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Dexrazoxane for rapid extended livedo reticularis-like skin reaction due to systemic epirubicin diffusion during transcatheter arterial chemoembolization procedure for hepatocellular carcinoma

1 Bergamo Poison Control Center, Papa Giovanni XXIII Hospital, Bergamo, Italy
2 Department of Gastroenterology and Transplantation Hepatology, Papa Giovanni XXIII Hospital, Bergamo, Italy

Date of Submission05-May-2020
Date of Decision18-Jun-2020
Date of Acceptance01-Oct-2020
Date of Web Publication22-Nov-2021

Correspondence Address:
Andrea Giampreti,
Bergamo Poison Control Center, Papa Giovanni XXIII Hospital, Bergamo 24100
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Source of Support: None, Conflict of Interest: None

DOI: 10.4103/jcrt.JCRT_574_20

 > Abstract 

Skin reactions after transarterial chemoembolization (TACE) with anthracyclines are rare and mostly limited to small areas. We describe a 56-year-old male with hepatocellular carcinoma treated with epirubicin chemoembolization. Immediately the procedure, pain on the right side and an extended livedo reticularis-like skin reaction appeared. Since dexrazoxane, a topoisomerase-II catalytic-cycle inhibitor, has been shown to be effective in preventing or reducing skin necrosis and ulceration following anthracycline extravasation, the drug was administered 8 h after TACE and repeated in the following 2 days. Due to marked extrahepatic diffusion of epirubicin as evidenced by computed tomography imaging, the patient showed signs of systemic organ involvement. The critically ill patient required close follow-up and intensified treatment including blood supply and pulmonary drainage of a pleural effusion. The patient presented a significant clinical improvement of the skin lesions and resolution of organ involvement with normalization of laboratory parameters after dexrazoxane. In conclusion, adverse extended skin reactions and severe systemic effects related to anthracyclines diffusion could be properly treated with dexrazoxane infusion.

Keywords: Adverse drug reaction, anthracyclines, dexrazoxane, skin

How to cite this URL:
Giampreti A, Lucà M, Gallo M, Baldan A, Eleftheriou G, Schranz M, Contessa G, Faraoni L, Butera R, Fagiuoli S, Bacis G. Dexrazoxane for rapid extended livedo reticularis-like skin reaction due to systemic epirubicin diffusion during transcatheter arterial chemoembolization procedure for hepatocellular carcinoma. J Can Res Ther [Epub ahead of print] [cited 2022 Jul 3]. Available from: https://www.cancerjournal.net/preprintarticle.asp?id=330882

 > Introduction Top

Subcutaneous fat necrosis and supraumbilical skin rash after transarterial chemoembolization (TACE) are rare, but possible complications of intra-arterial chemotherapy infusion, as documented for conventional TACE[1],[2],[3],[4] or treatment with anthracycline-loaded drug-eluting beads.[1],[5] Most cutaneous adverse reactions related to TACE procedures with anthracyclines are limited to small areas. Moreover, with exception of local chemotherapeutic agent extravasation, to our knowledge, no data are reported concerning the use of dexrazoxane in the treatment of toxic skin reactions due to systemic diffusion of anthracyclines after TACE procedures. We describe the case of a patient with an extended livedo reticularis-like skin reaction after TACE with epirubicin and lipiodol for the treatment of hepatocellular carcinoma (HCC) that resolved completely with dexrazoxane treatment.

