Cancer Treatment Retiegs (1980)7, 17-27 Therapy of local toxicities caused by extravasation of cancer chemotherapeutic drugs Robert J. Ignoffo* and Michael A. Friednaan'~ Department of Pharmacr, Division of Clinical Phalwmcr,* and Department of ~Wedieine, Cancer Research Institute'f, 15tiversity of California, San Francisco, California 94 t43, ~ LS.,.I. Introduction Despite tile utmost care.- exercised by physicians, nurses, or other health personnel, toxic local tissue reactions, both vascular and extravascttlar, do occur and account lbr ~Ot approximately 2-~ ~o of all adverse effects fi'om antineoplastic drugs (30, 37). The onset and intensity of these local reactions range considerably from hours to weeks, and from minor skln or venous discoloration to severe local necrosis of the dermis and underlying structures. Currently, little experimelxtat data have been published and few guidelines have been established for the management of this serious complication which occurs infi'equently, but is difficult to treat. In this review our objectives are to discuss the specific risk factors associated with these reactions, to describe their pathophyslologicat mechanisms and clinical manifestations, and to present the,. ta'eatmcnt measures currently available. Factors increasing the risk of extravasation Several factors--some concerned with the anatomy and physiology of the patient, others with tile properties of the drug and the site of administration, and still others with previotts or concurrent radiation therapy--appear to enhaucc the risk of local vascular and extravascular reactions. These, along with precautions to minimize certain risks, are noted below. A list of vesicant, irritant, and non-vesicant cancer drugs is given in Table 1. Supported in part by Cancer Education Grant CA 17995-03. Requests for reprints should be sent to: 12,obert J. Ignoffo, Pharrn.D., Depag-tment of Pharmacy, Division of Clinical Pharmacy, University of California, San Fmnc/3co, California 94143, U.S.A. 0303--7372/801010017q-11 $02.00/0 ~. 1980 Academic Press Inc. (London) Ltd. 17
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`18 R.J. IGNOFFO AND IM[. A. FRIEDhLAN Anatomic factors The fact that elderly, debilitated patients with generalized vascular disease seem to be more prone to local vascular and extravascular toxicity supports the notion that venous integrity, vessel diameter, and local blood flow may be implicated in the develop- ment of local tissue reactions. In our experience, such patients can develop these reactions even th0.ugh no gross signs ofextravasation are apparent during drug adminis- tration. Similarly., injcctions into fragile, small diameter veins or those with decreased circulatory dynamics can result in high drug concentrations and extravasation. Physiologic factors An increased potential for systemic as well as local morbidity exists in patients with elevated venous pressure, such as those With superior vena cava (SVC) syndrome or obstructed vcnous drainage and extremity edema after axillary surgery. We obsexwed severe necrotizing mucositis in a patient with SVG after the intravenous administration of 5-fluorouracil (5FU). Before the onset of the SVC syndrome, while receiving 5FU therapy, this patient showed no signs of muco~:utaneous reactions. We postulate that there was decreased distribution of the 5FU to the regions affected by the SVCI obstruction resulting in a higher concentration of drug in the rest of the patient's body. Thus, in patients ,a, idl SVC syndrome, we suggest that the amount of drug be decreased by 25% to compensate for the smaller volume of distribution for that drug. Table 1. Vesicant, irritant, and non-vesicant cancer drugs Drugs commonly associated with severe local necrosis (~,~sicants) Drugs uncommonly associated with severe local necrosis (irritants1" or non-vesicants) Actinomycin D Chromomycin Aa Daunomyehx Doxorubichx Mechlorethamine Mithramycirt Mitomycin C Streptozotocin Vinblastlne Vizlcristine Asparaginase Azacytidine Bleomycin Garmusfine (?BCNU) Gyclocytidlne Gyclophosphamide Cytarabine (ARA-C) Fluorouracil Ftorafur Irnldazole carbox amlde (DTIC)t Iphosphamide l~lercaptopurine tXtethotrexate cis-Platinurn Thiotepa]" VNI-26 VP-IG-213 1" Vesicant--an agent flint when extravasated produces local necrosis. Irritant--an agent that when extravasated produces burning or incormequential inflammation without necrosis. Non-veaicant--an agent devoid of significant vesicant or irritant effects. After surgical