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Topical Corticosteroid Therapy for Corneal Toxicity from Systemically Administered Cytarabine
TOPICAL CORTICOSTEROID THERAPY FOR CORNEAL TOXICITY FROM SYSTEMICALLY ADMINISTERED CYTARABINE JONATHAN H. LAss, M.D., HILLARD M. LAZARUS, M.D., MICHAEL D. REED, PHARM. D., AND ROGER H. HERZIG, M. D. Cleveland, Ohio
Eleven patients with leukemia refractory to conventional therapy were treated with high doses of cytarabine (3 'lJml intravenously every 12 hours for six days) followed by daunorubicin (30 m'lJm1/day intravenously for three days). Each patient received, in a double-masked, randomized manner, either 1% prednisolone phosphate or placebo eyedrops in each eye 12 hours before and along with the cytarabine so that we could determine whether a topical corticosteroid prevents corneal toxicity from systemic cytarabine. Ten of the 11 patients had a significant reduction in the intensity and duration of the symptoms and signs of corneal toxicity in the corticosteroid-treated eye (P<.OO05). In the placebo-treated eye, pain, photophobia, and tearing occurred at a median time of 6.5 days after initiation of therapy but resolved in approximately one week. Patients receiving high doses of intravenously administered eytarabine should receive topical corticosteroid prophylaxis to reduce the corneal toxicity associated with this treatment. High-dose intravenous cytarabine therapy (3 glm2) has been used to treat patients with leukemia refractory to conventional chemotherapy. 1,2 There have been several reports of corneal toxicity from systemic high-dose cytarabine therapyU resembling the corneal toxicity caused by topical cytarabine therapy. 6,7 This toxicity is characterized by conjunctivitis, fine corneal epithelial opacities
Accepted for publication Aug. 20, 1982. From the Divisions of Ophthalmology (Dr. Lass), Hematology/Oncology (Drs. Lazarus and Herzig), and Pediatric Pharmacology (Dr. Reed), Case Western Reserve University School of Medicine and the University Hospitals of Cleveland, Cleveland, Ohio. This study was supported in part by grant ROICAI5584-05 from the National Institutes of Health and by grants from the American Cancer Society (Dr. Lazarus) and the Leukemia Society of America (Drs. Lazarus and Herzig). Reprint requests to Jonathan H. Lass, M.D., University Hospitals of Cleveland, 2065 Adelbert Rd., Cleveland, OH 44106.
with superficial punctate keratitis, and pain with photophobia within one week of the initiation of treatment. These findings spontaneously resolve after another week. In a study of 48 patients treated with high-dose cytarabine we noted that patients treated with topical corticosteroids had a rapid resolution of the symptoms and signs of corneal toxicity, compared to patients who did not receive topical corticosteroid therapy. 5 We conducted a placebo-controlled, randomized, double-masked evaluation of topical corticosteroid prophylactic therapy for corneal toxicity in 11 patients receiving high-dose systemic cytarabine. SUBJECTS AND METHODS
Subjects-The study included seven men and four women with a mean age of 42 years (range, 22 to 67 years). All patients had leukemia in bone marrow relapse. Disease categories included
CAMERICAN JOURNAL OF OPHTHALMOLOGY 94:617~21, 1982
617
618
AMERICAN JOURNAL OF OPHTHALMOLOGY
acute myelogenous leukemia (seven patients), acute lymphoblastic leukemia in relapse (three patients), and erythroleukemia (one patient). All patients had received conventional doses of cytarabine at some previous time. Three of the ten patients had also received high-dose cytarabine therapy before this study began. Patient 10 was observed during two separate courses for this study. These studies were approved by the Institutional Review Board for Human Investigation and informed consent was obtained from each patient. Antileukemia treatment-All patients received 3 g/m! of cytarabine intravenously over one hour every 12 hours for six days. On days 7 through 9, each patient also received a conventional dose of daunorubicin HCI (30 mg/rnvday) by intravenous bolus. Topical treatment-Each patient served as his or her own control. One eye, preselected randomly, received corticosteroid and the other eye received placebo eyedrops. Randomization was done with a