Summary
Extravasation of certain cytotoxic agents during peripheral intravenous administration may cause severe local injuries. Most extravasation can be prevented with the systematic implementation of careful administration techniques. However, the management of this complication, the aim of which is to prevent progression to tissue necrosis and ulceration, remains an important challenge in the care of cancer patients. Many antidotes have been evaluated experimentally and a few may be able to reduce the local toxicity of the more common vesicant cytotoxic drugs. Because no randomised trial on the management of cytotoxic drug extravasation in humans has ever been completed, recommendations must be based on the more consistent experimental evidence and on cumulative clinical experience from available case reports and uncontrolled studies, which are reviewed in this article.
Empirical guidelines recommend the use of topical dimethylsulfoxide (DMSO) and cooling after extravasation of anthracyclines or mitomycin, locally injected hyaluronidase after extravasation of vinca alkaloids, and locally injected sodium thiosulfate (sodium hyposulfite) after extravasation of chlormethine (mechlorethamine; mustine). Plastic surgery may be necessary when conservative treatment fails to prevent ulceration. The possibility of late local reactions must also be considered in the management of patients receiving chemotherapy.
Similar content being viewed by others
References
Barlock AL, Howser DM, Hubbard SM. Nursing management of adriamycin extravasation. Am J Nurs 1979; 137: 94–6
Larson DL. Treatment of tissue extravasation by antitumor agents. Cancer 1982; 49: 1796–9
Schneider SM, Distelhorst CW. Chemotherapy-induced emergencies. Semin Oncol 1989; 6: 572–8
Rudolph R, Larson DL. Etiology and treatment of chemotherapeutic agent extravasation injuries: a review. J Clin Oncol 1987; 5: 1116–26
Marnocha RSM, Hutson PR. Intradermal carboplatin and ifosfamide extravasation in the mouse. Cancer 1992; 70: 850–3
Leyden M, Sullivan J. Full-thickness skin necrosis due to inadvertent interstitial infusion of cisplatin [letter]. Cancer Treat Rep 1983; 67: 199
Algarra SM, Dy C, Bilbao I, et al. Cutaneous necrosis after intra-arterial treatment with cisplatin. Cancer Treat Rep 1986; 70: 687–8
Teta JB, O’Connor L. Local tissue damage from 5-fluorouracil extravasation [letter]. Oncol Nurs Forum 1984; 11: 77
Lewis KP, Medina WD. Cellulitis and fibrosis due to cisdiaminedichloroplatinum infiltration. Cancer Treat Rep 1980; 64: 1162–3
MacDonald JR, Pegg DG. Extravasation injury potential of CI-980, a novel synthetic mitotic inhibitor. Cancer Chemother Pharmacol 1993; 32: 365–7
Ajani JA, Dodd LG, Daugherty K, et al. Taxol-induced soft-tissue injury secondary to extravasation: characterization by histopathology and clinical course. J Natl Cancer Inst 1994; 86: 51–3
Wetmore N. Extravasation: the dreaded complication. J Natl Intravenous Ther Assoc 1985; 8: 47–49
Oncology Nursing Society. Cancer chemotherapy guidelines. Pittsburgh: Oncology Nursing Society Publications, 1988
Gallina EJ. Practical guide to chemotherapy administration for physicians and oncology nurses. In: DeVita Jr VT, Hellman S, Rosenberg SA, editors. Cancer: principles and practice of oncology. Philadelphia: Lippincott, 1993: 2570–80
Strum S, McDermed J, Korn A, et al. Improved methods for venous access: the Port-a-Cath, a totally implanted catheter system. J Clin Oncol 1986; 4: 596–603
Brothers TE, Niederhuber JE, Roberts JA, et al. Experience with subcutaneous infusion ports in three hundred patients. Surg Gynecol Obstet 1988; 166: 295–301
Bach F, Videbaek C, Holst-Christensen J, et al. Cytostatic extravasation. A serious complication of long-term venous access. Cancer 1991; 68: 538–9
Dorr RT. Antidotes to vesicant chemotherapy extravasations. Blood Rev 1990; 4: 41–60
Reilly JJ, Neifield JP, Rosenberg SA. Clinical course and management of accidental adriamycin extravasation. Cancer 1977; 40: 2053–6