treatment with radical mastectomy and axiilary exploration, patients with breast cancer fi'equently will develop ineffective lymphatic drainage in the ipsilateral arm. If this extremity is the site of drug injection, extravasatiort is more likely to occur, since decreased blood flow or increased venous pressm'e in that arm increases rite locM concentration of drug as welt as file duration of exposure to the drug (3). Tliis is supported by a recent report in which doxorubicin extravasation reaction occurred in five of 6ight patients on the side of the radical mastectomy (3). ~Vhen venous drainage is impaired, obviously itis best to avoid injecting vesicant drugs in the affected extremity,
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`THER.*'~PY OF LOCAL TOXICITIES 19 and for patients with SVC syndrome it may be pret%rable to obtain venous access via a lower extremity. Pharmacologic factors The degree of local tissue damage appears to be related to the anaount of drug extra- vasated and the duration of exposure (29, 30). For example, extravasatlon of highly concentrated solutions of doxorublcln produce a greater incidence of reactions than would the appropriately diluted drug (3). High e.~:tracellular concentrations often result in more drug being transported across cell membranes than occurs with lower concentrations of that drug. Thus, in order to minimize local concentration, slow infusion might be the optimal method for the administration of these agents. However, since prolonged drug infusion increases exposure time, vesicant drugs mixed in the appropriate dilution should be administered over the shortest period of time consistent with the patient's venous capacity and tolerance. Radiologic factors Local reactions may be enhanced in paticnts who have had previous radiation therapy to the site of drug injection (17). Such patients are likely to have very severe local reactions from extravasated chemotherapy. N~[oreover, cutaneous abnormalities in irradiated areas that are distant from the injection site may be exacerbated by radio- potentiating chemotherapeutic agents (11). Several cases of "recall phelaomenon" in patients treated with doxorubicin have been reported in which local effects of previous radiation were reactivated by the drug (9, 11, 37). Thus, patients should receive their injections in non-irradlated sites, and previously irradiated areas should bc carefully observed for evidence of recall phenomenon. Logistic factors (site of injection) The occurrence of local reaction appears to be associated with the site of injection (3, 4, 29), a factor which may be under the clinician's control. The antecubital fossa generally should be avoided because extravasation is difficult to detect in this area, and a local slough can expose critical nerves and tendons resulting in permanent dysfunction. Veins overlying vital ne~a, es and tendons of the wrist and dorsum of the ha~ld are particularly morbid sites for vesicant drugs. Theoretically , the optimal location is the forearm wtaich has superficial veins and sufficient soft tissue to prevent tendons and nerves becoming exposed. However, it must be recognized that these guidelines are often untenable for patients with poor venous access. Iatrogenic factors Not only is the site of injection important, but also the technique of venipuncturc. 1VIost severe local reactions are caused by individualswho are inexperienced in ad- ministering cancer chemotherapeuti c agents or who do not take' the appropriate measures irmnediately before or after extravasation (3, 29). Unfortunately , a vein may bepunctured several times when an i.v. is established before t]ie drug is finally ad- ministered. This creates a situation that iS more likeIy to lead to drug Icakage. We think that extrava~sation cart be minimized by using a systematic technique of drug administration. There are many appropriate ways of adminlstering chemotherapy but, based on our clinical experience, we recommend the following procedures which have proved useful to us:
