond the origin of the ophthalmic artery (white arrow).
1472
In three patients, an infraopthalmic infusion was performed because of inability to advance the catheter tip beyond the origin of the ophthalmic artery. Patient 6 received one infraophthalmic infusion (ofatotal of2); pa-
CHROUSOS, et al •
BCNU TOXICITY
Fig 2. Fundus picture of the left eye of case 9 before intracarotid chemotherapy, left, and a few weeks after the third infraophthalmic infusion, right. Note cotton wool exudates and hemorrhages of the posterior pole.
tient 8, one (of 1); and patient 9, three (of 3) infusions (Table 1). Minor complications of conjunctival hyperemia, flushing of the skin, and pain in the side of the infusion occurred during all infraophthalmic infusions and only occasionally and to a lesser degree during supraophthalmic infusions. The conjunctival hyperemia usually resolved within several hours of the infusion, but in a few cases it lasted up to two days. Hemiparesis was noted in two patients immediately after an infusion. In one patient, it was transient and lasted only 30 minutes, and in the other patient it was permanent. Delayed ocular complications of retinitis or neuroretinitis were not observed in any of the patients who received supraophthalmic infusions, or in those patients who received only one infraophthalmic infusion (patients 6 and 8). In contrast, patient 9, who received three infraophthalmic infusions, developed retinal complications ipsilateral to the side of infusion. A delayed complication of focal cerebral necrosis was noted in three patients (by computerized tomography). CASE REPORT Patient 9 was a 30-year-old oriental woman who underwent a subtotal resection of a left frontal glioblastoma grade III in December 1982. After surgery, she received radiation therapy to the site of the tumor (5200 rad over six weeks). In May 1983, she developed aphasia and hemiparesis from tumor regrowth. Her preinfusion ophthalmologic examination revealed 20/20 visual acuity in each eye with her myopic correction on. A myopic conus and tilt of the optic nerve head was noted in both eyes. The rest ofthe examination was normal. She then received
monthly infraophthalmic infusions ofBCNU (cumulative dosage, 1098 mg) over three months. She experienced pain in the left eye and flushing of the periorbital skin during each infusion. Conjunctival hyperemia also occurred during the infusions and lasting from a few hours to one day after each infusion. The patient was monitored for late ocular complications. She had no ocular complaints and her examinations were unchanged until three weeks after her third infusion, when she complained of distortion and micropsia with her left eye. Visual acuity in that eye was 20/30. There were cotton wool spots and hemorrhages of the posterior pole and along the superior arcade of that eye (Fig 2). The macula was minimally involved. Fluorescein angiography, however, revealed some dye leakage. Her visual loss progressed to 20/40 over the next few weeks and has remained stable since. No further BCNU infusions were given. At her last clinic visit in November 1984, her ocular conditions were stable.
DISCUSSION BCNU is a nitrosourea derivative with lipophilic properties, small molecular weight, and limited binding to plasma proteins. 12 These contribute to its ability to penetrate the blood-brain and blood-retina barrier. BCNU derives its activity by alkylation of nucleic acids and other cell constituents. 12 As with other alkylating agents, high peak concentrations ofBCNU may be more effective than chronic low levels of the drug. 13 Brain concentrations of BCNU can be increased fourfold when the same dose of the drug is administered into the carotid artery rather than intravenously. 14 The agent causing tumor cell death may be one or more of the metabolites of carmustine. These metabolites persist 1473
OPHTHALMOLOGY
•
NOVEMBER 1986
