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Ocular Adverse Reactions Associated with Adriamycin (Doxorubicin)
Ocular Adverse Reactions Associated with Adriamycin (Doxorubicin) Charles F. Curran, Ph.D., and James K. Luce, M.D. To assess the ocular safety of doxorubicin, we reviewed doxorubicin-associated ocular adverse reactions reported to Adria Laboratories or published in the clinical literature. Conjunctivitis was the most frequently reported reaction. Periorbital edema was reported in two patients, and lacrimation was reported in a published study. Blepharospasm, keratitis, and decreased visual acuity were reported once each in patients treated with combination chemotherapeutic regimens containing doxorubicin. These reactions usually resolved rapidly on discontinuation of the drug. Conjunctivitis frequently followed accidental ocular exposure to doxorubicin. All but a few of these reactions cleared within 24 hours of exposure. The infrequent nature and usually rapid resolution of these ocular adverse reactions suggest that when ocular toxicities occur in patients undergoing doxorubicin-containing chemotherapy, the cautious reintroduction of doxorubicin, if further antineoplastic therapy is indicated, should be considered. available in the United States since 1974, has proven to be one of the most active and widely used chemotherapeutic agents. The drug is useful in the treatment of a variety of solid and hematologic malignancies. Adverse reactions affecting the eye have been reported infrequently, and the package insert (January 1988) for this agent states that conjunctivitis and lacrimation occur only rarely. We describe ocular adverse reactions associated with doxorubicin that have been reported either to Adria Laboratories or published in the clinical literature. ADRIAMYCIN (DOXORUBICIN),
Accepted for publication Aug. 25, 1989. From the Medical Services Department, Adria Laboratories, Columbus, Ohio. Reprint requests to Charles F. Curran, Ph.D., Associate Director of Medical Services, Adria Laboratories, P.O. Box 16529, Columbus, OH 43216.
©AMERICAN JOURNAL OF OPHTHALMOLOGY
108:709-711,
Case Reports Case 1 woman treated with 20 mg of A 62~year-old doxorubicin weekly for adenocarcinoma of the breast developed low-grade bilateral iritis and conjunctivitis after four months of therapy. Keratic precipitates were not reported. Doxorubicin was discontinued, and the patient was placed on a regimen of topical dexamethasone and homatropine. She recovered fully after 49 days of treatment. The patient had previously received chemotherapy consisting of cyclophosphamide, methotrexate, and fluorouracil. The prior regimen had been discontinued 10 months before the doxorubicin regimen was initiated. Case 2 A 69-year-old woman with carcinoma of the ovary with left occipital lobe metastasis was treated by radiation therapy directed to the left occipital lobe followed four weeks later by a course comprising 75 mg of doxorubicin and 750 mg of cyclophosphamide. Several hours after completing the first course, the patient developed moderate periorbital edema, which resolved several days later. After a second course of chemotherapy with the same drugs and dose, the patient developed severe periorbital edema and mild left facial edema. The reaction resolved, and the patient was converted to alternate chemotherapy. The alternate therapy was not specified. Case 3 A 12-year-old boy with acute lymphocytic leukemia received a single course of doxorubicin at a dose of 39 mg/day for three days. Seventeen days after completing this course of treatment, keratitis developed in the left eye and later in the right eye. During the previous three years, the patient had received intravenous vincristine, prednisone, and cyclophosphamide and methotrexate intravenously and DECEMBER,
1989
709
710
intrathecally. A pediatric ophthalmologist examined the patient and made a diagnosis of herpes simplex keratitis. The patient responded to idoxuridine administration to both eyes. The patient's side ,effects do not appear to be strongly associated with the administration of doxorubicin. Case 4
December, 1989
AMERICAN JOURNAL OF OPHTHALMOLOGY
A 51-year-old woman treated with fluorouracil, doxorubicin, and cyclophosphamide and tamoxifen for breast cancer experienced no difficulties during the first six months of therapy. During the next three courses of treatment, the patient experienced decreased visual acuity occurring two to four days after injections of fluorouracil and doxorubicin. An ophthalmologist and a neuro-ophthalmologist both diagnosed an idiopathic optic neuropathy. Chemotherapy was discontinued, and the patient was placed on a regimen of prednisone. Although fluorouracil was discontinued, doxorubicin, cyclophosphamide, and tamoxifen were sequentially reintroduced and well tolerated. When the patient was reassessed four months after the onset of symptoms, her visual acuity was nearly normal. Other cases-At one site, transient visual disturbances were reported in five patients who were being treated for a variety of neoplasms. The disturbances were described by each patient as the sensation that objects appeared more distant than the patients knew them to be. No changes in pulse or blood pressure were associated with these visual disturbances. Visual acuity and visual fields were not assessed. There is no evidence that these patients discussed their symptoms with one another. When each patient was converted to doxorubicin in diluents not containing propylparaben or methylparaben preservatives, subsequent doses were not associated with any visual disturbances. In addition to Case 2, another patient who developed periorbital edema after her third dose of doxorubicin was reported. The swelling was not accompanied by changes in vision. Subsequent doxorubicin doses, with diphenhydramine pretreatment, were not associated with periorbital edema. Accidental splashings of doxorubicin into one or both eyes were reported by 15 medical personnel (physicians, nurses, and pharmacists). Immediate treatment consisted of flushing the exposed eyes with water or saline.