programmable calculator and random number program. The active drug consisted of a sterile, commercially available ophthalmic prednisolone sodium phosphate 1% solution with benzalkonium chloride 0.01%, disodium ethylenediaminetetraacetate, monobasic and dibasic sodium phosphate, and sodium chloride. The sterile, filtered placebo solution used was similar to the active drug solution but contained no prednisolone sodium phosphate or ethylenediaminetetraacetate. Placebo and the commercially available ophthalmic solutions were identical in packaging, appearance, and pH. The random code was kept in the pharmacy. The drugs were dispensed and administered without the examining physicians knowing which was which. After the initial ocular examination, each patient received two drops of either
NOVEMBER, 1982
corticosteroid or placebo solution three times a day from day 0 (the day before initiating cytarabine therapy) through day 9. Those patients who developed severe, symptomatic keratitis also received bacitracin ointment and cyclopentolate HCl1 % eyedrops three times a day for five days in the affected eye after a follow-up ocular examination. Ocular examination-An ocular examination, including visual acuity testing, slit-lamp biomicroscopy, fluorescein staining of the corneal epithelium, and ophthalmoscopy with the pupils dilated, was performed in a double-masked fashion by one of us (J. H. L.) on day 0 before the chemotherapy began. This examination was repeated on day 6 of treatment, or earlier if an eye became symptomatic. The examinations were then performed weekly for the next six weeks. Because the degree of microcystic changes in the corneal epithelium best correlated with the degree of symptomatology, this characteristic was quantitated on the first symptomatic day to determine the effect of the corticosteroid. We graded the effect as follows: 0, normal corneal epithelial appearance; 1+, zero to ten microcysts in the central corneal epithelium with no punctate keratitis on fluorescein staining (Figure, left); 2+, ten to 20 microcysts in the corneal epithelium with minimal superficial punctate keratitis; 3+, 20 to 40 microcysts in the corneal epithelium with moderate superficial punctate keratitis; and 4+, extensive microcyst formation throughout the corneal epithelium with severe superficial punctate keratitis (Figure, right). Statistical analYSis-We used Student's t-test for paired comparisons for the statistical analysis. 8 RESULTS
After the randomized code was broken, we found that ten of the 11 patients (11 of 12 eyes) developed foreign-body sensa-
VOL. 94, NO.5
CORTICOSTEROID FOR CYTARABINE TOXICITY
619
Figure (Lass and associates). Left, A I + microcyst reaction in the central corneal epithelium after six days of systemically administered cytarabine and topical corticosteroid therapy. Right, A 4+ microcyst reaction associated with severe pungtate keratitis is present diffusely throughout the corneal epithelium after six days of systemically administered cytarabine and topically administered placebo.
tion, intense photophobia, redness, tearing, and blurred vision in the placebotreated eye. The median time to onset of symptoms was 6.5 days after antileukemic therapy was instituted. In three patients the onset of ocular symptoms was delayed until two or three days after the conclusion of cytarabine therapy. One placebo-treated eye did not develop significant symptoms. In contrast, 11 of 12 eyes treated with topical corticosteroid developed only mild irritation and redness without photophobia or pain. All ocular findings were normal before chemotherapy and there was no evidence of infectious or leukemic ocular involve-
ment during the entire study period. Eleven of the 12 placebo-treated eyes had decreased visual acuities (20/40 to 20/200) and moderate conjunctival hyperemia. The cornea showed diffuse superficial punctate keratitis on fluorescein staining. Underlying the punctate changes were fine, refractile microcysts, most of which were clear; a few were opaque. There was also mild stromal edema and striae were present in Descemet's membrane. These signs corresponded with intense pain and photophobia in the affected eye. Five of these 11 eyes required bacitracin and cyclopentolate ncr to relieve the ocular symptoms and signs.
