Brief Communications

Liposomal doxorubicin extravasation

oxil is a pegylated liposomal formulation containing doxorubicin, a known vesicant. The formulation uses liposomes that release the drug preferentially into tumor tissue through the basement membrane gaps of an aberrantly formed neovasculature. Fever and an acidic environment enhance the dissolution of the liposomes, increasing the release of active doxorubicin. Doxil has a longer half-life in the circulation, less cumulative cardiotoxicity, less myelotoxicity, but more hand-foot syndrome than soluble doxorubicin. Its extravasation risk is categorized as an irritant, not as a vesicant. Experience with liposomal doxorubicin extravasation is limited. One series of eight events occurred among more than 400 intravenous doses given to 75 patients enrolled in ve clinical trials of AIDS-related Kaposis sarcoma patients. These extravasations consisted of 0.251.01 mg in 36 mL of D5W, using 21or 23-gauge scalp veins in the upper extremity. Treatment consisted of removing the intravenous catheter, elevating the extremity, and applying ice for 3060 minutes. Transient, mild irritation at the infusion site and local edema, with or without erythema, developed, but tissue necrosis did not occur.1 Extravasations associated with subclavian access ports pose greater risks than those given via scalp veins. An elderly woman with breast cancer received an infusion of liposomal doxorubicin (250 mL) into the tissue near the port, resulting in a red, swollen, and tender left breast. Despite
Costs associated with preparing this report were underwritten by Ortho Biotech Products, LP. The authors alone determined its content and had nal responsibility for the decision to publish.
2007 Elsevier Inc. All rights reserved.

the local application of ice, the breast tissue had weeping of serous uids and blisters appeared within 96 hours. She required a simple mastectomy for pain management.2 A second case occurred in a 72year-old woman with fallopian tube cancer who experienced extravasation when a Huber needle dislodged from the subcutaneous access device, delivering the entire 40-mg dose into the soft tissue of the chest wall and breast. In week 1, a hematoma developed in the medial and inferior-lateral breast below the nipple. In week 2, a necrotic area measuring 8 cm replaced the hematoma. In the following 2 weeks, the necrotic area evolved into an eschar and a second necrotic area developed in the dependent portion of the breast, 8 cm inferior to the injection site.3 The patient experienced signicant pain but died of progressive cancer before a planned palliative mastectomy could be performed.4 We describe a large dose of liposomal doxorubicin extravasated into the breast from a severed right atrial catheter. Treatment with ice and topical dimethyl sulfoxide (DMSO) resulted in slow resolution of the swelling, pain, blisters, and erythema over the ensuing 6 months. Case report In February 2005, a 40-year-old woman with advanced ovarian cancer experienced an extravasation of Doxil (60 mg in 500 mL) into the left breast following fracture of an Infusaport catheter. The catheter, put in place 2 years earlier, never had an adequate blood return, but it functioned successfully in the administration of multiple doses of carboplatin and paclitaxel, as well as two prior liposomal doxorubicin doses. Patency of the

catheter was always assessed prior to chemotherapy infusion by administration of 250 mL of IV uid, with careful evaluation for the ease of infusion and for the absence of local symptoms or swelling of the chest wall. On the day of the extravasation, the patient reported swelling of the left breast 30 minutes after completion of the uid and chemotherapy infusion. Xrays revealed a severed catheter at the level of the clavicle and rst rib and a catheter fragment in the right atrium. Ultrasonography showed diffuse uid accumulation around the port and throughout the upper two thirds of the left breast without an identiable loculation amenable to drainage. An interventional radiologist removed the right atrial catheter fragment. Topical treatment consisted of ice, DMSO, vitamin E cream, and aloe several times each day, and breast swelling, pain and erythema resolved gradually over 10 weeks. MRI at 6 weeks revealed diffuse enhancement, especially in the lower half of the breast, and a slight thickening of the left pectoral muscle, but without tissue necrosis. Two months after the extravasation, the damaged Infusaport was removed and another placed in the right subclavian. The patient subsequently received four more doses of liposomal doxorubicin without an adverse event. An examination at 6 months found the left breast completely normal. The ovarian cancer worsened, however, and the woman died of progressive cancer in January 2006. Discussion The two previous case reports of large-dose, large-volume extravasations demonstrate potential danger. These two cases prompted us to consider a prophylactic mastectomy in our patient, but the attending surgeon and
Commun Oncol 2007;4:464465

464 COMMUNITY ONCOLOGY

July 2007

www.CommunityOncology.net

patient chose to watch and wait. Our experience provides reassurance that large-dose Doxil extravasations may have better outcomes than previously reported and offers suggestions for their management. Our patient was younger and healthier than the two previously reported and she was highly motivated and compliant in applying ice and topical medications. The topical DMSO may have been particularly helpful. This agent can be used to deliver drugs through the skin, but it may also assist in the withdrawal of drugs from tissue. DMSO has demonstrated efcacy in treating extravasations of cytotoxic vesicants5 and doxorubicin6 and is useful in managing the hand-foot syndrome associated with liposomal doxorubicin.7 Lastly, our case demonstrates again the risks associated with chemotherapy infusions via implanted

subclavian access devices. At the time of this event, our routine practice permitted the delivery of chemotherapy via devices that did not yield a blood return, if a large bolus of uid could be infused quickly without swelling or symptoms. We now require radiographic proof of catheter patency following infusion of contrast material as well as regular assessment of catheter integrity by routine x-ray. We still infuse large test volumes of nonirritant solutions prior to the administration of vesicants and remain diligent in assessing the local effect of these infusions. Leslie R. Laufman, MD Brenda Sickle-Santanello, MD Jean Paquelet, MD
Grant Medical Center Columbus, OH

References

1. Madhavan S, Northfelt D. Lack of vesicant injury following extravasation of liposomal doxorubicin. J Natl Cancer Inst 1995;87:1556 1557. 2. Masoorli S. Extravasation injuries associated with the use of central vascular access devices. J Vasc Access Devices 2003;8:2123. 3. Lokich J. Doxil extravasation injury: a case report. Ann Oncol 1989;10:735736. 4. Lokich J. Discussion of Doxil extravasation case report; 2005. 5. Bertelli G, Gozza A, Forno G, et al. Topical dimethylsulfoxide for the prevention of soft tissue injury after extravasation of vesicant cytoxic drugs: a prospective clinical study. J Clin Oncol 1995;13:2851. 6. Olver I, Aisner J, Hament A, Buchanan L, Bishop J, Kaplan R. A prospective study of topical dimethyl sulfoxide for treating anthracycline extravasation. J Clin Oncol 1988;6:1732. 7. Lopez A, Wallace L, Dorr R, Koff M, Hersh E, Alberts D. Topical DMSO treatment for pegylated liposomal doxorubicin-induced palmar-plantar erythrodysesthesia. Cancer Chemother Pharmacol 1999;44:303306.

Volume 4/Number 7

July 2007

COMMUNITY ONCOLOGY 465