 > Case Report Top

A 56-year-old male with hepatitis C virus-related cirrhosis, portal hypertension (Child-Pugh A6, esophageal varices F1), and mononodular HCC was admitted for conventional TACE (segment I, size: 20 mm × 17 mm). According to an interdisciplinary tumor board decision, thermoablation was not feasible due to the close proximity of the nodule to major vascular structures. Apart from thrombocytopenia (platelets 70 × 109/L; normal range 150–400 × 109/L), hematological, hepatobiliary, and coagulation parameters were within the normal range [Table 1]. Clinical evaluation at admission did not reveal any relevant cardiopulmonary findings, and the abdominal examination was unremarkable without signs of ascites. Furthermore, hepatic encephalopathy was clinically excluded. The patient had a body mass index of 23.6 (body weight 62 kg and height 162 cm). Blood pressure was slightly heightened (150/80 mmHg) at admission, but heart rate (90 bpm) and oxygen saturation (97%) on room air were within the normal range. After the exclusion of contraindications, TACE has been performed by catheterization of the left hepatic artery and super selection of the segmental artery feeding the HCC nodule, followed by infusion of ethiodized oil (Lipiodiol™) and 50 mg of epirubicin. An anatomic variation of an afferent tumor artery has been identified during arteriography that originated from the right renal artery and was also catheterized and infused with Lipiodiol™, 25 mg of epirubicin, and 40 micron-sized embolizing microspheres. At the end of the procedure, pain on the right torso appeared immediately in association with the occurrence of a livedo reticularis-like skin reaction extending from the right flank to the hypochondrium [Figure 1]. Blood pressure, oxygen saturation on room air, and heart rate were normal and not significantly different from admission. Acetaminophen (1 g intravenous), chlorpheniramine (10 mg intravenous), ranitidine (50 mg intravenous), ondansetron (2 mg intravenous), and ketorolac (30 mg intravenous) were administered promptly after the procedure in the angiographic room with scarce benefit. Ketorolac (30 mg intravenous), tramadol (100 mg intravenous), and morphine (5 + 5 mg intramuscular) were further administered once the patient had been transferred to the gastroenterology unit, and subsequently, a continuous infusion of morphine (20 mg/24 h) was started. Since clinical symptoms and blood tests were interpreted as adverse reaction due to systemic diffusion of epirubicin, antidotal therapy with dexrazoxane (Savene™) 1720 mg intravenous (1000 mg/m2 body surface) was administered 8 h after the procedure, followed by 1720 mg intravenous (1000 mg/m2 body surface) on day 2 and 860 mg intravenous (500 mg/m2 body surface) on day 3. A systemic inflammation developed immediately after TACE throughout the first 24 h after the procedure. it was characterized by intense local pain scarcely treatable by morphine infusion and signs of severe tissue injury with increased lactic acid and significantly elevated creatine phosphokinase [Table 1]. Multiorgan involvement occurred manifesting as acute hepatitis [Table 1] without signs of hepatic dysfunction (e.g. clinical signs of ascites), and inflammation of the gut with abdominal pain associated to evacuation impairment, and slight respiratory distress, which was treated with beta 2 adrenergic receptor agonists and corticosteroid inhalation and on demand oxygen supply. Demarcation of the skin lesions was observed. Abdominal computed tomography (CT) scan evidenced the ethiodized oil (Lipiodiol™) distribution within the target HCC lesion in segment I, but also in segment IV and in segments V–VIII of the right hepatic lobe and in the right hemidiaphragm, which was elevated and associated with a right basal pleural effusion. CT imaging further evidenced the hyperdensity of the gallbladder wall and the right lower pulmonary lobe. The right abdominal wall was diffusely thickened. The parts of the gastrointestinal tract seemed congested with mild thickening of the gastric, duodenal, and right colic wall surrounded by a perigastric and perisplenic fluid layer [Table 1]. The patient was treated with intravenous hydration and broad-spectrum antibiotic. The total parenteral nutrition and low-molecular-weight heparin prophylaxis were started. Thoracentesis was performed, and an external thoracic drain was placed to improve respiratory function. After 1 week, the patient developed signs of bone marrow dysfunction with pancytopenia [Table 1]. The patient received blood supply and granulocyte-colony-stimulating factor (G-CSF). During the following days, the hematological analysis showed a gradual improvement with a progressive increase of white and red blood cell counts and recovery of platelets [Table 1]. Transaminases normalized after 2 weeks and inflammatory parameters returned to basic values [Table 1]. Heart function was closely monitored, but despite a slight increase of troponin I and creatine kinase-MB, which subsequently normalized spontaneously, no clinical signs of cardiac ischemia were found and echocardiogram was unremarkable [left ventricular function evaluation = 60%; [Table 1]]. The cutaneous manifestation progressively improved after treatment with dexrazoxane. Hyperemic lesions and skin and abdominal pain gradually resolved and the livedo reticularis manifestations disappeared completely 1 month after TACE [Figure 2]. Furthermore, systemic clinical symptoms resolved. Signs of gastrointestinal congestion were not detectable anymore on abdomen CT on day 16 [Table 1], and thoracic drainage could be removed. Alopecia occurred 2 to 3 weeks after TACE. The patient was discharged with a total weight loss of 6 kg, in stable clinical conditions, asymptomatic, afebrile, with normal vital parameters, 32 days after TACE.
Table 1: Laboratory and instrumental exams performed after transcatheter arterial chemoembolization (TACE) with epirubicin. Laboratory signs of severe tissue injury, acute hepatitis and bone marrow dysfunction are shown. Multi-organ involvement is also confirmed by abdominal CT scan (Day 4)

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Figure 1: Livedo reticularis-like reaction developed a few hours after the transarterial chemoembolization with epirubicin. As illustrated, skin manifestations expanded on the right torso from the right flank to the hypochondrium

