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For citation purposes: Thakur A, Thakur JS. Extravasational toxicity of anticancer chemotherapy and its management. OA Case Reports 2013 Mar 01;2(3):26.

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Onco

logy

Extravasational toxicity of anticancer chemotherapy and its management

A Thakur1, JS Thakur2*

AbstractIntroductionAnticancer drugs have a number of side effects, including toxic effe-cts on bone marrow, kidney, lymp-horeticular tissue, mucosa and cochlea. Extravasational toxicity is a complication of anticancer drugs, unmentioned in the majority of clinical textbooks other than on-cology, explaining why residents may be unaware of this preventa-ble catastrophe. The objective of this paper is to review and present the clinical features and manageme-nt of extravasation of these antican-cer drugs so that first line staff get acquainted to this complication and its management. After reading this paper, residents and clinicia-ns will be more vigilant in antica-ncer drug infusion and managem-ent of extravasation.Conclusion

Once extravasation occurs, tis-sue injury is inevitable but can be reduced with the proper antidote. A trained member of staff should ad-minister this, preferably from the on-cology department only.

IntroductionAs the incidence of cancer is increas-ing, cancer management has become a team effort consisting of family members, physicians, surgeons, ra-diations and medical oncologists, psychiatrists and physiotherapists.

The objective of this team is to pro-vide a cure or palliation with mini-mal side effects and quality of life to the patient.

Radiation therapy has become target-orientated to avoid injury to normal tissue but now chemora-diation is the preferred modality. In spite of giving promising results, these anticancer drugs have a num-ber of side effects, which include toxic effects on bone marrow, kid-ney, lymphoreticular tissue, mucosa and cochlea1. In India, the oncology department is overloaded with can-cer patients; hence, anticancer drugs are being infused in the parent de-partments by nurses and residents. However, extravasational toxicity is one of the dreaded complications of anticancer drugs, which didnot find a place in the majority of clini-cal textbooks1–7 other than oncology, and hence many of the residents may be unaware of this preventable catastrophe8.

The incidence of extravasations in adults is 0.1% to 6.5%9,10. Ex-travasation can occur in any centre and even in highly advanced oncol-ogy centres11, but these advanced centres have specially trained on-cology-nursing staff. Commonly, chemotherapy is infused in clinical or parental departments of the pa-tient, and work of infusion is left to a house surgeon or an intern, who may not have yet acquired a rea-sonable experience in venepunc-ture. Even the resident may not have adequate knowledge of the measures to be undertaken in case of extravasation due to absence of this complication and its manage-ment in the majority of clinical textbooks.

The objective of this paper is to review and present the clinical features and management of extravasation of these anticancer drugs so that the first line s-taff (residents/nurses) gets acquaint-ed to this complication and its management.

Classification based on mode of tissue injuryExtravasation of anticancer drugs causes tissue damage by different mechanisms12: (a) DNA-binding drugs are initially absorbed locally causing direct cell death. Later, the drug is released from the nearby dead cells and causes further damage in surrounding tissue10, 13, 14. (b) Non-DNA-binding drugs are metabolized and cleared early; thus, tissue dam-age is less and easily neutralized by the antidote12.

On the basis of extravasational tox-icity, anticancer drugs are classified as irritants or vesicants (Table 1)8, 9,15,16.

Vesicant drugs: They cause blister formation, tissue death and ulcer for-mation at extravasation site.

Irritant drugs: They act as irri-tants on the injection site, and pain is the main symptom. Ulcer forma-tion is rare but extravasation of large amount can lead to ulceration.

* Corresponding author Email: anujagdeep@yahoo.co.in1 Department of Pharmacology, Indira Gandhi

Medical College, Shimla, Himachal Pradesh, 171001, India

2 Department of Otolaryngology-Head and Neck Surgery, Indira Gandhi Medical College, Shimla, Himachal Pradesh, 171001, India

DiscussionThe authors have references some of their own studies in this review. These referenced studies have been conducted in accordance with the D-eclaration of Helsinki (1964),and th-e protocols of these studies have be-en approved by the relevant ethics committees related to the institution in which they were performed. All h-uman subjects gave informed conse-nt to participate in these studies.

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Guidelines for infusion of cytotoxic drugsInstitutional policyThere are specific guidelines for in-fusion of anticancer drugs15,17–21, but the institutes or hospitals should also have their own policy on chemo-therapy infusion. The attending phy-sician and nursing staff should be familiar with the anticancer drug and its complication. The infusion should be given at the time of maximum staff strength and care. The ward should have information charts displayed both for staff and patient22. All the antidote drugs should be at the bed-side of the patient. Patient should be informed about the symptoms of extravasation and its complications, and explained that despite best ef-forts, extravasation can occur22. All extravasation incidences should be brought to the notice of the depart-ment and institutional oncology board. They can review the case and decide on further management of the patient and preventive measures.

