`
`Antidotes to Vesicant Chemotherapy
`Extravasations
`
`R. T. Dorr
`
`The extravasation of vesicant cancer chemotherapeu-
`tic agents remains one of the single most distressing
`complications that hematologists and oncologists
`face. Vesicant agents, or drugs that cause ulcera-
`tion upon direct tissue contact, are among the most
`frequently used compounds in clinical cancer chemo-
`therapy. The list of vesicarrt drugs includes anthracy-
`clincs such as donorubicin,"9 daunorubicin"‘” and
`other DNA intercu.lat.ors,“"15 alkylating agents such
`as nitrogen mustard“-” and mitomycin C2041
`and the plant alkaloids, vincristine and vinblastitie.“|
`Table 1 identifies the cancer chemotherapeutic drugs
`that can produce soft tissue ulceration upon extrava-
`sation. Antidotes have been proposed for many of
`these agents.
`Besides the pharmacologic treatment of vesicant
`extravasations, a variety of non-pharmacologic ap-
`proaches must be considered. First and foremost
`among these is prevention. In this regard, it is clear
`that the utmost caution must be placed on the careful
`administration of these medications. One important
`means of preventing vesicant extravasations has been
`the development of subcutaneous indwelling vascular
`access devices. However, despite the advent and ex-
`tensive use of these vasaular access devises, drug
`extravasation continues to be a problem.
`
`Vascular Access Devices
`
`In a review of 329 procedures using vascular devices
`in over 300 patients, an extravasation incidence of
`6.4% was reported.“ This is similar to the reported
`
`R. T. Dart PhD, Ill'h, Research Associate Professor, Medicine and
`Phannacology. Arimna Cancer Center, ISIS N Campbell Avenue.
`Tucson, AZ 85724, USA.
`
`Blood Revkwr [1990) d. fl—W
`© I990 Lehman Group UK Ltd
`
`
`
`incidence of doxorubicin extravasation of 6.5% when
`peripheral venipuncture techniques are used.3 Reed et
`al have also reported drug extravasation from venous
`access devices and surprisingly in 1 case, severe skin
`necrosis from the antimetabolite fluorouraci! was
`described." One mechanism for this type of extra-
`vasation injury can involve retrograde subcutaneous
`leakage
`from percutaneously
`inserted catheters
`clogged by a fibrin sl’teath.’S In addition, indwelling
`catheters from subcutaneous reservoirs can also spon-
`taneously retract from the subciavian vein.” Thus,
`even with the best techniques, and the use of indwell-
`ing access devices, chemotherapy extravasation has
`not been eliminated.
`
`Surgery to Remove Trapped Drug
`
`Once an extravasation has occurred, it is imperative
`to terminate the infusion of the medication and
`evaluate the site for potential definitive treatment.
`Ollentimes, serious extravasations will require surgi-
`cal excision of the tissue and this should not be
`delayede” One cogent reason for rapid evaluation
`for potential surgery is exemplified by extravasations
`of doxorubicin. This agent can be trapped in skin
`tissues for several months following a serious extra-
`variationm“63 (Table 2). In these cases it is hypothe-
`sized that active drug is sequentially released from
`dying cells and is taken up again by adjacent healthy
`cells. This would explain the prolonged retention of
`doxorubicin in skin and underlying soft tissues.“ The
`results in the Figure show that following an extra-
`vasation doxorubicin can be partially metabolized to
`doxorubicinol andfor to the inactive aglycone in skin
`tissues.
`One of the best clinical indicators of the need for
`
`OZHrMXMW—m-ll 510.00
`
`Medac Exhibit 2097
`
`Koios Pharmaceuticals v. Medac
`
`IPR2016-01370
`
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`Koios Pharmaceuticals v. Medac
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`42 ANTIDOTES T0 VESICANT CHEMOTHERAPY manvnsnnous
`
`Table I Propensity for cancer drugs to product necrosis upon inadvertent extravasation
`
` High Low None
`
`
`DNA tittertflifltors
`
`
`
`Doatoruhicitt“9
`Daunorubicin"”
`Dactinornycin1"”
`Epirubicinum’
`Biaantrene"—”
`Cyanornorpholinyl ticxorulzticin“2
`Amsacrine ‘
`Alkyiatt‘ng or DNA-binding agents
`Mechloroethaminemfl
`Mitomycin C“"22
`
`Amhmabolim
`—
`
`Plant products
`Vincrisdne”-"'
`\«"il'1blastitle“"3z
`Vindesinemz.”