Although no reactions occurred in five individuals, the remaining ten developed conjunctivitis, which resolved in a day or less in all but two individuals who required up to one week for resolution. One of these patients complained of residual photophobia, which was relieved by an ocular corticosteroid and homatropine. These patients are described in more detail elsewhere. I Other ocular adverse reactions to doxorubicin have been reported infrequently in the clinical literature. In a summary of clinical studies performed at the National Cancer Institute, Milan, Italy, Bonadonna and associates! reported that the incidence of conjunctivitis in the 485 patients examined was approximately 2% to 3% (ten to 15 patients), but they provided no details. Blum summarized early U.S. clinical studies and reported some cases of lacrimation associated with doxorubicin with an onset of five to 15 days following the initiation of each intravenous infusion." The number and incidence of these reactions were not reported. Blepharospasm was reported in a patient treated with doxorubicin, cyclophosphamide, and high-dose tegafur (furanyl-5-fluorouracil). 4 An ophthalmic examination showed no abnormalities except for repeated contraction of the orbicularis oculi. These contractions subsided when drugs were discontinued. None of the three drugs was reintroduced. One of the two accidental eye exposures to doxorubicin resulting in persistent photophobia, described above, was subsequently reported by Wertenbaker. 5 This report describes a case in which accidental ocular splashing resulted in a corneal infiltrate and iritis. The patient responded to a course of topical dexamethasone and homatropine.
Discussion Conjunctivitis has been the most commonly reported ocular adverse reaction associated with systemically administered doxorubicin. Conjunctivitis is frequently associated with accidental splashing of this agent into the eyes of medical personnel. The low pH of doxorubicin may be responsible for conjunctivitis following contact with the eyes. When the powder formulation is reconstituted with sodium chloride injection, the pH of the resulting solution is 3.8 to 6.5. 6 Doxorubicin is also available in an
Vol. 108, No.6
Ocular Adverse Reactions With Adriarnycin (Doxorubicin)
isotonic solution that has a pH adjusted during drug manufacture to approximately 3 (range, 2.5 to 3.5).6 The patient who developed severe periorbital edema and mild facial edema after postirradiation administration of doxorubicin and cyclophosphamide appeared to have developed a radiation recall reaction. Radiation recall reaction is a drug-induced inflammatory reaction at the site of prior radiation exposure. Radiation recall has been documented with doxorubicin, dactinomycin, and less frequently with other antineoplastic agents." The five patients who reported that objects appeared more distant are puzzling because such patients usually describe objects as being smaller than they know them to be. Literature searches using several databases yielded no pertinent references to either doxorubicin in propylparaben- or methylparaben-containing diluents or ocular reactions associated with the administration of these agents. In the absence of a more plausible explanation, we speculate that a staff member at the reporting site might have inadvertently asked leading questions after one patient's report. We are unable to offer a suitable hypothesis based on the pharmacology and clinical experiences of doxorubicin. Ocular toxicity has been associated with some of the other chemotherapeutic agents used with doxorubicin in this series. The patient discussed in Case 4 was treated with cyclophosphamide, doxorubicin, fluorouracil, and tamoxifen and experienced decreased visual acuity. Similar findings have been associated with both cyclophosphamide and tamoxifen.Y Adriamycin is an anthracycline antibiotic that lacks a single, well-defined mechanism of action. The most clearly established action of doxorubicin and several of its metabolites is the ability to bind DNA and inhibit the synthesis of nucleic acids. Other mechanisms of action are related to the chelation of divalent cations, participation in oxidation-reduction reactions, and the formation of free radicals." It is presently unclear which specific mechanism or mechanisms of action function in the ocular adverse effects of doxorubicin.
