Caution in reconstituting bleomycin

Volume 13 Number 3 September, 1985 lower extremities has been reported in a few cases of chronic vitamin A intoxicationS and in a patient after etretinate therapy. 9 Coincidence of peripheral edema and benign intracranial hypertension could result from pathophysiology. In our two cases, serum albumin was low; in one, the low level was hidden by marked dehydration. In this patient, dramatic improvement of edema and of the neurologic picture followed albumin perfusion. We postulate that lower serum albumin concentration was induced either by hepatic toxicity of etretinate or loss of protein in the urine (Case 1) or the feces (Case 2). Decrease of serum albumin could induce in part cerebral and peripheral edema and in part elevation of free retinoid metabolites in the blood. The main metabolite of etretinate detected in plasma is the corresponding carboxylic acid (Ro 10-1670). Etretinate and Ro 10-1670 are more than 98% bound to albumin and lipoproteins in plaSma. 10 These hypotheses must be supported by further evaluation, such as the dosage of metabolites in plasma in new cases of intoxication following etretinate therapy. Similar explanation is proposed for chronic hypervitaminosis A: high level of free form of vitamin A in the bloo~ induces clinical manif~stations. II

We think that retinoid therapy may induce all manifestations of vitamin A intoxication. Such a risk has been evoked recently for long-term use of synthetic retinoid therapy.12 In these cases, active investigation of all symptoms of vitamin· A intoxication should be performed and plasma level of retinoid should be evaluated. '

Roland Viraben, M.D., Claire Mathieu, M.D., and Bernard Fontan, MD. Department of Dermatology (Pr. Dupre), Purpan Hospital 31059 Toulouse Cedex, France

REFERENCES 1. FDA: Adverse effects with isotretinoin. FDA Drug Bull 13:21-23, 1983. 2. Lombaert A, Carton H: Benign intracranial hypertension due to A-hypervitaminosis in adults and adolescents. Eur Neurol14:340-350, 1976. 3. Windhorst DB, Nigra T: General clinical toxicology of oral retinoids. JAM ACAo DERMATOL 6:675-682, 1982. 4. Peck GL: Retinoids in clinical dermatology, in Fleischmajer R, editor: Progress in diseases of the skin. New York; 1981, Grune& Stratton Inc., vol. 1, pp. 227-269, 1981.

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5. Bonnetblanc 1M, Hugon J, Dumas M, Rupin D: Intracranial hypertension with etretinate. Lancet 2:974, 1983. 6. Beran RG: Pseudotumor cerebri associated with mincicycline therapy for acne. Med J Aust 1:323-324, 1980. 7. Weiss VC, West DP, Ackennan R, Robinson L: Hepatotoxic reactions in a patient treated with etretinate. Arch Dennatol120:104-106, 1984: ' 8. MuenterMD, Perry HO, Ludwig J: Chronic vitamin A intoxication in adults. Hepatic, neurologic, and dermatologic complications. Am J Med 50: 129-136, 1971. 9. Lauharanta J: Oedema a rare adverse reaction to etretinate (Tigason). Br J Dermatol106:251, 1982. 10. Brazzell RK, Colburn WA: Phannacokinetics of the retinoids isotretinoin and etretinate. JAM ACAo DERMAToL 6:643-651, 1982. 11. Smith FR, Goodman DS: Vitamin A transport in human vitamin A toxicity. N Engl J Med 294:805-808, 1975. 12. Digiovanna JJ, Peck GL: Oral synthetic retinoid treatment in children. Pediatr Dermato11:77-78, 1983.

Caution in reconstituting bleomycin To the Editor: Recently, intralesional bleomycin has ~eceived cautious acceptance as therapy for recalcitrllnt verrucae. This seemingly effective therapy will 'likely become more widely used in the future. Except for pain and local irritation, the well-documented side effects of bleomycin are not observed 'after the small doses employed in dennatologic therapy: Proper handling of bleomycin and exposure to cytostatic agents by health care personnel are concerns not yet addressed in the dennatologic literature. Reports in the literati.rre focus on the increased mutagenicity of urine, indicating excretion of cytotoxins in hospital personnel handijngchemotherapeutic agents. I Some widely cited studie'S'report increased chromosome gaps and increased lymphocytic sister chromatid exchanges in oncology nurses.2. ~n­ other study showed detectable airborne levels of chemotherapeutic agents, in particular fluorouracil, in preparation rooms of several oncology clinics. 3 In this study, precautions such as ventilation hoods, gloves, and covered waste receptacles were rarelyeIl1ployed. In general, the use of such precautions is vi~wed as crucial. 4-6 In none of these studies was bleomycin the single agent used; however, it seems prudent to be aware of the published recommendations for handling antineoplastic drugs. Specifically, for bleomycin, it is recommended that surgical gloves be used when reconstituting or administering the drug; that reconstitution of bleomycin from the powdered' form be done preferably ~y a phamiacist under a vemcal ~!lminar airflow