`Miscellan
`—
`Biological:
`—
`
`Liposomal anthracyclineszu’
`Mitoxanttonen‘J“
`Est:trubit:in3“36
`Menogarilm‘H
`Aclacinomycin’
`
`Cisplatin'7'37-‘3"’
`
`Fluorouracil"“".T
`
`+
`Etoposides" 5‘ 1'
`
`Mithramycin"
`
`Melphalnn“
`Camustine
`Daearbazine“‘l
`
`Cytarbine
`Methotrexate
`
`Teniposide"?
`
`LAsparaginase
`a—Intetferon
`Interleukin-21
`Tumor necrosis factor?
`
`Bleomycins-“t
`
`" Very rare reports of clinical soft tissue ulceration following cxtravasation.
`TOccasionally causes local phlebitis and soft tissue irritation but usually not ulceration.
`
`Tillie 2 Experimental doxorubicin extravasation treatment
`studies
`
`Agents
`
`Glucocorticosteroids
`
`Dimelhylsulfoxide
`Vitamin E
`
`Efiective
`
`Mice”
`Rats-:4.”
`
`Rats"
`Pigs"g
`Guinea Piston
`
`Sodium bicarbonate
`
`Rats"
`
`Radical dimer {DHMQ
`Saline
`
`Pig’s-9‘
`
`Beta-adrenergics
`
`Antioxidants
`(cg. BHT)
`
`Mice"
`Rats”
`
`Mice“
`Rats”
`
`Antihistamines
`Hyaluronidase
`Non-phommot‘ogic procedures
`Topical heating
`Topical cooling
`
`Surgical excission
`
`Mice‘”
`Pigs“)!
`Raw—“~69
`
`Inefi'cctive
`
`Rabbitsm’"
`Rats“
`Mice’l
`Guinea Pig”
`Mice“
`ReuniteTo
`Hgsicmoz
`REESE
`RabbitsW-Tm
`Mice"2
`Rats”
`
`Miceu“
`Rats”
`
`Mice91
`Mice" '91
`
`Mice‘”
`Rats”
`
`subsequent surgery is reported to be pain at the site of
`the extravasation 1—2 weeks following the event?1
`When surgery is indicated, a wide excision of the
`tissues is necessary to completely remove [ten-viable
`tissues and any locally trapped drug.°'”‘°° Because
`of the very prolonged evolution of anthracyciine
`extravasation injuries,
`it
`is advisable that surgical
`consultation not be delayed so that large tissue areas
`may be spared subsequent drug exposure.”-“ In
`contrast, if an open ulcer is allowed to develop, the
`
`area of excision may need to be quite large and
`may involve deep structures such as nerves and
`tendons.”
`
`Interpreting Pharmacologie Treatment Reports
`
`Because of the severity of the ulcers which develop
`and the need for extensive local surgery to control
`evolving ulcerations, a variety of phannacologic anti-
`dotes have been postulated to prevent the develop-
`ment of this serious complication.“ Oftentimes,
`putative antidotes have been reported in clinical
`anecdotes which, while helpful, do not have the
`rigorous controls needed for an unequivocal test of
`efficacy. Secondly, as Larson has shown. only about
`one third of known vesicant extravasations will pro-
`duce ulcers when conservative local management is
`used (ice and elevation of the effected limb)” This
`means that there is a high likelihood of overestimat-
`ing the true efficacy of a putative local antidote since
`the majority of patients will have a good outcome
`following a vesicant extravasation with only conser-
`vative therapy.
`In the following sections a variety of pharmacolo-
`gic approaches to extravasation management are
`reviewed for different vesicant cancer chemotherapeu-
`tic agents. ln each case, both clinical and experimental
`studies are analyzed with the intent
`to provide a
`comprehensive survey of this important area of
`cancer drug t0xicity.