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`20 R.J. IGNOFFO AND l~I. A. FRIEDMAN I. Dilute the drug in the appropriate amount of diluent to avoid high concentrations. 2. Select an infusion site in the following order of preference: forearm ~> dorsum of hand ~ wrist ;> antecubital fossa. 3. Insert a 20 or 21 gauge "butterfly" needle (one vcnipuncturc only) into the veitl. 4. Lightly rope the tubing of the "butterfly" distal to the needle. Do not obscure the injcctio n site by covering it with tape. 5. Administer 5 ml of normal saline (NS) and withdraw a small amount of blood to test vein integrity and flow. Observe for extravasation. 6. If extravasation of NS is obvious, select another site (the other arm, or lateral or proximal to the initial site in that arm). Avoid a distal point on the same vein because of the potential for extravasation "upstream". 7. Administer the drug over at least 3 rain or approximately 5 ml per minute. (Scc Table 2 for administration rate of specific agents.) ~Vithdraw blood once for each I to 2 ml of solution administered Io assure proper needle placement. Repeatedly ask the patient if hc feels any pain or Imrning. 8. Follow the drug injection with 5 to 10 ml or more of a saline infusion to flush tubing and needle of all drug. 9. If muhiple drugs are prescribed, inject tim non-vesicant agents first. If all drugs are vesicants, inject tile one with the least amount of diluent first. Separate each administered drug with 3 to 5 ml of'saline. This systematic approach to drug administration does not require extraordinary time mad has been successfully" used by our staff. However, even this method can lead to occasional extravasations which must be treated immediately. '~Ve believe that rational treatment should be based on inhibiting tile mechanisms by which the extravasated Table 2. UCSF method of bolus drug administration Administration Technique of Drug Volume of diluent rate administration Actinomycin D Normal saline 10 ml 3-5 mln (0.5 rag/vial) (non-bacteriostatic) Carmustine DS~,V 250 ml 30-60 rain (100 mg vial) Daunorubiein Normal saline or 5 rain (20 rag/vial) D5W 10 ml Doxorubicin NormM saline to 5 rain (10,50 mg vial) provide 2 mr/rot Fluorouracil Normal saline 10 ml 3-5 rain (500 mg/lO ml) Meehlorethamine Normal saline 10 ml 2-3 mln (10 mg vial) b, llthramycin Normal saline 4.9 ml 3-5 rain (2.5 rag/vial) (non-bacteriostatic) Mitomycin C Normal saline or 3-5 rain (.5,20 mg vial) sterile water to per 20 ml provide 0.5 rng/ml Vinblastine Normal saline 10 mg 2 mill (10 nag vial) to provide I mg/ml Vincristine Normal saline to a 1-2 rain (t ~5mg vlal) concentration of 0.5 rag/rot Double syringe Rapid infusion Double zyringe or T-site injection Double syringe or T-site injection Single syringe Double syringe or Z-site injection Double syringe or T-site injection Double syringe or /'-site injection Double syringe or T-slte injection Double syringe or 2"-site injection
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`THERAPY Ol: LOCAL 'FOXIC1TIES 21 drug produces tissue cytotoxicity, mad that a~a understanding of these mechanisms is important. Thus, in the fol|owia~.g sections we will describe the mechanisms of action (documented and proposed) of ~hc agents that can produce toxic vascular a~d extra- vascular reactions, and the clinical course of these reactions ('Fable 3). Cancer chemotherapeutic agents associated with extravasation reaction~ .4ntitumor antibiotics The antitumor antibiotics that have demonstrated efficacy in treating maligtlant diseases affect the function or synthesis of nucleic acids (16). However, it has not bectl established that their cytotoxlcity is entirely ~t consequence of altered I)NA filnctiou. ]n addition, relating in vitro to in vivo effects is complicated by significantly different concentrations of" drug required to produce a given effect, such as inhibition of DNA synthesis. This section will focus on those agents for which well-documented cases of local tissue reactions have been reported. In additio~l, conditions that alter the bindblg of drug to DNA which may have clinical significance will be described. Table 3. Summary of extravasation reactions from vaa'ious cancer drugs "|"~'p? o1 reactio:l On,~et of Dttratiot~ of Drug inflammation .%ymptortV~ teactiou Mechaniem Actinomycilt D Vesicant. recall 1-2 ~eeks Pain geveral xsceks Inhibition of DNA- directed RNA s:,'tathe,q.t Carmu,-tir.e Vein phlebitis 10-14 day-~ Pain 7 da~'s Endothelial alkylati,m Daunorttbicln X't~iratat 1-2 -.'~.ek,. I~ait~ ,qcveral weeks Ti-,,tle DNA itttereaLttiort ~uperoxtde forttxation Do.xorubicJn Vesicant, reeal! 1-2 weekr Pain Several ~-eek*, Tis'~ue DNA mterealatiort ~u.,x'roxlde lornm t k'*tl Fluorour=¢il Discoloration I week No paitz I week Uuknown Mechtotethamitte Vesicant 12-X4 h l*:,i*l -I-G weeks "l'#sr, ue all~ylation Vein di-,ct,loratiora ~ x,.'eekn 1:o p.d,t 3-4 wt-eks l:ntlothelLd alkylatlolt Xhthlamycirl Vesic.'lt~t I ,.,.rek ]Min Scvezal ut*k.