711
The available evidence indicates that ocular adverse reactions to doxorubicin are infrequent and usually resolve rapidly upon discontinuation of the drug. The infrequent nature of adverse reactions suggests that when ocular toxicities are encountered in patients on doxorubicin-containing chemotherapy, cautious early reintroduction of doxorubicin should be considered in treating the patient's neoplastic disease if further doxorubicin therapy appears indicated. References 1. Curran, C. F., and Luce, J. K.: Accidental acute exposure to doxorubicin. Cancer Nursing (in press). 2. Bonadonna, G., Beretta, G., Tancini, G., DePalo, G. M., Gasparini, M., and Doci, R.: Adriamycin as a single agent in various forms of advanced neoplasia of adults and children. Tumori 60:373, 1974. 3. Blum, R.: An overview of studies with Adriamycin in the United States. Cancer Chemother. Rep. 6:247, 1975. 4. Salminen, L., Jantti, v. and Gronross, M.: Blepharospasm associated with tegafur combination chemotherapy. Am. J. OphthalmoI. 97:649, 1984. 5. Wertenbaker, c.: Intraocular inflammation from accidental instillation of doxorubicin. Cancer Treat. Rep. 71:221, 1987. 6. McEvoy, G. K. (ed.): American Hospital Formulary Service Drug Information. Bethesda, Maryland, American Society of Hospital Pharmacists, 1989, p. 488. 7. Wallenborn, P. A., III, and Postma, D. S.: Radiation recall supraglottitis. A hazard in head and neck chemotherapy. Arch. Otolaryngol. 110:614, 1984. 8. Fraunfelder, F. T., and Meyer, S. M.: Ocular toxicity of antineoplastic agents. Ophthalmology 90:1, 1983. 9. Kaiser-Kupfer, M. I., and Lippman, M. E.: Tamoxifen retinopathy. Cancer Treat. Rep. 62:315, 1980. 10. Chabner, B. A., and Myers, C. E.: Clinical pharmacology of cancer chemotherapy. In DeVita, V. T., Hellman,S., and Rosenberg, S. A. (eds.): Cancer. Principles & Practice of Oncology. Philadelphia, J. B. Lippincott, 1989, pp. 349-395.
Accepted for publication Aug. 25, 1989. From the Medical Services Department, Adria Laboratories, Columbus, Ohio. Reprint requests to Charles F. Curran, Ph.D., Associate Director of Medical Services, Adria Laboratories, P.O. Box 16529, Columbus, OH 43216.