620
AMERICAN JOURNAL OF OPHTHALMOLOGY
In contrast, 11 of the 12 corticosteroidtreated eyes had normal visual acuities and minimal conjunctival hyperemia. These eyes also showed similar microcystic epithelial changes, but to a lesser degree, and had no fluorescein staining, stromal edema, or striae. The corticosteroid-treated eyes had significantly fewer microcystic corneal epithelial changes than the placebo-treated eyes (P<.0005) (Table). None of these eyes required additional topical medication. All the corticosteroid-treated eyes were asymptomatic within one week of the end of the cytarabine therapy, and at one month the corneal epithelium appeared to be normal. In contrast, the placebo-treated eyes remained symptomatic until two weeks after cytarabine therapy ended, and three of the eyes (Patients 1, 4, and 7) still had 1+ microTABLE MICROCYST SCORES FOR CORNEAL EPITHELIUM AFTER HIGH-DOSE SYSTEMIC CYTARABINE THERAPY
Microcyst Scores' Patient No.
CorticosteroidTreated Eye"
PlaceboTreated Eye
1 2 3 4 5 6 7
1 3 1 1 1 1
4 1 2 4 3 3 7 3 3 3 3 4
8 9
lOA:!:
10B:j: 11
1
o 2 1 1 1
• Microcyst grading: 0, normal appearance; 1+, zero to ten microcysts with no superficial punctate keratitis on fluorescein staining; 2+, ten to 20 microcysts with minimal superficial punctate keratitis; 3+, 20 to 40 microcysts with moderate superficial punctate keratitis; 4+, extensive microcyst formation with severe superficial punctate keratitis. tThe corticosteroid-treated eyes had a significantly lower score (P<.OOO5). :j:Patient 10 received two different courses of systemic therapy.
NOVEMBER, 1982
cystic corneal epithelial changes one month after cytarabine therapy was completed. DISCUSSION
Cytarabine has been a principal agent in the primary treatment of acute nonlymphoblastic leukemia.P" Because later remissions are achieved less often and are of shorter duration than the first remission,10,11 the treatment of acute leukemia in relapse remains a difficult problem. There is evidence that high concentrations of antitumor therapy increase response rates,12,13 and investigators have had success with high-dose cytarabine in refractory leukemias. 1,2 Several investigatorss" have noted that this high systemic dose produces conjunctivitis and keratitis similar to that found with topically administered cytarabine, Both in animal models'i" and in humans.i' fine, refractile opacities in the epithelium have been found, progressing to punctate keratitis and more severe involvement, accompanied by intense pain and photophobia in some of the human cases. One of the mechanisms of action of cytarabine is the inhibition of DNA polymerase which affects cells during the S-phase of cell division. 14 Thus, a significant toxic effect on rapidly dividing normal cells, such as the corneal epithelium, can be expected. The route by which systemic cytarabine reaches the corneal epithelium is unknown. It may reach the cornea by the anterior chamber, since the drug penetrates the blood-brain barrier, especially in high doses. 5,12 We have not observed corneal toxicity with conventional doses of cytarabine (100 mg/m"). It may also be distributed in the tears. Hande and associates" reported levels of 22 and 39 umoles in the tears after 3 g/m" of cytarabine was given intravenously.P We noted that topical corticosteroids significantly reduced morbidity and the
VOL. 94, NO. 5
CORTICOSTEROID FOR CYTARABINE TOXICITY
degree of corneal epithelial microcyst formation associated with high doses of intravenously administered cytarabine. The mechanism by which a topical corticosteroid reduces the toxic effect of an antimetabolite may be twofold. First, it may act purely as an anti-inflammatory agent." This possibility, however; does not account for the reduction in microcyst formation observed clinically. Also, on pathologic examinations of human biopsy specimens, the microcystic changes have been shown to be degenerating epithelial cells with microcyst formation, and not inflammatory cell inflltration.! The second mechanism that may account for the attenuation or prevention of symptoms is the partial inhibition of DNA and protein synthesis in sensitive cell types, including the epidermal cells. 17,18 A reduction in DNA replication would make the corneal epithelial cells less susceptible to the effects of an antimetabolite drug, such as cytarabine. We recommend the prophylactic use of a topical corticosteroid for the prevention of the severe keratitis associated with systemic high-dose cytarabine therapy. REFERENCES 1. Rudnick, S. A., Cadman, E. C., Capizzi, R. L., Skeel, R. T., Bertino, J. R., and McIntosh, S.: High dose arabinoside in refractory acute leukemia. Cancer 44:1189, 1979. 2. Herzig, R. H., Herzig, G. P., Lazarus, H. M., Wolff, S. N., and Philips, G. L.: Successful treatment of patients with refractory acute nonlymphocytic leukemia using high-dose cytosine arabinoside with and without anthracycline. Blood 58:141, 1981. 3. Hopen, G., Mondino, B. J., Johnson, B., and Chervenick, P.: Corneal toxicity with systemic cytarabine. Am. J. Ophthalmol. 91:500, 1981.