Intravenous accessThis is the most important step in the prevention of extravasation. First of all, assess the general condition and

age of the patient. Patient with pa-ralysis, sensory deficit, tracheostomy or impaired higher mental function needs extra care due to inability to alert the staff during extravasation23. Elderly patients have increased risk of extravasation due to fragile veins. Similar risk is involved with deep veins, previous infusion within 48 h, multiple attempts for venous access, radiation or regional lymph node clearance of the limb15, 22.

The second most important step is to decide on central or peripheral in-travenous access. Commonly, periph-eral intravenous access is preferred. However, drugs to be given longer than 1 h should be administered only via a central line15,23,24. The flexible intracatheter devices should be used, as other rigid devices have a ten-dency for vessel injury8,15. Forearm is the preferred site due to catheter stability and muscle protection for the nerve and tendons in the event of extravasation, which is inevitable in case of access on hand or wrist8.Venous access should be secured in a single attempt and in case of failure, the site should be changed to another proximal vein. The device should be covered with transparent dressing

so that the signs of extravasation are visible to the patient and staff. Intra-venous access should be checked by running normal saline intravenously. This step immediately confirms ex-travasation and also hydrates the patient, a prerequisite for chemo-therapy. Now, anticancer drugs are started, and the patient is instructed to alert the attending staff if there is any pain, itching, stoppage of infu-sion or oedema in the limb.

Clinical features of extravasationExtravasation of cytotoxic drugs leads to stoppage of infusion, and the patient will complain of excruciating pain and itching in the infusion site. Within a few hours, the extravasation area will show erythema, oedema and induration. Without interven-tion, these sign and symptoms will increase, and skin will show discol-ouration and desquamation of epi-dermis or blister formation in a few days. Extravasation of a large dose of cytotoxic drug leads to ischaemia and ulcer formation (Figure 1).

Management of extravasation• Immediate bedside manage-

ment: Immediate management of extravasation reduces the tissue injury, and morbidity is inevitable if this step is delayed. On extrava-sation, infusion of drug should be stopped at once and normal saline infusion should be started. In case of an irritant drug, intravenous cannula should be removed while it is left in place in case of vesicant drug and proper antidote should be given15. The limb is elevated, and cold pack is applied to the lo-cal site. Hot packs are applied in extravasation of vinca alkaloids, as it causes vasodilatation and dif-fusion of the drug from the site. Parenteral strong analgesic helps in the reduction of inflammatory reaction and its symptoms.

• Use specific antidotes: There area number of studies and case re-ports in literature9,10,18,25–45 to show

Table 1 Vesicant and irritant chemotherapeutic drugs

Vesicant drugs Irritant drugs

Alkylating agents (DNA-Binding): Mechlorethamine (MustineHCl)**

Alkylating agents: Cyclophosphamide, Ifosfamide, Melphalan, Carmustine, Dacarbazine, Thiothepa

Antitumour antibiotics (Anthracyclines, DNA-Binding)**: Mitomycin C, Dau-norubicin (Rubidomycin), Doxorubicin (Adriamycin), Epirubicin, Idarubicin, Actinomycin D (Dactinomycin)

Antimetabolites: Methotrexate, 5-Fluo-rouracil (5-FU)*, Cytarabine (Cytosine arabinoside), Fludarabine, Gemcitabine

Vinca alkaloids (Non-DNA Binding)**: Vincristine (Oncovin), Vinblastine, Vinorelbine

Antitumour antibiotic: Bleomycin

Taxanes (Non-DNA Binding)*: Docetaxel, Paclitaxel

Epipodophyllotoxin: Etoposide*

Platinum analogs: Cisplatin*, Carboplatin, Oxaliplatin*

** Highly vesicant, * Low vesicant.

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the efficacy of various antidotes for extravasation of anticancer drugs.a) Dimethylesulfoxide (DMSO):

This drug is applied topically in case of extravasation of anthra-cyclines and mitomycin C. 1–2 ml of 1 mM 50%–99% DMSO is applied to the effective area thrice a day for 1–2 weeks. Oli-ver et al.25 used topical DMSO every 6 h for 14 days in 20 pa-tients with extravasation of an-thracycline and in a follow-up of 16 patients for 3 months; no patient developed skin ulcera-tion or necrosis. Bertelli et al.27 used 99% DMSO topically every 8 h for 7 days in 127 patients with various vesicant drugs, and only one patient had skin ulceration.

b) Hyaluronidase: This drugbreaks hyaluronic acid and increases the permeability of connective tissue and hence the diffusion of extravasated drug10,15,24. It is recommended in vinca alkaloids, epipodo-phylotoxin and taxanes26,31

extravasations. It is injected through the existing cannula or subcutaneously in a clockwise manner if cannula has been re-moved. About 1–6 ml of 150 U/ml hyaluronidase is sufficient, but its dose corresponds to the amount of extravasated drug.