`
`Doxorubicin Extravnsations
`
`Doxorubicin extravasations are reported to occur in
`up to 6% of patients given the drug by peripheral
`
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`
` BLOOD REVIEWS 43
`
`
`
`Page 0000
`
`- DOXORUBICIN
`DOXORUBICINOL
`m AGLYCONE
`
`
`
`l 0000
`
`4
`
`1000
`
`100
`
`10
`
`
`.0fife-330733.05.
`
`sou.-9..v
`
`.....’‘'‘fofo‘o_o.._o.o.o.o.o.e.oo0.0..o. 9.0.0to
`'a'o'o’o'o
`g'a'o‘o'oa.’e
`
`-e..{cafefo'n'ph'ofof
`
`
`
`-i.a;
`
`
`
`A
`
`B
`
`C
`
`D
`
`E
`
`F
`
`G
`
`Figure A comparison of doxorubicin. doxombicinol or doxombicin agivcone levels in human skin and soft tissues excised from
`extravasation sites 5 5 months after extravasation oi 24 n-ig.‘51 (two dermis specimens, A and B); 1 month after an extravasation of
`15 mg“ (dermis specimen C]; 1 week after extravasation of 8 mg (subcutaneous tissue specimen 0); 28 days after extravasation of
`an unknown amount of a 5 mglml solution‘51 (specimens E. [central ulcer] and F [peripheral ulcer area]) and 2 weeks after
`extrevesation of an unknown amount of 2.? niglml solution“ (central ulcer area composed of fat and muscle tissue. G).
`
`venous injection.3 A much more realistic figure is the
`0.5% incidence described by Laughlin et 31.5 Perhaps
`the most common local complication from doxo-
`rubicin administration is not extravasation but the
`occurrence of a venous flare reaction.” “ It
`is
`characterized by local edema, venous streaking and
`pruritus over the area of the injection site. This
`reportedly occurs in up to 3% of injections“ and
`generally has a benign outcome. Corticosteroids and
`antihistamines are frequently used either prophylacti-
`cally or to treat a fulminant reaction with equivocal
`results.
`
`the
`For the more serious extravasation injuries.
`typical hailmark is pain and swelling at the injection
`site which is usually quite severe and is not generally
`delayed.1‘s Attendant with this symptomatology is
`the inability to obtain a blood return from the site.3
`In this setting it is imperative that the administration
`of any remaining dcxorubicin solution be disccm
`tinned. While it is recommended to try to ieave the
`needle in place to evacuate extravasated material this
`is generally not productive due to tissue blockage at
`the needle terminus. Nevertheless,
`this procedure
`should
`be
`attempted since
`occasionally,
`large
`amounts of extravasated fluid containing drug can be
`recovereda'” Following attempted evacuation of lo-
`cally extravasated doxorubicin solution, the clinician
`is left with a variety of options for local treatment.
`
`Doxorublcin Antidotes
`
`Glucoccrticosteroids
`
`Glucocorticosteroids, such as hydrccortisone, have
`been advocated as local anthracycline antidotes in a
`number of clinical reports.“3 The underlying phar-
`
`macologic consideration for the use of glucocortico-
`steroids is that some component of doxorubicin
`extravasatiori
`injury involves acute inflammation.
`However. in a rabbit model Luedke et a1 were not
`able to demonstrate a significant acute inflammatory
`reaction in response to ulcerogenic doses of doxorubi-
`cin given intradermally.“ In contrast, in the subcuta-
`neous rat model, Rudolph et al did describe a delayed
`acute inflammatory response in histological sections
`of skin obtained 1 week following subcutaneous
`administration of donorubicin.69 Clearly though, the
`majority of doxorubicin soft tissue damage appears to
`be mediated by direct necrosis. Thus. there is not a
`confirmed histopathologic rationale for glucocortico-
`Steroid use in treating doxorubicin extravasatiorts.
`Despite these Considerations, glucocorticosteroids
`have long been used in the treatment of doxorubicin
`extravasations.