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Figure 2: Complete resolution of the skin manifestations with restitutio ad integrum on the right side of the torso 1 month after transarterial chemoembolization

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 > Discussion Top

Supra-umbilical abdominal wall injury has been described in patients who have undergone TACE.[1],[2],[3],[4],[5] The main risk factor seems the perfusion by the chemotherapeutic agent of the hepatic falciform artery (HFA) that provides partial blood supply around the umbilicus and communicates with branches of the internal thoracic and superior epigastric arteries.[1],[3],[6] Adverse cutaneous reactions related to anthracyclines systemic diffusion during TACE are limited to a localized skin area (peri-/supraumbilical) and present as nodular spotted-like skin eruptions with onset time of 1–30 days from the procedure[2],[5] and time to resolution up to several months.[2] In our case, skin manifestations presented immediately after TACE as a livedo reticularis-like reaction on the right torso extending from the right flank to the hypochondrium [Figure 1]. The rapid onset of skin manifestations indicates a pivotal role of the chemotherapeutic agent itself, as seen with local extravasation,[6] than an embolic complication. Cutaneous lesions in our patient were probably caused by rapid diffusion of epirubicin by superficial arteries of the abdominal wall originating from the HFA and aberrant branches of the right renal artery evidenced and chemoembolized during the intervention. The absence of ulceration may be due to dilution of the chemotherapeutic agent within an extended skin area compared to the typical ulcerative lesions caused by local extravasation. The causative role of epirubicin is also supported by CT imaging that showed an inflammatory thickening reaction involving the mesenteric and subcutaneous region of the right abdominal wall and by the hematological course and the occurrence of alopecia 2 to 3 weeks after the intervention.

Dexrazoxane is effective in preventing/reducing skin lesions following anthracycline local extravasation from peripheral or central lines in preclinical[7] and clinical studies[7],[8],[9],[10] by inhibiting the topoisomerase II catalytic cycle induced by anthracyclines.[11],[12],[13] It might play also a protective role protecting from free radical cardiotoxicity induced by anthracycline-iron complexes.[14] No data concerning dexrazoxane use for the treatment of toxic cutaneous reactions due to TACE procedures with epirubicin are reported so far. In our case, a triple dosage of dexrazoxane was administered without side effects. Local pain improved already during dexrazoxane treatment and skin manifestations resolved completely within 1 month from TACE [Figure 2]. Heart function was never compromised. Hepatitis improved within 2 weeks and hematological disorders were well controlled with blood transfusions and G-CSF administration. Preclinical studies indicate that a delay in the administration of dexrazoxane may be acceptable up to 6 h from anthracycline extravasation. In our patient, even if administered 8 h after the procedure, treatment with dexrazoxane was successful and resulted in progressive resolution of the skin manifestations and clinical improvement of abdominal inflammatory reactions and hematological disorders within 1 month. Dexrazoxane displays a biphasic elimination kinetics in humans with a distributive alpha-phase half-life of 0.8 h and an elimination beta-phase half-life of 9.1 h.[15],[16] It may be considered a drug with high penetration in peripheral tissues considering the elevated volume of distribution of 1.3 L/kg[17] and the absence of bond with plasma proteins.[18] These aspects make reasonable to consider this drug effective also if administered slightly above the 6 h cutoff. Moreover, in a recent report, late administration of dexrazoxane, 3 days after doxorubicin systemic extravasation, seemed effective for complete skin lesions improvement.[1] To conclude, in our experience, treatment with dexrazoxane resulted in complete resolution of the skin manifestations, abdominal inflammatory reactions, and hematological disorders within 1 month. It is most likely that it played a pivotal role in limiting hepatic and gastrointestinal injury and hematological disorders, as well as in resolving skin lesions, and protection of the cardiac function.

Declaration of patient consent

The authors certify that they have obtained all appropriate patient consent forms. In the form the patient(s) has/have given his/her/their consent for his/her/their images and other clinical information to be reported in the journal. The patients understand that their names and initials will not be published and due efforts will be made to conceal their identity, but anonymity cannot be guaranteed.

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Conflicts of interest

There are no conflicts of interest.