621
4. Castleberry, R. P., Crist, W. M., Holbrook, T., Malluh, A., and Gaddy, D.: The cytosine arabinoside (Ara-C) syndrome. Med. Pediatr. Oneol. 9:257, 1981. 5. Lazarus, H. M., Herzig, R. H., Herzig, G. P., Philips, G. L., Roessmann, D., and Fishman, D.: Central nervous system toxicity of high dose systemic cytosine arabinoside. Cancer 48:2577, 1981. 6. Kaufman, H. E., Capella, ]. A., Maloney, E. D., Robbins, J. E., Cooper, G. M., and Dotila, M. H.: Corneal toxicity of cytosine arabinoside. Arch. Ophthalmol. 72:535, 1964. 7. Elliot, G. A., and Schut, A. L.: Studies with cytarabine HCl (CA)in normal eyes of man, monkey, and rabbit. Am. J. Ophthalmol. 60:1074, 1965. 8. Sokal, R. R., and Rohlf, F. J.: Biometry. San Francisco, W. H. Freeman, 1969, pp. 328-333. 9. Bodey, G. P., Coltman, C. A., Hewlett, J. S., and Freireich, E. J.: Review of regimens containing cytarabine studied by the Southwest Oncology Group. Arch. Intern. Med. 136:1383, 1976. 10. Cline, M. J., Golde, D. W., Billing, R. J., Groopman, J. E., Zighelboim, J., and Gale, R. P.: Acute leukemia. Biology and Treatment. Ann. Intern. Med. 91:758, 1979. 11. Gale, R. P.: Advances in the treatment of acute myelogenous leukemia. N. Engl. J. Med. 300:1189, 1979. 12. Ho, D. H. W., and Frei, E.: Clinical pharmacology of I-f3-D-arabinofuroanosylcytosine. Clin. Pharmacol. Ther. 12:944, 1971. 13. Frei, E., and Canellos, G. P.: Dose. A critical factor in cancer chemotherapy. Am. J. Med. 69:585, 1980. 14. Furlong, N. B., and Gresham, C.: Inhibition of DNA synthesis but not of poly-dAT synthesis by the arabinoside analogue of cytidine in vitro. Nature N. BioI. 233:212, 1971. 15. Hande, K. R., Stein, R. S., McDonough, D. A., and Wolff, S. N.: Pharmacokinetics of highdose cytosine arabinoside. Clin. Res. 29:436, 1981. 16. Leibowitz, H. M., and Kupferman, A.: Antiinflammatory effectiveness in the cornea of topically administered prednisolone. Invest. Ophthalmol. 13:757, 1974. 17. Schulster, D., Burstein, S., and Cooke, B.: Mode of action of glucoeorticoids. In Molecular Endocrinology of the Steroid Hormones. London, John Wiley and Sons, 1976, p. 73. 18. Fisher, L. B., and Maibach, H. I.: The effect of corticosteroids on human epidermal mitotic activity. Arch. Dermatol. 103:39, 1971.