Rudolph R, Stein RS, Pattilo RA. Skin ulcers due to adriamycin. Cancer 1976; 38: 1087–94
Zweig J, Kabakow B. An apparently effective countermeasure for doxorubicin extravasation. JAMA 1978; 239: 2116–7
Luedke DW, Kennedy PS, Rietschel RL. Histopathogenesis of skin and subcutaneous injury induced by adriamycin. Plast Reconstr Surg 1979; 63: 463–5
Bhawan J, Petry J, Rybak ME. Histologic changes induced in skin by extravasation of doxorubicin (adriamycin). J Cutan Pathol 1989; 16: 158–63
Cohen MH. Amelioration of adriamycin skin necrosis: an experimental study. Cancer Treat Rep 1979; 63: 1003–4
Petro JA, Graham WP, Miller SH, et al. Experimental and clinical studies of ulcers induced with adriamycin. Surg Forum 1979; 30: 535–7
Coleman JJ, Walker AP, Didolkar MS. Treatment of adriamycin-induced skin ulcers: a prospective controlled study. J Surg Oncol 1983; 22: 129–35
Dorr RT, Alberts DS, Chen HSG. The limited role of corticosteroids in ameliorating experimental doxorubicin skin toxicity in the mouse. Cancer Chemother Pharmacol 1980; 5: 17–20
Dorr RT, Alberts DS. Vinca alkaloid skin toxicity: antidote and drug disposition in the mouse. J Natl Cancer Inst 1985; 74: 113–20
Bartkowski-Dodds L, Daniels JR. Use of sodium bicarbonate as a means of ameliorating doxorubicin-induced dermal necrosis in rats. Cancer Chemother Pharmacol 1980; 4: 179–81
Gaze NR. Tissue necrosis caused by commonly used intravenous infusions. Lancet 1978; 2: 417–9
Jackson IT, Robinson DW. Severe tissue damage following accidental subcutaneous infusion of bicarbonate sodium [letter]. Scott Med J 1976; 21: 200
Kappel B, Hindeburg A, Taub RN. Treatment of anthracycline extravasation — a warning against the use of sodium bicarbonate. J Clin Oncol 1987; 5: 825–6
Britton RC, Habif DV. Clinical uses of hyaluronidase: a current review. Surgery 1953; 33: 917–42
Laurie SW, Wilson KL, Kernahan DA, et al. Intravenous extravasation injuries: the effectiveness of hyaluronidase in their treatment. Ann Plast Surg 1984; 13: 191–4
Zenk KE, Dungy CI, Greene GR. Nafcillin extravasation injury. Use of hyaluronidase as an antidote. Am J Dis Child 1981; 135: 1113–4
Raszka WV, Kueser TK, Smith FR, et al. The use of hyaluronidase in the treatment of intravenous extravasation injuries. J Perinatol 1990; 10: 146–9
Dorr RT, Alberts DS. Skin ulceration potential without therapeutic anticancer activity for epipodophyllotoxin commercial diluents. Invest New Drugs 1983; 1: 51–9
Bertelli G, Dini D, Forno G, et al. Hyaluronidase as an antidote to extravasation of vinca alkaloids: clinical results. J Cancer Res Clin Oncol 1994; 120: 505–6
Depierre A, Lemarie E, Dabouis G, et al. Efficacy of Navelbine (NVB) in non-small cell lung cancer (NSCLC). Semin Oncol 1989; 16 Suppl. 4: 26–9
George MJ, Heron JF, Kerbrat P, et al. Navelbine in advanced ovarian epithelial cancer: a study of the French oncology centers. Semin Oncol 1989; 16 Suppl. 4: 30–2
Chait LA, Dinner M. Ulceration caused by cytotoxic drugs. South Afr Med J 1975; 49: 1935–6
Dorr RT, Soble M, Alberts DS. Efficacy of sodium thiosulfate as local antidote to mechloretamine skin toxicity in the mouse. Cancer Chemother Pharmacol 1988; 22: 299–302
Owen OE, Dellatorre DL, Van Scott EJ, et al. Accidental intramuscular injection of mechloretamine. Cancer 1980; 45: 2225–6
Dorr RT, Alberts DS, Einspahr J, et al. Experimental dacarbazine antitumor activity and skin toxicity in relation to light exposure and pharmacological antidotes. Cancer Treat Rep 1987; 71: 267–72
Howell SB, Taetle R. Effect of sodium thiosulfate on cisdichlorodiammineplatinum (II) toxicity and antitumor activity in L1210 leukemia. Cancer Treat Rep 1980; 64: 611–6
Tsavaris NB, Komitsopoulou P, Karagiaouris P, et al. Prevention of tissue necrosis due to accidental extravasation of cytostatic drugs by a conservative approach. Cancer Chemother Pharmacol 1992; 30: 330–3
Kligman AM. Topical pharmacology and toxicology of dimethyl sulfoxide. Part I. JAMA 1965; 193: 796–804