`
`Clinical Cases
`
`Reilly et a1 published an analysis of 10 patients experi-
`encing dcxorubicin extravasation.2 Three patients
`were treated with 100 mg of hydrocortisone and ulcer-
`ation occurred in only 1 patient. All of these extravasa-
`tions occurred on the forearm. In a detailed nursing
`study by Barloclt et al, hydrocortisone was given by 2
`methods to 9 patients experiencing a doxorubicin
`extravasation.3 Importantly, local ice packs were also
`used following these hydrocortisone treatments. No
`ulcers occurred in any of the 9 patients treated with
`hydrocortisone and ice. However, the 100mg hydro~
`cortisone sodium succinate injections used in this study
`did not prevent pain, erythema, a loss of vein patency
`and a limited range of motion in 5 of the 9 patients.
`Three of these latter 5 patients received second intra-
`
`
`
`
`
`
`
`DRUGCONCENTRATION(rig/gwettissue}
`
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`44 ANTIDOTES T0 VESICANT CHEMOTHERAPY EXTRAVASATIONS
`
`dermal or subcutaneous hydrocortisone injections
`around the site for 14' days after the extravasation.
`While this seemed to alleviate some symptoms, it did
`not restore vein patency. Another 4 patients in this
`series were treated with multiple ID. and S.Q. injec-
`tions of hydrocortisone (50—200 mg total) and had no
`local complications. A 1% hydrooortisone cream was
`also applied to the site in these patients twice daily until
`erythema disappeared. Vein patency was preserved in
`these patients and the only residual symptoms involved
`mild tenderness and a brownish skin discoloration
`
`which slowly resolved.3 Thus, aggressive hydrocorti-
`sone treatments appeared to be elfective in this small
`clinical series.
`
`The limited number of patients studied and the
`uncontrolled nature of the extravasation event makes
`
`this report difficult to evaluate. It should also be
`emphasized again that only one third of clinical
`vesicant extravasations may be expected to produce
`ulcers when conservative (non-phannacologic) man-
`agement is used.” Thus, it is unclear if the use of
`hydrocortisone truly impacts on the evolution of
`ulcers following doxorubicin extravasation. However,
`the lack of ulceration in the 9 patients reported by
`Barlock does suggest some antidotal activity for local
`hydrocortisone3
`
`Experimental Studies
`
`In contrast to the paucity of clinical doxorubicin
`extravasation cases treated with glucocorticosteroids,
`a large number of experimental studies are available
`wherein topical or locally injected corticosteroids
`have been tested. In New Zealand rabbits, the potent
`fluorinated corticosteroid triamcinolone (10 mgfml)
`was not able to block subcutaneous doxorubicin
`
`bicin ulceration was produced by 5 mg of intradermal
`hydrocortisone.T5 Of interest, this study also showed
`that multiple hydrocortisone injections were no: more
`beneficial than a single injection. Indeed, the multiple
`injection hydrocortisone regimen actually deepened
`skin ulcers produced by doxorubicin?s In a final
`study, hydrocortisone was shown to be inefl'ective
`against doxorubicin ulceration in rats although early
`surgical excision was highly effective at decreasing
`ulcer size and enhancing ulcer healing.66
`These 7 experimental studies describe inconsistent
`antidotal activity for hydrocortisone as a local doxo-
`rubicin extravasation antidote:
`3 reports describe
`moderate ulcer size reduction with glucocortico-
`steroids;”""“"’5 and 5 reports desoribe no antidotal
`eflects.53'7°'” Conversely, when very high doses are
`used”2 or multiple injections are given,"'5 hydrocorti-
`sone can significantly increase doxorubicin ulcer sizes
`in these experimental settings. In addition, since the
`histopathologic studies of doxorubicin skin ulcers do
`not describe acute inl‘lammation,‘53 the pharmacologic
`rationale for glucocorticosteroid use is unclear. De-
`spite this, hydrocortisone is still suggested as a local
`remedy in the package insert for Adriamycin" (Adria
`Laboratories, Columbus) and low hydrocortisone
`doses given by a single injection, should not increase
`doxorubicin soft tissue damage. Furthermore, hydro-
`cortisone is frequently recommended as a treatment
`for doxorubicin-induced venous flare reactions which
`
`are probably much more common than extravasa-
`tions.‘57 Thus, hydrocortisone may be a useful agent
`to have on hand during doxorubicin administration
`but
`its role as a direct doxorubicin extravasation
`antidote is not established.