It is contraindicated in case of infection and cancerous infil-tration of the site, as it can ease the spread of disease.

c) Dexrazoxane: It is a recentFDA-approved antidote for anthracycline extravasation. Exact mechanism of action is unknown but some evidences suggest reversible topoisomer-ase II inhibition and binding to iron, which prevents the forma-tion of free radicals responsible for tissue injury22,32. It is infused slowly over 1–2 h in a large vein other than the injured vein in a dose of 1 gm m-2 within 6 h of extravasation, and repeated again on the second day with the same dose and 500 mg m-2 on the third day. Based on anecdo-tal reports, DMSO interacts with dexrazoxane and decreases its efficacy; therefore, concurrent use should be avoided32. Fever, fatigue, gastrointestinal distur-bances, headache, transient el-evation of liver transaminases and decrease in blood count are a few of the side effects.

d) Sodium thiosulfate: Thisdrug is indicated in extrava-sation of mustineHCl and cis-platin. Its exact mechanism of action is also unknown, but is thought to chemically neu-tralize the reactive alkylating

species of mustine HCl and decrease the production of hydroxyl radicals33.

e) Miscellaneous drugs: Thisgroup includes drugs with low level of evidence in the man-agement of extravasation of an-thracycline. These drugs have shown efficacy in experimental animals only, and include vita-min C34,35, and E36–59, heparin fraction41, melatonin42, hyper-baric oxygen43. Scuderi et al.44 have reported local injection of saline (20–90 ml) with oc-clusive topical application of corticosteroid to avoid skin ne-crosis. Local infiltration of hy-drocortisone in anthracycline extravasation did not prevent skin necrosis in mice model45.

• Surgical intervention: Surgicalintervention is reserved in casesthat have not received antidote orpresented late with erythema ornecrosis. In two studies46,47, salinewashout with liposuction prevent-ed skin necrosis, performed within24 h of various extravasation inju-ries. This procedure is performedby irrigating the subcutaneous tis-sue with normal saline through a4-mm blunt tipped liposuction can-nula, and removing subcutaneoustissue with the extravasated drug.

Untreated extravasation leads to skin necrosis and needs plas-tic surgeon intervention. Surgi-cal intervention involves two approaches48–55. One approach involves extensive surgical de-bridement preferably under fluo-rescence microscope within 24 h to 1 week after extravasation and secondary wound closure. The second conservative approach in-volves daily saline dressing. The wound is then covered with split skin graft or flap. Necrosis of pe-ripheral vessels and nerves of limb may need amputation. How-ever, immediate intervention is indicated in case of non-resolving

Figure 1: Extravasation on the forearm leading to skin necrosis.

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(granulocyte macrophage colony stimu-lating factor) on doxorubicin- induced tis-sue necrosis and wound healing. Indian J Cancer. 2000 Dec;37(4):153–157.20. Jacobson JO, Polovich M, McNiff KK, Lefebvre KB, Cummings C, Galioto M, et al. American Society of Clinical Oncol-ogy/Oncology Nursing Society chemo-therapy administration safety standards. J Clin Oncol. 2009 Nov;27(32):5469–75.21. Pérez Fidalgo JA, García Fabregat L, Cervantes A, Margulies A, Vidall C, Roila F, et al. Management of chemotherapy extravasation: ESMO-EONS Clinical Prac-tice Guidelines. Eur J Oncol Nurs. 2012 Dec;16(5):528–34.22. Schulmeister L. Preventing and man-aging vesicant chemotherapy extravasa-tions. J Support Oncol. 2010 Sept–Oct; 8(5):212–5.23. Schulmeister L. Extravasation. In:Polovich M, Whitford JM, Olsen M, editors. Chemotherapy and biotherapy guidelines and recommendations for practice, 3rd ed. Pittsburgh: Oncology Nursing Society; 2009. pp105–11.24. Ener RA, Meglathery SB, Styler M. Extravasation of systemic hemato-on-cological therapies. Ann Oncol. 2004 Jun;15(6):858–62.25. Olver IN, Aisner J, Hament A, Buchanan L, Bishop JF, Kaplan RS, et al. A prospec-tive study of topical dimethyl sulfoxide for treating anthracycline extravasation. J Clin Oncol. 1988 Nov;6(11):1732–5.26. Bertelli G, Dini D, Forno GB, Gozza A, Silvestro S, Venturini M, et al. Hyaluroni-dase as an antidote to extravasation to vinca alkaloids. J Cancer Res Clin Oncol. 1994;120(8);505–6.27. Bertelli G, Gozza A, Forno GB, Vidili MG, Silvestro S, Venturini M, et al. Topical di-methyl sulfoxide for the prevention of soft tissue injury after extravasation of vesi-cant drugs: a prospective clinical study. J Clin Oncol. 1995 Nov;13(11):2851–5.28. Dissa JJ, Chang RR, Mucci SJ, Goldberg NH. Prevention of adriamycin- induced -full thickness skin loss using hyaluro-nidase infiltration. PlastReconstr Surg. 1998 Feb;101(2):370–4.29. Langer SW, Sehested M, Jensen PB.Treatment of anthracycline extravasa-tion with dexrazoxane. Clin Cancer Res. 2000;6:3680–6.30. Langer SW, Sehested M, Jensen PB,Buter J, Giaccone G. Dexrazoxane in an-thracycline extravasation. J Clin Oncol. 2000;18(16):3064.