Gorog P, Kovacs IB. Effect of dimethyl sulfoxide (DMSO) on various experimental and cutaneous reactions. Pharmacology 1969; 2: 313–9
David NA. The pharmacology of dimethyl sulphoxide 6544. Annu Rev Pharmacol 1972; 12: 353–74
Friend C, Freedman HA. Effects and possible mechanisms of action of dimethyl sulphoxide on friend cell differentiation. Biochem Pharmacol 1978; 27: 1309–13
Svingen BA, Powis G, Appel PL, et al. Protection against adriamycin-induced skin necrosis in the rat by dimethyl sulfoxide and alpha-tocopherol. Cancer Res 1981; 41: 3395–9
Desai MH, Teres D. Prevention of doxorubicin-induced skin ulcers in the rat and pig with dimethylsulphoxide (DMSO). Cancer Treat Rep 1982; 66: 1371–4
Nobbs P, Barr RD. Soft-tissue injury caused by antineoplastic drugs is inhibited by topical dimethyl sulphoxide and alpha tocopherol. Br J Cancer 1983; 48: 873–6
Soble MJ, Dorr RT, Plezia P, et al. Dose-dependent skin ulcers in mice treated with DNA binding antitumor antibiotics. Cancer Chemother Pharmacol 1987; 20: 33–6
Dorr RT, Soble MJ, Liddil JD, et al. Mitomycin C toxicity studies in mice reduced ulceration and altered pharmacokinetics with topical dimethyl sulfoxide. J Clin Oncol 1986; 4: 1399–404
Okano T, Ohnuma T, Efremidis A, et al. Doxorubicin-induced skin ulcer in the piglet. Cancer Treat Rep 1983; 67: 1075–8
Dorr RT, Alberts DS. Failure of DMSO and vitamin E to prevent doxorubicin skin ulceration in the mouse. Cancer Treat Rep 1983; 67: 499–501
VanSloten Harwood K, Bachur N. Evaluation of dimethyl sulfoxide and local cooling as antidotes for doxorubicin extravasation in a pig model. Oncol Nurs Forum 1987; 14: 39–44
Lawrence HJ, Goodnight SH. Dimethyl sulfoxide and extravasation of anthracycline agents [letter]. Ann Intern Med 1983; 98: 1025
Lawrence HJ, Walsh D, Zapotowski A, et al. Topical dimethyl-sulfoxide may prevent tissue damage from anthracycline extravasation. Cancer Chemother Pharmacol 1989; 23: 316–8
Olver IN, Schwarz MA. Use of dimethyl sulfoxide in limiting tissue damage caused by extravasation of doxorubicin. Cancer Treat Rep 1983; 67: 407–8
Olver IN, Aisner J, Hament A, et al. A prospective study of topical dimethyl sulfoxide for treating anthracycline extravasation. J Clin Oncol 1988; 6: 1732–5
Ludwig CU, Stoll HR, Obrist R, et al. Prevention of cytotoxic drug induced skin ulcers with dimethyl sulfoxide (DMSO) and α-tocopherole. Eur J Cancer Clin Oncol 1986; 23: 327–9
Argenta LC, Manders EK. Mitomycin C extravasation injuries. Cancer 1983; 51: 1080–2
Kahnna AK, Kahnna A, Asthana AK, et al. Mitomycin C extravasation ulcers. J Surg Oncol 1985; 28: 108–10
Herrera D, Burnham N. DMSO and extravasation of mitomycin [letter]. Oncol Nurs Forum 1989; 16: 155
Alberts DS, Dorr RT. Case report topical DMSO for mitomycin-C-induced skin ulceration. Oncol Nurs Forum 1991; 4: 693–5
Bertelli G, Dini D, Forno G, et al. Dimethylsulfoxide and cooling after extravasation of antitumor agents. Lancet 1993; 341: 1088–9
Dorr RT, Alberts DS. Pharmacologic antidotes to experimental doxorubicin skin toxicity: a suggested role for beta-adrenergic compounds. Cancer Treat Rep 1981; 65: 11–2
Daugherty JP, Khurana A. Amelioration of doxorubicin-induced skin necrosis in mice by butylated hydroxytoluene. Cancer Chemother Pharmacol 1985; 14: 243–6
Upton PG, Yamaguchi KT, Myers S, et al. Effects of antioxidants and hyperbaric oxygen in ameliorating experimental doxorubicin skin toxicity in the rat. Cancer Treat Rep 1986; 70: 503–7
Schwartsmann G, Sander EB, Vinholes J, et al. N-acetylcysteine protects skin lesions induced by local extravasation of doxorubicin in a rat model. Am J Pediatr Hematol Oncol 1992; 14: 280–1
Vasilev SA, Morrow C, Morrow P. Basic fibroblast growth factor in retardation of doxorubicin extravasation injury. Gynecol Oncol 1992; 44: 178–81
Averbuch SD, Gaudiano G, Koch TH, et al. Doxorubicin-induced skin necrosis in the swine model: protection with a novel radical dimer. J Clin Oncol 1986; 4: 88–94