`
`Local pH Manipulations
`
`Considerable interest was generated by an anecdotal
`report of the successful
`treatment of doxorubicin
`extravasation (40 mg) using hydrocortisone plus
`8.4% sodium bicarbonate (pl-I 8.15).76 The rationale
`for this treatment has been reported to involve insta-
`bility of the doxorubicin glycosidic bond at an alka-
`line pH. In one animal trial, Wistar rats receiving
`0.6 mg doxorubicin intradermally were partially pro-
`tected from ulceration by an immediate intradermal
`injection of 0.3 ml of 8.4% sodium bicarbonate solu-
`tion.‘H In contrast, a large number of other experi-
`mental studies have described no antidotal efficacy for
`sodium bicarbonate as a doxorubicin antidote in
`
`ulceration?o Similarly, CDF mice given 0.25 mg of
`subcataneous doxorubicin were not protected from
`ulceration by doses of 5—50 mg of hydrocortisone
`sodium succinate or Img of de'itamethasone.71 In
`another study using dehaired BALch mix, a large
`intradennal hydrocortisone dose of 12.5 mg actually
`increased doxorubicin ulceration." A lower ‘interrne-
`diate‘ hydrocortisone dose of 6.25 mg was ineffective,
`but a ‘low’ 2.5 mg dose partially blocked doxorubi»
`cin skin ulceration.” In this same study, neither
`intramuscular hydrocortisone nor daily topical 0.5%
`hydrocortisone cream applications blocked doxo-
`rubicin-induced skin ulcers."2 Another trial studied
`guinea pigs given intradermal doxorubicin. These
`mice," rattan-“film” rabbits"5 and guinea pigs.”
`animals also were not protected from skin ulceration
`In addition, one study has shown that doxorubicin
`by either intradermal or subcutaneous hydrocortisone
`ulcers in rats are consistently produced despite con—
`used at several unspecified concentrations.73
`trolled manipulation of the drug‘s pH over the range
`In contrast, a preliminary study performed in rats
`and mice at Adria Laboratories showed a beneficial
`of 5.5-3.0.“3 Furthermore, sodium bicarbonate is
`itself a known vesicant if extravasated.5°'“ In one
`effect for 0.6 mg of betamethasone (20 mg hydrocorti-
`report, 8 of 11 patients experiencing a bicarbonate
`sone equivalent)“ But in another study, a lower dose
`extravasation required skin grafts to satisfactorily
`of 0.2 mg of hydrocortisone was ineffective in rats
`resolve large areas of soft tissue necrosis. Import-
`given intraderma] doxorubicin.” In Sprague—Dawley
`antly, each of these cases involved the same 8.4%
`rats it was reported that a minor reduction in doxoru-
`____.—p——.__—__-—-—-———-———-—‘-——-——-'—__
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`for treating doxorubicin extravasations.
`
`Hydrocorrtrone~50dium Bicarbonate
`
`Sodium bicarbonate has been combined with hydro-
`cortisone in 2 experimental studies. No antidotal
`efl‘ects were noted for this combination in rats53-75 or
`in mice.12 Indeed, in some studies there was evidence
`of enhanced doxorubicin skin tissue damage follow-
`ing the injection of hydrocortisone mixed with 8.4%
`sodium bicarbonate.”
`
`The experimental studies and the clinical cases of
`severe bicarbonate extravasation injuries clearly dis-
`count any role for sodium bicarbonate as a doxorubi-
`cin antidote. This conclusion has recently been echoed
`in the oncology nursing literature.“I
`
` solution of sodium bicarbonateas was recommended
`
`Antioxidants
`
`Doxorubicin can produce oxygen free-radicals fol-
`lowing enzyme-mediated redox cycling of the quinone
`moiety.83 This is a postulated mechanism of cardio-
`toxicity for the drug” and similar oxidant effects
`could occur
`in doxorubicin-exposed skin tissues.
`Thus, a variety of antioxidants have been tested as
`local antidotes to doxorubicin skin extravasation.