~ TL~su¢ alky!,at/ort Mitomycin C Vc~icattt I v, tx-k Pain Several week,i "l'i~sue alkylation sllperoxid,r ~ofttlatit)tt \'itabla~tine Vesicaltt 12-24 h Palu .qevet;tl x~et.k.- Mitotic inhihlti,m X'ineriMine Vesic:~nt 12-24 h l'aist .<~:x'*:ral wcek~ 3htotlc inhihittot~ ..lnthracyclines. Several mechanisms of action have been suggested for die anthracyclines (daunonwcln and doxorubicha). :Vlost of them are attributed to aheration ot" DNA fimction through (1) intercalation between base-pairs of double-stranded DNA, and (2) hydrophobic bonding between the glycone ga'oup of the drug and sugar phosphate groups of the DNA (16, 18, q-l). In addition to these actions, other evidence suggests that the al~thracyctines afl~rct cell replication by mechanisrrLs unrelated to DNA metabolism (18). Anthracyclines may also work by interference of mitochondrial oxidation (1, 10, 25) or microtubular function (7). These non-DNA effects must be seriously considered as potential mechanisms of cytotoxicity. Local tissue reactions fi-om extravasated anthracyclines are clinically similar in onset (1 week), duration (1 to 4 months), and symptoms (severe local pain and plflebitls) (3, 29, 30). The duration of necrosis is prolonged, possibly because as some affected cells are killed dae drug disassociates from those cells and binds to surrounding viable ones eventually causing their death (3, 13). This local recycling ot" drug continues until the drug is either completely inactivated or is systemically absorbed. The local instill- ation of cortlcosteriods and sodium bicarbonate has been reported to ameliorate these
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`22 R.J. IGNOFFO AND M. A. FRIEDMAN local effects of the anthracyclines (29, 42). The biochemical explanation for this observation is not known, but perhaps the high ionic strength of the sodium bicarbonate 9nhances DNA-anthracyeline dissociation and helps inactivate the drugs (15. 18). 3Iitono'cin C. Mi~omycin (7: acts as an alkylating agent that, after being activated intra- cellularly by reductive metabolism (13, 15, 42), crossllnks covah:ntly to DNA to produce ahered replication and transcriplion (21). Tomasz ha.,;, shown d~at the partially reduced scmiquinone form of rnitomycln (the scmiquinone radical) is the reactive intermediate, and dtat intercalation precedes the covalent attachment to DNA (35). Mitomycin C also inhibits RNA synthesis, probably by a sintilar mechanism (22). The clinical characteristics of mitomycin cxtrava_sation are similar (o dmse of the anthracyclines (3). The duration of the. local toxic efti;ct is usually prolonged and painful. There l)avc been no systematic studies in which local antidotes have been used in the treatment ot" mitomycin extravasation in humans. Sokoloff has sho~'n in rabbits that flavonoids (possibly acting as non-specific anti- intlammatory agents) can ameliorate the local toxicity of mitomycin injected intra- dermally (34). Flavonoids probably bind to the aziridine group and tlms antagonize its cytotoxic effect (24). Other investigators have examined in vitro chemical inactivation of mitomycin C by strong reducing agents, like ascorbic acid and sodium thiosulfate. These agents have been shown to directly antagonize its biologic effect (13), but none have been carefully tested in humans. :lctinomycin D. Like the anthracycline antibiotics, actinomycin D binds to DNA by an intercalation mechanism with additional stabilization fi-om hydrophobic bonding (8, 26. 33). The resuhing complex principally inhibits DNA-dirccted RNA synthesis (5, 6, I6, 26, 28, 38). Chemically, the binding of this drug to DNA is significantly decreased in the presence of high ionic (sodium) concentrations (26). However, the biologic activity of tim drug is related not only to its rate of binding but equally to its very slow dissociation fi-om DNA (26). In vitro surfactants such as sodium lauryl sulfate enhance drug dissociation fi-om DNA (26). The clinical manifestations of actinomycin D extravasation are similar to those for other antitumor antibiotics and cun'ently there are no accepted antidotes for actino- mycin D local reactions (12). AIithram)vin. Mithramycin inhibits RNA synthesis by inhibiting RNA polymerase through its binding to DNA (38). Because the sugar :noieties on mithramycin are very large, intercalation as the mode of DNA binding is unlikely. The interaction with DNA is believed to be mediated by a mithramycin-Mg ''2 complex and depends on the guanine content and the presence of double-stranded DNA (38). The symptoms ofmithramycin extravasation are simil,-r to those of die anthracyclinc reactions but they occur earlier. Burning and erythema in the area of extravasation is evident within 48 h. No known antidote exists lbr this reaction. Vinca alkaloids Vincristine and vhzblastine. The precise mechanism of vinea alkaloid cytotoxicity is in- completely understood. The vinca alkaloids rapidly gain access into tile cells and produce their cytotoxic effects by inhibiting mitosis through inhibition of microtubular and spindle protein (2). Mitotic arrest may be reversed by dilution oz" elimination of