Eleven patients with leukemia refractory to conventional therapy were treated with high doses of cytarabine (3 'lJml intravenously every 12 hours for six days) followed by daunorubicin (30 m'lJm1/day intravenously for three days). Each patient received, in a double-masked, randomized manner, either 1% prednisolone phosphate or placebo eyedrops in each eye 12 hours before and along with the cytarabine so that we could determine whether a topical corticosteroid prevents corneal toxicity from systemic cytarabine. Ten of the 11 patients had a significant reduction in the intensity and duration of the symptoms and signs of corneal toxicity in the corticosteroid-treated eye (P<.OO05). In the placebo-treated eye, pain, photophobia, and tearing occurred at a median time of 6.5 days after initiation of therapy but resolved in approximately one week. Patients receiving high doses of intravenously administered eytarabine should receive topical corticosteroid prophylaxis to reduce the corneal toxicity associated with this treatment. High-dose intravenous cytarabine therapy (3 glm2) has been used to treat patients with leukemia refractory to conventional chemotherapy. 1,2 There have been several reports of corneal toxicity from systemic high-dose cytarabine therapyU resembling the corneal toxicity caused by topical cytarabine therapy. 6,7 This toxicity is characterized by conjunctivitis, fine corneal epithelial opacities
Accepted for publication Aug. 20, 1982. From the Divisions of Ophthalmology (Dr. Lass), Hematology/Oncology (Drs. Lazarus and Herzig), and Pediatric Pharmacology (Dr. Reed), Case Western Reserve University School of Medicine and the University Hospitals of Cleveland, Cleveland, Ohio. This study was supported in part by grant ROICAI5584-05 from the National Institutes of Health and by grants from the American Cancer Society (Dr. Lazarus) and the Leukemia Society of America (Drs. Lazarus and Herzig). Reprint requests to Jonathan H. Lass, M.D., University Hospitals of Cleveland, 2065 Adelbert Rd., Cleveland, OH 44106.
with superficial punctate keratitis, and pain with photophobia within one week of the initiation of treatment. These findings spontaneously resolve after another week. In a study of 48 patients treated with high-dose cytarabine we noted that patients treated with topical corticosteroids had a rapid resolution of the symptoms and signs of corneal toxicity, compared to patients who did not receive topical corticosteroid therapy. 5 We conducted a placebo-controlled, randomized, double-masked evaluation of topical corticosteroid prophylactic therapy for corneal toxicity in 11 patients receiving high-dose systemic cytarabine. SUBJECTS AND METHODS
Subjects-The study included seven men and four women with a mean age of 42 years (range, 22 to 67 years). All patients had leukemia in bone marrow relapse. Disease categories included
CAMERICAN JOURNAL OF OPHTHALMOLOGY 94:617~21, 1982
617
618
AMERICAN JOURNAL OF OPHTHALMOLOGY
acute myelogenous leukemia (seven patients), acute lymphoblastic leukemia in relapse (three patients), and erythroleukemia (one patient). All patients had received conventional doses of cytarabine at some previous time. Three of the ten patients had also received high-dose cytarabine therapy before this study began. Patient 10 was observed during two separate courses for this study. These studies were approved by the Institutional Review Board for Human Investigation and informed consent was obtained from each patient. Antileukemia treatment-All patients received 3 g/m! of cytarabine intravenously over one hour every 12 hours for six days. On days 7 through 9, each patient also received a conventional dose of daunorubicin HCI (30 mg/rnvday) by intravenous bolus. Topical treatment-Each patient served as his or her own control. One eye, preselected randomly, received corticosteroid and the other eye received placebo eyedrops. Randomization was done with a programmable calculator and random number program. The active drug consisted of a sterile, commercially available ophthalmic prednisolone sodium phosphate 1% solution with benzalkonium chloride 0.01%, disodium ethylenediaminetetraacetate, monobasic and dibasic sodium phosphate, and sodium chloride. The sterile, filtered placebo solution used was similar to the active drug solution but contained no prednisolone sodium phosphate or ethylenediaminetetraacetate. Placebo and the commercially available ophthalmic solutions were identical in packaging, appearance, and pH. The random code was kept in the pharmacy. The drugs were dispensed and administered without the examining physicians knowing which was which. After the initial ocular examination, each patient received two drops of either