of internal medicine. 17th ed. New York: The McGraw-Hills Companies Inc; 2008. 6. Foon KA, Geskin LJ, Ghobrial I, Jacobs SA. The non-hodgkin lymphomas. In: Lichtman MA, Beutler E, Kipps TJ, Selig-sohn U, Kaushansky K, Prchal JT, editors. Williamshematology. 7th ed. Singapore: The McGraw-Hills Companies Inc; 2007.7. Payne S, Miles D. Mechanisms of anti-cancer drugs. In: Gleeson M, Browning G, Burton J, Clarke R, Hibbert J, Jones NS, et al., editors. Scott-Brown’s otolaryngol-ogy. Vol I, 7th ed. London: Hodder Arnold; 2008. pp 34–46.8. Thakur JS, Chauhan CG, Diwana VK, Chauhan DC, Thakur A. Extravasational side effects of cytotoxic drugs: a prevent-able catastrophe. Indian J Plast Surg. 2008 Jul;41(2):145–50.9. Bertelli G. Prevention and management of extravasation of cytotoxic drugs. Drug Safety. 1995 Apr;12(4):245–55.10. Dorr RT. Antidotes to vesicant chemo-therapy extravasations. Blood Review. 1990 Mar;4(1):41–60.11. Schulmeister L. Managing vesicantextravasations. Oncologist. 2008 Mar; 13(3):284–8.12. Dorr RT. Pharmacologic managementof vesicant chemotherapy extravasations.In: Dorr RT, Vonn Hoff DD, editors. Cancer chemotherapy handbook, 2nd edition. Norwalk, CT: Appleton & Lange; 1993. pp109–18.13. Dorr RT, Dordal MS, Koenig LM, Taylor CW, McCloskey TM. High levels doxoru-bicin in the tissues of a patient experienc-ing extravasation during a 4-day infusion. Cancer 1999 Dec;64(12):2462–4.14. Sonneveld P, Wassenaar HA, Nooter K. Long persistence of doxorubicin in human skin after extravasation. Cancer Treatment Rep. 1984 Jun;68(6):895–896.15. Schrijvers DL. Extravasation: a dread-ed complication of chemotherapy. Ann Oncol. 2003;14 (Supp 3):iii26–30.16. Herrington JD, Figueroa JA. Severe ne-crosis due to paclitaxel extravasation. Phar-macotherapy. 1997 Jan–Feb;17(1):163–5.17. Burd DAR, Santis G, Milward TM.Severe extravasation injury: an avoid-able iatrogenic disaster? BMJ. 1985 May;290(6481):1579–80.18. Alberts DS, Dorr RT. Case report:topical DMSO for Mitomycin C induced skin ulceration. Oncol Nurs Forum. 1991 May–Jun;18(4):693–5.19. Eroglu E, Sari A, Altuntas I, Delibas N,Candir C, Agalar F, et al. The effect of GM-CSF

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• Physiotherapy: It is indicated inlate complications (functional or neural loss of the limb), but is rare.

Conclusion Extravasation is a dreaded complica-tion of anticancer drugs and can be avoided through proper guidelines. Once extravasation occurs, tissue injury is inevitable but can be re-duced with the proper antidote. All anticancer drugs should be infused by trained staff, and preferably in the oncology department only. The clinical textbooks should cite this complication and its management, so that primary clinical physicians are able to handle this complication in its golden hour.

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