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`THERAI'$" OF LOCAl. TOXICITIES 23 the drug in cell systems. In addition, the extent of mitotic arrest can be ahered by" other compounds or ex'pcrimental conditions, snell ~ corticostcroids or glutamic acid and low or high temperature (6). Local tissue reactions are probably date to this antimitotic effect and last for relatively prolonged periods of time. The reactions occur in roughl.v 3 to 4 weeks; somewhat earlier than those resulting fi'om tile antitumor antibiotics. The nlanufacturer recom- mends the use ofhyaluronldase and local ]teat which facilitates the local absorption of all fluids. In contrast, others have reconltnended diltttional techniques (norlnal saline injections alone with glucocorticosteroids) G)llowed by" cold contprcsscs to "~"tinimize spread of tile reaction (19). Little experimental data and few case reports supt:~ort eitJlcr of these contentions. Alt~j'lating a~ents attd nitrosoureas illechlorethamine. ~X]echlorethamine (nitrogen mustard) rapidly fixes to all tissues. It ubiquitously alkylates protein and DNA. It appears that the drug is not locally recycled like the antiturnor antibiotics probably because it is spontaneously arid rapidly degraded by body water. Since it is unstable izl alkaline solutions, the drug itself is reco~tstituted in an acidic solution (pI-I 3 "to 5) in order to minimize chemical degradation h~ vitro. It is unknown whether the low pt-I of the mustard solution is izlvolved in tile local tissue reaction. Phlebit is, local pain, and eryt hema usually occur w'ithin hours of extravasation. Even in patients in whom mcchlorcthanfine is not extravasated, vein irritation is not un- common mid eventually (over several days) progresses to dark bluish-grey hyper- pigmentation. Erythema alone need not be treated. The management of mechloreth- amine extravasation must be carried out quickly because of file drug's rapid local toxic effects. Dilutional techniques with local alkaline solutions may be effective in treating extravasations. The manufacturer recommends the local injection of sodium thiosulfate which provides an alternative substrate to tissue alkylation. Sodium thiosulfate is welt tolerated locally and is relatively non-toxic itself (36). In animals, sodium thiosulfate has been shown to decrease local edema caused by the injection of mechh~rcthamine (40). However, no extensive clinical reports of benefit have been published. Carmv.stine (BCNU). Tile exact mechanism of action of carmustinc and its related agents is not clear, but the drug appears to act as a polyfimctional alkylating agent. The drug is passively transported into cells and then activated to alkylating metabolites before binding to DNA (27, 39). The drug is very unstable and quickly inactivated in an alkaline environment (23). We have observed two types of local vascular rt:actiolts to BCNU: (1) an acute bttrning along the course of the injected vein and (2) a delayed phlebitis (onset 7 to 10 days) which lasts tbr about 7 days and is not associated with "classic" vesication and necrosis. The acute reaction probably results fi'om the diluent (absolute alcohol) flint is used to reconstitute this relatively insoluble nitrosourea. The delayed reaction probably results from alkylation of endothelial cells in the vessel wall. Acute local reactions fi'om BCNU cat1 be managed by simply decreasing the infusion rate or concentration of drugs in solution. A ntlmetabolites 5-Fluorouracil (5FU). 5-FluorouracE does not produce severe local tissue toxicity but can produce a local bluish-grey hyperpigmentation in 2-5% of all patients (20). Often