NOVEMBER, 1982
corticosteroid or placebo solution three times a day from day 0 (the day before initiating cytarabine therapy) through day 9. Those patients who developed severe, symptomatic keratitis also received bacitracin ointment and cyclopentolate HCl1 % eyedrops three times a day for five days in the affected eye after a follow-up ocular examination. Ocular examination-An ocular examination, including visual acuity testing, slit-lamp biomicroscopy, fluorescein staining of the corneal epithelium, and ophthalmoscopy with the pupils dilated, was performed in a double-masked fashion by one of us (J. H. L.) on day 0 before the chemotherapy began. This examination was repeated on day 6 of treatment, or earlier if an eye became symptomatic. The examinations were then performed weekly for the next six weeks. Because the degree of microcystic changes in the corneal epithelium best correlated with the degree of symptomatology, this characteristic was quantitated on the first symptomatic day to determine the effect of the corticosteroid. We graded the effect as follows: 0, normal corneal epithelial appearance; 1+, zero to ten microcysts in the central corneal epithelium with no punctate keratitis on fluorescein staining (Figure, left); 2+, ten to 20 microcysts in the corneal epithelium with minimal superficial punctate keratitis; 3+, 20 to 40 microcysts in the corneal epithelium with moderate superficial punctate keratitis; and 4+, extensive microcyst formation throughout the corneal epithelium with severe superficial punctate keratitis (Figure, right). Statistical analYSis-We used Student's t-test for paired comparisons for the statistical analysis. 8 RESULTS
After the randomized code was broken, we found that ten of the 11 patients (11 of 12 eyes) developed foreign-body sensa-
VOL. 94, NO.5
CORTICOSTEROID FOR CYTARABINE TOXICITY
619
Figure (Lass and associates). Left, A I + microcyst reaction in the central corneal epithelium after six days of systemically administered cytarabine and topical corticosteroid therapy. Right, A 4+ microcyst reaction associated with severe pungtate keratitis is present diffusely throughout the corneal epithelium after six days of systemically administered cytarabine and topically administered placebo.
tion, intense photophobia, redness, tearing, and blurred vision in the placebotreated eye. The median time to onset of symptoms was 6.5 days after antileukemic therapy was instituted. In three patients the onset of ocular symptoms was delayed until two or three days after the conclusion of cytarabine therapy. One placebo-treated eye did not develop significant symptoms. In contrast, 11 of 12 eyes treated with topical corticosteroid developed only mild irritation and redness without photophobia or pain. All ocular findings were normal before chemotherapy and there was no evidence of infectious or leukemic ocular involve-
ment during the entire study period. Eleven of the 12 placebo-treated eyes had decreased visual acuities (20/40 to 20/200) and moderate conjunctival hyperemia. The cornea showed diffuse superficial punctate keratitis on fluorescein staining. Underlying the punctate changes were fine, refractile microcysts, most of which were clear; a few were opaque. There was also mild stromal edema and striae were present in Descemet's membrane. These signs corresponded with intense pain and photophobia in the affected eye. Five of these 11 eyes required bacitracin and cyclopentolate ncr to relieve the ocular symptoms and signs.