 > References Top

Stalder G, Deplanque G, Shabafrouz K, Orcurto A, Bize P, Duran R, et al. Dexrazoxane prevents skin necrosis in non-target embolization of falciform artery during transcatheter arterial chemoembolization (TACE). Diagn Interv Imaging 2018;99:179-80.  Back to cited text no. 1
Lin CC, Wu DK, Shih PM, Liu GC, Chuang WL. Supraumbilical skin rash and fat necrosis after transcatheter arterial chemoembolization: A case report. Kaohsiung J Med Sci 2004;20:36-40.  Back to cited text no. 2
Umemura T, Yamamura N, Nagata A, Shibata A, Yamashita K, Ohata T, et al. Case report: Steatonecrosis in the upper abdomen following transcatheter arterial embolization for hepatocellular carcinoma. J Gastroenterol Hepatol 1998;13:471-4.  Back to cited text no. 3
Ueno K, Miyazono N, Inoue H, Miyake S, Nishida H, Nakajo M. Embolization of the hepatic falciform artery to prevent supraumbilical skin rash during transcatheter arterial chemoembolization for hepatocellular carcinoma. Cardiovasc Intervent Radiol 1995;18:183-5.  Back to cited text no. 4
Kim HY, Bae SH, Park CH, Song MJ, Choi JY, Yoon SK, et al. Supraumbilical subcutaneous fat necrosis after transcatheter arterial chemoembolization with drug-eluting beads: Case report and review of the literature. Cardiovasc Intervent Radiol 2013;36:276-9.  Back to cited text no. 5
Baba Y, Miyazono N, Ueno K, Kanetsuki I, Nishi H, Inoue H, et al. Hepatic falciform artery. Angiographic findings in 25 patients. Acta Radiol 2000;41:329-33.  Back to cited text no. 6
Tyson AM, Gay WE. Successful experience utilizing dexrazoxane treatment for an anthracycline extravasation. Ann Pharmacother 2010;44:922-5.  Back to cited text no. 7
Langer SW, Sehested M, Jensen PB. Treatment of anthracycline extravasation with dexrazoxane. Clin Cancer Res 2000;6:3680-6.  Back to cited text no. 8
Muthuramalingam S, Gale J, Bradbury J. Dexrazoxane efficacy for anthracycline extravasation: Use in UK clinical practice. Int J Clin Pract 2013;67:244-9.  Back to cited text no. 9
Arroyo PA, Perez RU, Feijoo MA, Hernandez MA. Good clinical and cost outcomes using dexrazoxane to treat accidental epirubicin extravasation. J Cancer Res Ther 2010;6:573-4.  Back to cited text no. 10
Sehested M, Jensen PB, Sørensen BS, Holm B, Friche E, Demant EJ. Antagonistic effect of the cardioprotector (+)-1,2-bis (3,5-dioxopiperazinyl-1-yl) propane (ICRF-187) on DNA breaks and cytotoxicity induced by the topoisomerase II directed drugs daunorubicin and etoposide (VP-16). Biochem Pharmacol 1993;46:389-93.  Back to cited text no. 11
Sehested M, Jensen PB. Mapping of DNA topoisomerase II poisons (etoposide, clerocidin) and catalytic inhibitors (aclarubicin, ICRF-187) to four distinct steps in the topoisomerase II catalytic cycle. Biochem Pharmacol 1996;51:879-86.  Back to cited text no. 12
Ishida R, Miki T, Narita T, Yui R, Sato M, Utsumi KR, et al. Inhibition of intracellular topoisomerase II by antitumor bis (2,6-dioxopiperazine) derivatives: Mode of cell growth inhibition distinct from that of cleavable complex-forming type inhibitors. Cancer Res 1991;51:4909-16.  Back to cited text no. 13
Tanabe K, Ikegami Y, Ishida R, Andoh T. Inhibition of topoisomerase II by antitumor agents bis (2,6-dioxopiperazine) derivatives. Cancer Res 1991;51:4903-8.  Back to cited text no. 14
Hasinoff BB, Herman EH. Dexrazoxane: How it works in cardiac and tumor cells. Is it a prodrug or is it a drug? Cardiovasc Toxicol 2007;7:140-4.  Back to cited text no. 15
Schroeder PE, Jensen PB, Sehested M, Hofland KF, Langer SW, Hasinoff BB. Metabolism of dexrazoxane (ICRF-187) used as a rescue agent in cancer patients treated with high-dose etoposide. Cancer Chemother Pharmacol 2003;52:167-74.  Back to cited text no. 16
Vogel CL, Gorowski E, Davila E, Eisenberger M, Kosinski J, Agarwal RP, et al. Phase I clinical trial and pharmacokinetics of weekly ICRF-187 (NSC 169780) infusion in patients with solid tumors. Invest New Drugs 1987;5:187-98.  Back to cited text no. 17
Earhart RH, Tutsch KD, Koeller JM, Rodriguez R, Robins HI, Vogel CL, et al. Pharmacokinetics of(+)-1,2-di (3,5-dioxopiperazin-1-yl) propane intravenous infusions in adult cancer patients. Cancer Res 1982;42:5255-61.  Back to cited text no. 18


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