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`2-t R.J. IGNOFFC) AND Xl. A. I:RII';I)~IAN Table 4. Antidotes used at UCSF Extravas:ttctl drug Atttitlote Dose Xlechanism of antidote Actlnomycill I) CJodium thiosulKate 10~/o 4 ml Decreased DNA binding (4 ml+6 ml sterile H:O) or nscorbic acid injection 1 ml Decreased DNA binding (50 mg/ml) Daunorubicin Doxoru biciu .'~lcchlorethamine .'~ lithramycin .Nlitomycln G Vinl)lastine Vincristine Carmustine Sodium bicarbonate 8.4'Yo 5 ml Dexamethasone 4 mg/ml 1 ml n/ Sodium bicarbonate 8.4 ,o + 5 ml dex:maethasonc .I mg/ml ! ml o/ Sodit,m thiosulfate 10~o 4 ml ED'I'A 150 mg/ml 1 ml (sodlutn edatatc) Sodium thiosull~tte I0°o 4 ml (,l ml + 6 nil sterile H:O) or ascorbic acid injection I ml (50 mg/ml) Sodium bicarbnnate 8.4°~, 5 ml or hyalurotfidase 150 tx/ml 1 ml Sodium bicarbonate 8.4% 5 ml or hyaluronidase 150 v,/rrd I ml plus heat Sodium bicarbonate 8.4% 5 ml Decreased DNA binding Decreased inflammation Decreased DNA binding Decreased iitflarnmation Rapid alkylation l)ecreascd DNA binding Direct inactivation Direct inactivation Chemical precipitation Increased drug absorption Chemical precipitation Increased drug absorption Chemical deactivation Table 5. Drugs and materials to treat cxtravasat~on Drugs .Manufacturer Sodium bicarbonate 8.4°,b Ascorbic acid injection 50 mg/ml, 2 ml (Cevalin) Hyaluronidase 150 pt/ml (~,Vydase) Dexa met hasone 4 mg/ml Hydrocortisone phosphate 25 mg/ml Sodium thlosulfatc 1 gm/lO ml Sodium edetate (endrate) 150 mg/ml Various Lilly Wyeth Various Various Torlgian Laboratory Abbott AZaterlals 27 g TB syringe (2) l0 cc normal saline (non-bacteriostatic) 10 cc syringe (2) 4 X 4 gauze (4) Alcohol swabs Snap-lock plastic bags (for ice packs)
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`THERAPV O1" I.OCIAi. TOXICITIF.S 25 these reactions occur ovcr sun-cxposed areas in the arm injected with the drug. The mechanism of this action is unknown. We have observed a mild, delayed phlebitis in the injected venous site occut'ritlg 10-14 days post-therapy. Some mild pain of one week's dttration or less may aecompatly this phlebitis, but no necrosis has been noted. ,~fiscellaneous agents Several other agents have bcen observed to produce venous discoloration several days after or burning during drug administration. These agents include BCNU, DTIO, 5FU and streptozotocin. It has been shown that any agellt can produce local venous irritation as a result of needle or catheter insertion. However, in most cases the local phlebitis is short-lived and usually does not result in local nccrosis. Treatment of extravasations To our knowlcdge no controlled studies have as yet been performed to determine the bcst methods for the treatment of extravasations. '~Ve have empirically employed the following protocol based upon the available literature and our own experience and prejudice. We believe that once extravasation has occun'cd, tt'eatmcnt should be initiated immcdiatcly and consist of (1) local mcasuresj and/or (2) surgical dcbridcmcnt and engraftment. Local measures We recommend the following therapy, designed to inhibit tissue cytotoxicity. Once an extravasation is noted, wc perform these proccdttres sequcntiatly: 1. Stop the injection immediately, but do no¢ remove the needlc. 2. ~?¢ith the needle in place, withdraw 3 to 5 ml ofblood in order to remove some of the drug. 3. With a 27 gauge TB syringe, aspirate thc sxd~cutaneous blcb to withdraw as much of the remaining solution as possible. 4. Locally instill the rccommcnded amount of a~ltidote (Table 4). 5. Instill corticosteroids locally to reduce the inflammatory reaction (optional). 6. Remove the "butTerfly" needle. 7. Apply warm to hot compresses at tl~e site ofc×travasation for 60 mln.'[" The rationale for this regimen is based on (I) altering local pI-I to cnhancc drug inactivation, (2) altering the binding of drug to DNA, (3) chemically neutralizing the drug, (4) removing as much drug as possible, (5) diluting thc extravasated drug, and (6) preventing or minimizing non-specific inflammation. Table 5 lists those drugs and materials wc employ to treat extravasation of chenlotherapeutic agents. -1" It is well documented that drug absorption can be significatttly influenced by the temperature of the skin at the site of administration (14). The question arises as to which process is .re°re beneficial enhance- ment or inhibition of absorption. Heat will produce va.~odilation, facilitate fluid absorption, and decrease local drug concentration. Cold will produce vasoconstriction and dex:rease fluid absorption, which will concentrate e.xtravasated fluid at the site and potentiate local toxicity'. VCe think that/tot compre~es may be a better choice.