620
AMERICAN JOURNAL OF OPHTHALMOLOGY
In contrast, 11 of the 12 corticosteroidtreated eyes had normal visual acuities and minimal conjunctival hyperemia. These eyes also showed similar microcystic epithelial changes, but to a lesser degree, and had no fluorescein staining, stromal edema, or striae. The corticosteroid-treated eyes had significantly fewer microcystic corneal epithelial changes than the placebo-treated eyes (P<.0005) (Table). None of these eyes required additional topical medication. All the corticosteroid-treated eyes were asymptomatic within one week of the end of the cytarabine therapy, and at one month the corneal epithelium appeared to be normal. In contrast, the placebo-treated eyes remained symptomatic until two weeks after cytarabine therapy ended, and three of the eyes (Patients 1, 4, and 7) still had 1+ microTABLE MICROCYST SCORES FOR CORNEAL EPITHELIUM AFTER HIGH-DOSE SYSTEMIC CYTARABINE THERAPY
Microcyst Scores' Patient No.
CorticosteroidTreated Eye"
PlaceboTreated Eye
1 2 3 4 5 6 7
1 3 1 1 1 1
4 1 2 4 3 3 7 3 3 3 3 4
8 9
lOA:!:
10B:j: 11
1
o 2 1 1 1
• Microcyst grading: 0, normal appearance; 1+, zero to ten microcysts with no superficial punctate keratitis on fluorescein staining; 2+, ten to 20 microcysts with minimal superficial punctate keratitis; 3+, 20 to 40 microcysts with moderate superficial punctate keratitis; 4+, extensive microcyst formation with severe superficial punctate keratitis. tThe corticosteroid-treated eyes had a significantly lower score (P<.OOO5). :j:Patient 10 received two different courses of systemic therapy.
NOVEMBER, 1982
cystic corneal epithelial changes one month after cytarabine therapy was completed. DISCUSSION
Cytarabine has been a principal agent in the primary treatment of acute nonlymphoblastic leukemia.P" Because later remissions are achieved less often and are of shorter duration than the first remission,10,11 the treatment of acute leukemia in relapse remains a difficult problem. There is evidence that high concentrations of antitumor therapy increase response rates,12,13 and investigators have had success with high-dose cytarabine in refractory leukemias. 1,2 Several investigatorss" have noted that this high systemic dose produces conjunctivitis and keratitis similar to that found with topically administered cytarabine, Both in animal models'i" and in humans.i' fine, refractile opacities in the epithelium have been found, progressing to punctate keratitis and more severe involvement, accompanied by intense pain and photophobia in some of the human cases. One of the mechanisms of action of cytarabine is the inhibition of DNA polymerase which affects cells during the S-phase of cell division. 14 Thus, a significant toxic effect on rapidly dividing normal cells, such as the corneal epithelium, can be expected. The route by which systemic cytarabine reaches the corneal epithelium is unknown. It may reach the cornea by the anterior chamber, since the drug penetrates the blood-brain barrier, especially in high doses. 5,12 We have not observed corneal toxicity with conventional doses of cytarabine (100 mg/m"). It may also be distributed in the tears. Hande and associates" reported levels of 22 and 39 umoles in the tears after 3 g/m" of cytarabine was given intravenously.P We noted that topical corticosteroids significantly reduced morbidity and the
VOL. 94, NO. 5
CORTICOSTEROID FOR CYTARABINE TOXICITY
degree of corneal epithelial microcyst formation associated with high doses of intravenously administered cytarabine. The mechanism by which a topical corticosteroid reduces the toxic effect of an antimetabolite may be twofold. First, it may act purely as an anti-inflammatory agent." This possibility, however; does not account for the reduction in microcyst formation observed clinically. Also, on pathologic examinations of human biopsy specimens, the microcystic changes have been shown to be degenerating epithelial cells with microcyst formation, and not inflammatory cell inflltration.! The second mechanism that may account for the attenuation or prevention of symptoms is the partial inhibition of DNA and protein synthesis in sensitive cell types, including the epidermal cells. 17,18 A reduction in DNA replication would make the corneal epithelial cells less susceptible to the effects of an antimetabolite drug, such as cytarabine. We recommend the prophylactic use of a topical corticosteroid for the prevention of the severe keratitis associated with systemic high-dose cytarabine therapy. REFERENCES 1. Rudnick, S. A., Cadman, E. C., Capizzi, R. L., Skeel, R. T., Bertino, J. R., and McIntosh, S.: High dose arabinoside in refractory acute leukemia. Cancer 44:1189, 1979. 2. Herzig, R. H., Herzig, G. P., Lazarus, H. M., Wolff, S. N., and Philips, G. L.: Successful treatment of patients with refractory acute nonlymphocytic leukemia using high-dose cytosine arabinoside with and without anthracycline. Blood 58:141, 1981. 3. Hopen, G., Mondino, B. J., Johnson, B., and Chervenick, P.: Corneal toxicity with systemic cytarabine. Am. J. Ophthalmol. 91:500, 1981.