Rentschler R, Wilbur D. Pyridoxine a potential local antidote for mitomycin-C extravasation. J Surg Oncol 1988; 37: 269–71
Ignoffo RJ, Friedman MA. Therapy of local toxicities caused by extravasation of cancer chemotherapeutic drugs. Cancer Treat Rev 1980; 7: 17–27
Dorr RT, Alberts DS, Stone A. Cold protection and heat enhancement of doxorubicin skin toxicity in the mouse. Cancer Treat Rep 1985; 69: 431–7
Hahn GM. Hyperthermia in cancer. Plenum Press: New York, 1982
Block KB, Harris PA, Peale A. Preliminary observations on temperature-enhanced drug uptake by leukemic leukocytes in vitro. Cancer Chemother Rep 1975; 59: 985–8
Lane P, Vichi P, Bain D, et al. Temperature dependence studies of adriamycin uptake and cytotoxicity. Cancer Res 1987; 47: 4038–42
Buchanan GR, Buchsbaum HJ, O’Banion K, et al. Extravasation of dactinomycin, vincristine, and cisplatin: studies in an animal model. Med Pediatr Oncol 1985; 13: 375–80
Larson DL. What is the appropriate management of tissue extravasation by antitumor agents? Plast Reconstr Surg 1985; 75: 397–402
Dorr RT. What is the appropriate management of tissue extravasation by antitumor agents? [comment]. Plast Reconstr Surg 1985; 75: 403–5
VanSloten Harwood K. Treatment of anthracycline extravasation — recommendations for practice [letter]. J Clin Oncol 1987; 5: 1705
Loth TS. Minimal surgical debridement for the treatment of chemotherapeutic agent—induced skin extravasations. Cancer Treat Rep 1986; 70: 401–4
Preuss P, Partoft S. Cytostatic extravasations. Ann Plast Surg 1987; 19: 323–7
Dorr RT, Dordal MS, Koenig LM, et al. High levels of doxorubicin in the tissues of a patient experiencing extravasation during a 4-day infusion. Cancer 1989; 64: 2462–4
Sonneveld P, Wassenaar HA, Nooter K. Long persistence of doxorubicin in human skin after extravasation. Cancer Treat Rep 1984; 68: 895–6
Cohen FJ, Manganaro J, Bezozo RC. Identification of involved tissue during surgical treatment of doxorubicin-induced extravasation necrosis. J Hand Surg 1983; 8: 43–5
Andersson AP, Dahlstrom KK. Clinical results after doxorubicin extravasation treated with excision guided by fluorescence microscopy. Eur J Cancer 1993; 29A: 1712–4
Shaeffer J, El-Mahdi AM, Hamwey AE, et al. Detection of extravasation of antineoplastic drugs by microwave radiometry. Cancer Lett 1986; 31: 285–91
Baer D, Wilkinson S. Daunomycin, adriamycin, and recall effect. Ann Intern Med 1976; 85: 259–60
Cohen C, Dibella NJ, Michalak JC. Recall injury from adriamycin [letter]. Ann Intern Med 1975; 83: 232
Meehan JL, Sporn JR. Case report of taxol administration via central vein producing a recall reaction at a site of prior taxol extravasation. J Natl Cancer Inst 1994; 86: 1250–1
Raghavan V, Bloomer W, Merkel D. Taxol and radiation-recall dermatitis [letter]. Lancet 1993; 341: 1354
Fuller B, Lind M, Bonomi P. Mitomycin C extravasation exacerbated by sunlight [letter]. Ann Intern Med 1981; 94: 542
Sotos GA, Liebmann JE. Reactivation of thermal burn by methotrexate. J Natl Cancer Inst 1992; 84: 1936–8
Johnston-Early A, Cohen MH. Mitomycin-C-induced skin ulceration remote from infusion site [letter]. Cancer Treat Rep 1981; 65: 529
Bartowski-Dodds L, Reville B. Extensive tissue ulceration due to apparent sensitivity reactions to mitomycin. Cancer Treat Rep 1985; 69: 925–7
Cassidy J, Rankin M. Case report: hypersensitivity reaction to epirubicin. Med Oncol Tumor Pharmacother 1989; 6: 297–8
Harwood K, Gonin R. Short term vs long term local cooling after doxorubicin (DOX) extravasation: an Eastern Cooperative Oncology Group (ECOG) study [abstract 1544]. Proc Am Soc Clin Oncol 1994; 13: 447
Author information
Authors and Affiliations
Rights and permissions
About this article
Cite this article
Bertelli, G. Prevention and Management of Extravasation of Cytotoxic Drugs. Drug-Safety 12, 245–255 (1995). https://doi.org/10.2165/00002018-199512040-00004
Published:
Issue Date:
DOI: https://doi.org/10.2165/00002018-199512040-00004