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`26 R.J. ICNOFFO AND 1M. A. FRIEDMAN Surg?cal mtaJure.r If inflammation and induration of tissue continue despite local measures, the entire area should be evaluated /br possible excision and subsequent plastic surgery. Plastic surgery, especially in cases ot" doxorubicin extravasation (29), is effective when per- for~.ned early in the course of a serious.episode. XVhen surgical measures are used, it may be necessary to discontinue chenlotherapy m~til wound healing has occurred. Conclusions As has been stated, the preceding guidelines were developed from the available literature and our clinical experience. Few of our recommendations are scientifically established, but those we/mvc suggested will probably not produce systemic toxicity arid may prevent progression of a minor lesion to a severe: necrotic one. Obviously, studies arc accesser T to substantiate ntany of the currently used treat- ment measures. We are presently developing animal models to test several of these approaches, and until such rigorous testing is completed many of the tdlerapeutic recommendations will still remain empirical. '~Ve believe, however, that the systematic approach to prevention and treatment we have offered may benefit patient care. Acknowledgements The authors wi~h to thank ~[s Eleanor Haas for her exceptional editorial assistance, to Ms Kris Gallagher for her outstanding technical assistance, to Ms Michele Ignoffo for her superior organizatiotml efforts, and to Ntartin S. Apple, Ph.D., lbr reviewing this manuscript. References 1. Bachur, ~,V. R., Gordon, S. L. &Gec, ]kl. V. (1978) A 8eneral mechanism for microsomal activation Ol e qUillOlle antlcancer agents to free.radlcals. Can¢tr Res. 38:1745-1750. 2. Bensch, K. G. & ,Nlalawlsta, S. E~ (1968) ~Iicrotubule c~-stals: A new blophy,sical phenomena induced by vinca alkaloids. Nature 218" 1176-1177. 3. Bowers, D. G. & Lynch, J. B. (1978) Adriamycin extravasatlon. P[a3t. Recanstr. Surg. 61 : 86-92. 4. C, hait, L. A. & Dinner,/~,f. I. (1975) Ulceration caused by c)'totoxic drug~. 5". Afr. Aled.ff. 1 : 1935-i'936. 5. Cheng, C. C. & Kwang-Yuen Zee-Cheng (1972) Some antineoplastic antibiotics..)'. Pharm. ScL 61: 485-501. 6. Creasey~ ~,V. A. (1977) Plant alkaloids. In Cancer, vol. 5. (Ed. F. F. Becker). Plenum Press, New York. pp. 379-425. 7. Dana, K. (1972) Cro~s resistance between vinca alkaloids and anthracycline~ in Ehrlicb ascites tumor in uioo. Canter Chtnlolher. Rep. 56: 701-708. 8. Dingman, C. W. & Sporn, 1Mr. B. (I965) Actinomycin D and hydrocortisone: lntracellular binding in the rat. Sdence 149: 1251-I254. 9. Donaldson, S. S.~ et el. (1974) Adrlamycln activating a recall pher~omcnon after radiation therapy. Ann. Int. Afed. 81 : 407-408. 10. Dormandy, T. L. (1978) Free-radical oxidation and ant loxldants. Lancet i: 647--650. 11. Etcub:mas, E. (1975) Uncommon side elt~:cts o£adriamycitt. Canter Chtraother. Rep. ~8: 757-758. 12. Frel, E. III (1974) The clinical use ofactinomycln. Cancer Chemother. Rep. 58: 49-54. 13. Fujita, H. (1971 ) Comparative studies on the blood level, tissue distribution, excretion, and inactivation o£anticaneer drugs, flap. 07. Ctin. Oncol. 1"2,: 151-I62.
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