©AMERICAN JOURNAL OF OPHTHALMOLOGY
108:709-711,
Case Reports Case 1 woman treated with 20 mg of A 62~year-old doxorubicin weekly for adenocarcinoma of the breast developed low-grade bilateral iritis and conjunctivitis after four months of therapy. Keratic precipitates were not reported. Doxorubicin was discontinued, and the patient was placed on a regimen of topical dexamethasone and homatropine. She recovered fully after 49 days of treatment. The patient had previously received chemotherapy consisting of cyclophosphamide, methotrexate, and fluorouracil. The prior regimen had been discontinued 10 months before the doxorubicin regimen was initiated. Case 2 A 69-year-old woman with carcinoma of the ovary with left occipital lobe metastasis was treated by radiation therapy directed to the left occipital lobe followed four weeks later by a course comprising 75 mg of doxorubicin and 750 mg of cyclophosphamide. Several hours after completing the first course, the patient developed moderate periorbital edema, which resolved several days later. After a second course of chemotherapy with the same drugs and dose, the patient developed severe periorbital edema and mild left facial edema. The reaction resolved, and the patient was converted to alternate chemotherapy. The alternate therapy was not specified. Case 3 A 12-year-old boy with acute lymphocytic leukemia received a single course of doxorubicin at a dose of 39 mg/day for three days. Seventeen days after completing this course of treatment, keratitis developed in the left eye and later in the right eye. During the previous three years, the patient had received intravenous vincristine, prednisone, and cyclophosphamide and methotrexate intravenously and DECEMBER,
1989
709
710
intrathecally. A pediatric ophthalmologist examined the patient and made a diagnosis of herpes simplex keratitis. The patient responded to idoxuridine administration to both eyes. The patient's side ,effects do not appear to be strongly associated with the administration of doxorubicin. Case 4
December, 1989
AMERICAN JOURNAL OF OPHTHALMOLOGY
A 51-year-old woman treated with fluorouracil, doxorubicin, and cyclophosphamide and tamoxifen for breast cancer experienced no difficulties during the first six months of therapy. During the next three courses of treatment, the patient experienced decreased visual acuity occurring two to four days after injections of fluorouracil and doxorubicin. An ophthalmologist and a neuro-ophthalmologist both diagnosed an idiopathic optic neuropathy. Chemotherapy was discontinued, and the patient was placed on a regimen of prednisone. Although fluorouracil was discontinued, doxorubicin, cyclophosphamide, and tamoxifen were sequentially reintroduced and well tolerated. When the patient was reassessed four months after the onset of symptoms, her visual acuity was nearly normal. Other cases-At one site, transient visual disturbances were reported in five patients who were being treated for a variety of neoplasms. The disturbances were described by each patient as the sensation that objects appeared more distant than the patients knew them to be. No changes in pulse or blood pressure were associated with these visual disturbances. Visual acuity and visual fields were not assessed. There is no evidence that these patients discussed their symptoms with one another. When each patient was converted to doxorubicin in diluents not containing propylparaben or methylparaben preservatives, subsequent doses were not associated with any visual disturbances. In addition to Case 2, another patient who developed periorbital edema after her third dose of doxorubicin was reported. The swelling was not accompanied by changes in vision. Subsequent doxorubicin doses, with diphenhydramine pretreatment, were not associated with periorbital edema. Accidental splashings of doxorubicin into one or both eyes were reported by 15 medical personnel (physicians, nurses, and pharmacists). Immediate treatment consisted of flushing the exposed eyes with water or saline.
Although no reactions occurred in five individuals, the remaining ten developed conjunctivitis, which resolved in a day or less in all but two individuals who required up to one week for resolution. One of these patients complained of residual photophobia, which was relieved by an ocular corticosteroid and homatropine. These patients are described in more detail elsewhere. I Other ocular adverse reactions to doxorubicin have been reported infrequently in the clinical literature. In a summary of clinical studies performed at the National Cancer Institute, Milan, Italy, Bonadonna and associates! reported that the incidence of conjunctivitis in the 485 patients examined was approximately 2% to 3% (ten to 15 patients), but they provided no details. Blum summarized early U.S. clinical studies and reported some cases of lacrimation associated with doxorubicin with an onset of five to 15 days following the initiation of each intravenous infusion." The number and incidence of these reactions were not reported. Blepharospasm was reported in a patient treated with doxorubicin, cyclophosphamide, and high-dose tegafur (furanyl-5-fluorouracil). 4 An ophthalmic examination showed no abnormalities except for repeated contraction of the orbicularis oculi. These contractions subsided when drugs were discontinued. None of the three drugs was reintroduced. One of the two accidental eye exposures to doxorubicin resulting in persistent photophobia, described above, was subsequently reported by Wertenbaker. 5 This report describes a case in which accidental ocular splashing resulted in a corneal infiltrate and iritis. The patient responded to a course of topical dexamethasone and homatropine.