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hood with exhaust to the outside; that syringes and unused quantities of bleomycin be disposed of properly, Le., in puncture-proof containers for incineration; and that spills and splashes be washed with copious amounts of soap and water. M·t The use of a hood effectively reduces exposure; however, most dennatologists do not have access to a hood or the facilities of a hospital pharmacy. In an office setting, a useful device is a small, disposable ChemoDispensing Pin.:j: This device contains a vent with a hydrophobic filter allowing for equalization of air pressure while blocking the release of any aerosolized drug arising during reconstitution or withdrawal. The purpose of this communication is not to raise ungrounded fears, since the significance of chronic exposure to small amounts of cytostatic agents by health care workers, such as pharmacists or oncology nurses, who routinely prepare and administer these agents is still debated. § Many hospital pharmacies have just begun to address this problem. There can be no argument, however, that the potential for exposure is higher if cytostatic agents such as bleomycin are handled without proper respect. This issue should be of concern to all dennatologists who routinely use such drugs.

Joseph T. Majeski, M.D., and Joseph A. Niedzwiecki, M.D. Department of Dermatology Geisinger Medical Center, Danville, PA 17822 *Jeffrey LP, Anderson RW, Fortner CL, et al: Recommendations for handling cytotoxic agents. National Study Commission on Cytotoxic Exposure, September, 1984. tJeffrey LP, Anderson RW, Barker LF, et al: Consensus responses to unresolved questions concerning cytotoxic agents. National Study Commission on Cytotoxic Exposure, March, 1984. :j:Burron Medical Inc., Bethlehem, PA 18018. §Gross I, Johnson BL, Bertino IR: Hazards of working with cytotoxic agents-a response. Oncology Nursing Forum 9:13, 1982.

REFERENCES 1. Falck K, Grahn P, Sorsa M, et al: Mutagenicity in urine of nurses handling cytostatic drugs. Lancet 1:1250-1251, 1979. 2. Waksvik H, Klepp 0, Brogger A: Chromosome analyses of nurses handling cytostatic agents. Cancer Treat Rep 65:607-610, 1981. 3. DeWerk Neal A, Wadden RA, Chiou WL: Exposure of hospital workers to airborne antineoplastic agents. Am J Hosp Pharm 40:597-601, 1983. 4. Kolmodin-Hedman B, Hartvig P, Sorsa M, Falck K: Occupational handling of cytostatic drugs. Arch Toxico1 54:25-33, 1983. 5. Anderson RW, Puckett WH, Dana WJ, et al: Risk of

Journal of the American Academy of Dermatology handling injectable antineoplastic agents. Am J Hosp Pharm 39:1881-1887,1982. 6. Macek C: Hospital personnel who handle anticancer drugs may face risks. JAMA 247:11-12, 1982. 7. D'Arcy PP: Reactions and interactions in handling anticancer drugs. Drug Intell Clin Pharm 17:532-538, 1983.

Applicability of high-dose chemotherapy with autologous marrow transplantation for malignant melanoma To the Editor: Dr. Kessinger has written a succinct and concise review on the topic of high-dose chemotherapy with autologous marrow transplantation for malignant melanoma (J AM ACAD DERMATOL 12:337-343, 1985). The article is informative and up-to-date and should be mandatory reading for anyone interested in melanoma treatment. However, there are a number of points I would like to raise that may need closer scrutiny and examination with respect to the ultimate applicability of this treatment modality: 1. Ifdacarbazine (DTlC) is the most effective single chemotherapeutic agent for metastatic melanoma, why has it not been employed in the setting of autologous marrow transplantation? 2. Alkylating agents, such as melphalan and carmustine (BeND), have been linked to increased incidence of acute leukemias. J Will patients who survive after high-dose chemotherapy and marrow transplantation ultimately die from alkylating agent-induced leukemias? 3. Many patients with metastatic disease can tolerate chemotherapy as outpatients and do not require hospitalization. However, patients who undergo high-dose chemotherapy and autologous marrow transplant must be hospitalized and may have to spend much of their remaining days as in-patients, suffering the complications of marrow aplasia. This is obviously a significant investment of time and money. Is it worth it? 4. Although seventeen of the 105 patients reported in the literature have had complete response to treatment, in only six does duration of complete response equal or exceed one year (6%). This does not seem to represent a great advance when compared to the median survival of patients with metastatic disease who receive standard chemotherapy. Howard Koh, M.D. Department of Dermatology Boston University School of Medicine Boston, MA 02118