621
4. Castleberry, R. P., Crist, W. M., Holbrook, T., Malluh, A., and Gaddy, D.: The cytosine arabinoside (Ara-C) syndrome. Med. Pediatr. Oneol. 9:257, 1981. 5. Lazarus, H. M., Herzig, R. H., Herzig, G. P., Philips, G. L., Roessmann, D., and Fishman, D.: Central nervous system toxicity of high dose systemic cytosine arabinoside. Cancer 48:2577, 1981. 6. Kaufman, H. E., Capella, ]. A., Maloney, E. D., Robbins, J. E., Cooper, G. M., and Dotila, M. H.: Corneal toxicity of cytosine arabinoside. Arch. Ophthalmol. 72:535, 1964. 7. Elliot, G. A., and Schut, A. L.: Studies with cytarabine HCl (CA)in normal eyes of man, monkey, and rabbit. Am. J. Ophthalmol. 60:1074, 1965. 8. Sokal, R. R., and Rohlf, F. J.: Biometry. San Francisco, W. H. Freeman, 1969, pp. 328-333. 9. Bodey, G. P., Coltman, C. A., Hewlett, J. S., and Freireich, E. J.: Review of regimens containing cytarabine studied by the Southwest Oncology Group. Arch. Intern. Med. 136:1383, 1976. 10. Cline, M. J., Golde, D. W., Billing, R. J., Groopman, J. E., Zighelboim, J., and Gale, R. P.: Acute leukemia. Biology and Treatment. Ann. Intern. Med. 91:758, 1979. 11. Gale, R. P.: Advances in the treatment of acute myelogenous leukemia. N. Engl. J. Med. 300:1189, 1979. 12. Ho, D. H. W., and Frei, E.: Clinical pharmacology of I-f3-D-arabinofuroanosylcytosine. Clin. Pharmacol. Ther. 12:944, 1971. 13. Frei, E., and Canellos, G. P.: Dose. A critical factor in cancer chemotherapy. Am. J. Med. 69:585, 1980. 14. Furlong, N. B., and Gresham, C.: Inhibition of DNA synthesis but not of poly-dAT synthesis by the arabinoside analogue of cytidine in vitro. Nature N. BioI. 233:212, 1971. 15. Hande, K. R., Stein, R. S., McDonough, D. A., and Wolff, S. N.: Pharmacokinetics of highdose cytosine arabinoside. Clin. Res. 29:436, 1981. 16. Leibowitz, H. M., and Kupferman, A.: Antiinflammatory effectiveness in the cornea of topically administered prednisolone. Invest. Ophthalmol. 13:757, 1974. 17. Schulster, D., Burstein, S., and Cooke, B.: Mode of action of glucoeorticoids. In Molecular Endocrinology of the Steroid Hormones. London, John Wiley and Sons, 1976, p. 73. 18. Fisher, L. B., and Maibach, H. I.: The effect of corticosteroids on human epidermal mitotic activity. Arch. Dermatol. 103:39, 1971.