Discussion Conjunctivitis has been the most commonly reported ocular adverse reaction associated with systemically administered doxorubicin. Conjunctivitis is frequently associated with accidental splashing of this agent into the eyes of medical personnel. The low pH of doxorubicin may be responsible for conjunctivitis following contact with the eyes. When the powder formulation is reconstituted with sodium chloride injection, the pH of the resulting solution is 3.8 to 6.5. 6 Doxorubicin is also available in an
Vol. 108, No.6
Ocular Adverse Reactions With Adriarnycin (Doxorubicin)
isotonic solution that has a pH adjusted during drug manufacture to approximately 3 (range, 2.5 to 3.5).6 The patient who developed severe periorbital edema and mild facial edema after postirradiation administration of doxorubicin and cyclophosphamide appeared to have developed a radiation recall reaction. Radiation recall reaction is a drug-induced inflammatory reaction at the site of prior radiation exposure. Radiation recall has been documented with doxorubicin, dactinomycin, and less frequently with other antineoplastic agents." The five patients who reported that objects appeared more distant are puzzling because such patients usually describe objects as being smaller than they know them to be. Literature searches using several databases yielded no pertinent references to either doxorubicin in propylparaben- or methylparaben-containing diluents or ocular reactions associated with the administration of these agents. In the absence of a more plausible explanation, we speculate that a staff member at the reporting site might have inadvertently asked leading questions after one patient's report. We are unable to offer a suitable hypothesis based on the pharmacology and clinical experiences of doxorubicin. Ocular toxicity has been associated with some of the other chemotherapeutic agents used with doxorubicin in this series. The patient discussed in Case 4 was treated with cyclophosphamide, doxorubicin, fluorouracil, and tamoxifen and experienced decreased visual acuity. Similar findings have been associated with both cyclophosphamide and tamoxifen.Y Adriamycin is an anthracycline antibiotic that lacks a single, well-defined mechanism of action. The most clearly established action of doxorubicin and several of its metabolites is the ability to bind DNA and inhibit the synthesis of nucleic acids. Other mechanisms of action are related to the chelation of divalent cations, participation in oxidation-reduction reactions, and the formation of free radicals." It is presently unclear which specific mechanism or mechanisms of action function in the ocular adverse effects of doxorubicin.
711
The available evidence indicates that ocular adverse reactions to doxorubicin are infrequent and usually resolve rapidly upon discontinuation of the drug. The infrequent nature of adverse reactions suggests that when ocular toxicities are encountered in patients on doxorubicin-containing chemotherapy, cautious early reintroduction of doxorubicin should be considered in treating the patient's neoplastic disease if further doxorubicin therapy appears indicated. References 1. Curran, C. F., and Luce, J. K.: Accidental acute exposure to doxorubicin. Cancer Nursing (in press). 2. Bonadonna, G., Beretta, G., Tancini, G., DePalo, G. M., Gasparini, M., and Doci, R.: Adriamycin as a single agent in various forms of advanced neoplasia of adults and children. Tumori 60:373, 1974. 3. Blum, R.: An overview of studies with Adriamycin in the United States. Cancer Chemother. Rep. 6:247, 1975. 4. Salminen, L., Jantti, v. and Gronross, M.: Blepharospasm associated with tegafur combination chemotherapy. Am. J. OphthalmoI. 97:649, 1984. 5. Wertenbaker, c.: Intraocular inflammation from accidental instillation of doxorubicin. Cancer Treat. Rep. 71:221, 1987. 6. McEvoy, G. K. (ed.): American Hospital Formulary Service Drug Information. Bethesda, Maryland, American Society of Hospital Pharmacists, 1989, p. 488. 7. Wallenborn, P. A., III, and Postma, D. S.: Radiation recall supraglottitis. A hazard in head and neck chemotherapy. Arch. Otolaryngol. 110:614, 1984. 8. Fraunfelder, F. T., and Meyer, S. M.: Ocular toxicity of antineoplastic agents. Ophthalmology 90:1, 1983. 9. Kaiser-Kupfer, M. I., and Lippman, M. E.: Tamoxifen retinopathy. Cancer Treat. Rep. 62:315, 1980. 10. Chabner, B. A., and Myers, C. E.: Clinical pharmacology of cancer chemotherapy. In DeVita, V. T., Hellman,S., and Rosenberg, S. A. (eds.): Cancer. Principles & Practice of Oncology. Philadelphia, J. B. Lippincott, 1989, pp. 349-395.