in the plasma for several days or weeksY This would explain the clinically observed findings of delayed toxicity. Multiple systemic toxicities of the nitrosoureas have been extensively reported. However, ocular side effects have been recognized only recently. In 1973, DeWys and Fowler reported a necrotizing ateriolitis of the internal carotid artery system on the side of infusion in dogs treated with intracarotid BCNU. 15 In addition, they noted retinal and corneal edema that produced blindness in the majority of the animals. Subsequently, McLennan and Taylor reported acute bilateral optic neuroretinitis and permanent visual loss in a patient who received BCNU, procarbazine, cyclophosphamide, and prednisone. 9 Grimson and associates reported another patient who developed neuroretinitis ipsilateral to the infusion side after treatment with intracarotid BNCU. 8 More recently, Shingleton and associates found a 70% incidence of severe ipsilateral visual loss in patients treated with intracarotid BCNU. 7 This toxicity became apparent 2 to 14 weeks after intracarotid administration of BCNU. Retinal hemorrhages and cotton wool exudates were the most prominent ophthalmoscopic abnormalities. The authors suggested that the BCNU-induced retinal injury was caused by damage to the retina vessels. The lesions consisted of segmental intraretinal vasculitis and/or obstruction. One patient had light and electromicroscopic confirmation of cilioretinal artery occlusion and choroidal fibrin thrombi. Gebarski and associates reported orbital changes after intracarotid BCNU injections. 10 They describe increased orbital vascularity and vasodilation, as well as arteriovenous shunting. No neuroretinallesions occurred in our patients with supraophthalmic infusion ofBCNU, even though the dose of BCNU administered was equal or greater than that used in most of the previous studies and the patient followup was sufficiently long to cover the period during which the toxicity becomes manifest_1- 9•11 In our series of nine patients with intracarotid BCNU therapy, one patient developed retinopathy. This patient had the drug administered by the intracarotid route three times and had also received radiation to the head. Two other patients who had had a single infusion by the infraophthalmic route and no radiation developed no retinopathy. Nor did retinopathy develop in any of the six patients who had had supraophthalmic infusions even though the number of infusions and amount of radiation
•
VOLUME 93
•
NUMBER 11
in several cases exceeded that given to the affected patient of the infraophthalmic group. The evidence suggests, therefore, that retinopathic complications may be avoided by placing the canula above the exit site of the ophthalmic artery when multiple infusions are to be given.
REFERENCES 1. Walker MD, Alexander E Jr, Hunt WE, et al. Evaluation of BCNU and/ or radiotherapy in the treatment of anaplastic gliomas; a cooperative clinical trial. J Neurosurg 1978; 49:333-43. 2. Wilson CB. Current concepts in cancer; brain tumors. N Engl J Med 1979; 300:1469-71. 3. Walker MD, Green SB, Byar DP, et al. Randomized comparisons of radiotherapy and nitrosoureas for the treatment of malignant glioma after surgery. N Engl J Med 1980; 303:1323-9. 4. Greenberg HS, Ensminger WD, Seeger JF, et al. Intra-arterial BCNU chemotherapy for the treatment of malignant gliomas of the central nervous system: a preliminary report. Cancer Treat Rep 1981; 65: 803-10. 5. Yamada K, Bremer AM, West CR, et al. Intra-arterial BCNU therapy in the treatment of metastatic brain tumor from lung carcinoma: a preliminary report. Cancer 1979; 44:2000-7. 6. Greenberg HS, Ensminger WD, Chandler WF, et al. Intra-arterial BCNU chemotherapy for treatment of malignant gliomas of the central nervous system. J Neurosurg 1984; 61:423-9. 7. Shingleton BJ, Bienfang DC, Albert DM, et al. Ocular toxicity associated with high-dose carmustine. Arch Ophthalmol1982; 100:1766-72. 8. Grimson BS, Mahaley MS Jr, Dubey HD, Dudka L. Ophthalmic and central nervous system complications following intracarotid BCNU (Carmustine). J Clin Neuro-Ophthalmol1984; 1:261-4. 9. Mclennan R, Taylor HR. Optic neuroretinitis in association with BCNU and procarbazine therapy. Med Pediatr Oncol1978; 4:43-8. 10. Gebarski SS, Greenberg HS, Gabrielsen TO, Vine AK. Orbital angiegraphic changes after intracarotid BCNU chemotherapy. AJNR 1984; 5:55-8. 11. Miller DF, Bay JW, Lederman RJ, et al. Ocular and orbital toxicity following intracarotid injection of BCNU (Carmustine) and cisplatinum for malignant gliomas. Ophthalmology 1985; 92:402-6. 12. Oliverio VT. Toxicology and pharmacology of the nitrosoureas. Cancer Chemother Rep 1973; 4(Suppl):13-20. 13. Skipper HE. The effects of chemotherapy on the kinetics of leukemic cell behavior. Cancer Res 1965; 25:1544-50. 14. Crafts DC, Levin VA, Nielsen S. lntracarotid BCNU (NSC-409962): a toxicity study in six rhesus monkeys. Cancer Treat Rep 1976; 60: 541-5. 15. DeWys WD, Fowler EH. Report of vasculitis and blindness after intracarotid injection of 1,3-bis(2-chloroethyl)-1-nitrosourea (BCNU; NSC409962) in dogs. Cancer Chemother Rep 1973; 57:33-40.
Discussion
by
Andrew K. Vine, MD Dr. Chrousos and her colleagues have presented nine patients who underwent a total of 22 intracarotid infusions of carmustine (BCNU). Eighteen of these infusions were successfully given as supraophthalmic infusions. No retinal toxicity was seen in paFrom the Vitreo-Retina Service, The W.K. Kellogg Eye Center, The University of Michigan, Ann Arbor.
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tients who received only supraophthalmic injections or only one infraophthalmic injection. One patient who received three infraophthalmic injections developed retinal toxicity. The authors conclude that retinopathic complications may be avoided by supraophthalmic infusions. A variety of factors may contribute to BCNU-induced retinal toxicity. The authors have focused on one parameter, the intracarotid position of the catheter. Although no retinal toxicity
CHROUSOS, et al
occurred with supraophthalmic injections, significant neurologic complications, such as hemiparesis and cerebral necrosis, occurred. In this regard, it is noteworthy that one center with greater experience in supraophthalmic BCNU infusions (56 supraophthalmic infusions) subsequently discontinued this technique because of increased brain edema and leukoencephalopathy. 1 A second factor affecting both retinal and brain toxicity is the amount of BCNU injected into the carotid. As the ophthalmic artery receives a significant proportion of the flow of the internal carotid artery, the same dosage of BCNU injected above the ophthalmic artery will result in a significantly higher concentration reaching the brain, possibly causing toxic side effects. The dosage of BCNU may have to be adjusted depending on the actual intracarotid injection site. A third factor that may contribute to BCNU toxicity is its solubility and its solvent, ethanol. Several investigators have proposed that the recommended solvent (ethanol) may contribute to BCNU induced toxicity. 2 Although intracarotid injections of alcohol in dogs failed to show toxic effects, it is possible that alcohol, when combined with BCNU, does increase the potential toxicity. 3 Recent studies have shown that reducing the alcohol solvent dramatically decreaSes the amount of soluble BCNU that is available to the tissues. 4 To avoid possible ethanol induced
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BCNU TOXICITY
toxicity, BCNU can be slowly dissolved in 4% dextrose and water. BCNU in 4% dextrose and water has the same degree of soluble BCNU available to the tissues as the ethanol preparation. A fourth parameter that may influence both retinal and brain toxicity is the rate of infusion of intracarotid BCNU. In summary, the authors have demonstrated decreased retinal toxicity with supraophthalmic BCNU injections. A concurrent increase in cerebral toxicity may have occurred. Many factors appear to contribute to the BCNU retinal toxicity. The intracarotid position of the catheter is only one part of the puzzle.
References 1. Hochberg FH. Personal Communication. 2. Greenberg HS, Ensminger WD, Chandler WF, et al. Intra-arterial BCNU chemotherapy for treatment of malignant gliomas of the central nervous system. J Neurosurg 1984; 61:423-9. 3. DeWys WD, Fowler EH. Report of vasculitis and blindness after intracarotid injection of 1,3·bis(2-chloroethyl)-1-nitrosourea (BCNU; NSC409962) in dogs. Cancer Chemother Rep 1973; 57:33-40. 4. Layton PB, Greenberg HS, Stetson PL, et al. BCNU solubility and toxicity in the treatment of malignant astrocytomas. J Neurosurg 1984; 60:1134-7.
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