`
`Svingen et al observed substantial antidotal activity
`for the combination of dimethylsulfoxide (DMSO)
`and alpha tocopherol
`(Vitamin E)
`in rat skin.”
`Vitamin E alone however, was found to be ineffective
`in experimental studies in mice“ and rats?“53
`DMSO will be reviewed in depth in a following
`section.
`
`Butylated hydroxy toluene (Bill) is another potent
`antioxidant which is often added to foods and cook-
`
`ing oils to prevent oxidation (rancidity).” Daugherty
`et al were able to show significant reductions in
`doxorubicin ulcer size in mice given BHT." The most
`effective BHT dose was 4 mg per mouse and both ID.
`and topical routes of BHT administration were effec-
`tive. In another study in rats, oral BHT prefeedings
`were able to reduce doxorubicin ulcer sizes."5 This
`
`latter study also showed that hyperbaric oxygen and
`vitamin A did not significantly alter doxorubicin ulcer
`sizes but both BHT and another antioxidant,
`[3-
`carotene, significantly blocked high dose doxorubicin
`lethality."5
`These studies appear to rule out any antidotal
`efficacy for the antioxidant vitamins A and E. The
`consistent antidotal activity of BHT in the animal
`models does suggest that this antioxidant may be an
`effective antagonist to doxorubicin skin ulceration.
`However,
`in both positive studies, BHT did not
`completely prevent skin ulceration.
`In a clinical
`trial, Ludwig et ai have treated 6
`ant-hracycline extravasations with dressings soaked in
`90% DMSO and 10% alpha-tocopherol acetate (vita-
`min E).” These treatments were applied topically
`every 12 h for 2 days and no ulcers were observed.
`
`BLOOD REVIEWS
`
`45
`
`The only side-effect was local skin irritation under the
`dressings manifested by erythema and blisters in 2
`patients. The erythema always resolved promptly
`after stopping the DMSO. In addition, an estimation
`of the amounts of drug extravasated in each case
`(about 3 mg) suggests that some local
`toxic effects
`would have ocCurred in the absence of the DMSO!
`vitamin E treatment.
`
`Beta-adrenergic Agents
`
`Pharmacologic studies in dogs have shown that doxo-
`rubicin releases endogenous histamine and catechola—
`mines following intravenous administration.” These
`chemicals can then act as mediators of doxorubicin
`
`cardiotoxicity. In a mouse skin model, both propra-
`110101 and isoproterenol were shown to reduce doxo-
`rubicin skin ulceration. This effect appeared to be
`specific for BI receptors since it could not be repro-
`duced with the Biz-specific agonist, terbutaline.91 Iso-
`proterenol was also effective in a rat skin toxicity
`model“ and, propranolol has been shown to reduce
`doxorubicin uptake in isolated myocardial cells.92
`The reason for the eflectiveness of opposing fl-adren-
`ergic agents in the mouse is unexplained and in some
`models, neither isoproterenol nor propranolol were
`effective.” This seems to discount a role for B-
`adrenergic agents as local doxorubicin extravasation
`antidotes.
`Antihistamines also have not been effective as local
`
`antidotes to experimental doxorubicin skin ulcers
`including I-I1 antihistamines such as diphenhydramine
`and the H2 antihistamine cirnetidine.91 Because of the
`divergent findings with the fi-adrenergics and the lack
`of efficacy for antihistamines, there does not appear
`to be any role for these agents in managing clinical
`doxorubicin extravasations.
`
`Radical Dimer:
`
`Koch and coworkers have synthesized a series of
`oxornorpholinyl derivatives which can react with qui-
`none-containing drugs to produce inactive bypro-
`ducts.93 These new compounds include the radical
`dimer
`bi5(3,S-dimethyl—5—hydroxymcthyl~2—oxo-
`morpholin—3—yl) or DHM3 which reduces anthracy~
`clines such as doxorubicin to insoluble (and inactive)
`'i—deoxyaglycone metaliolites.”3 DHM3 has been
`shown'to protect animals from acute doxorubicin
`lethality.9“-95 In addition, the radical dimer DHM3
`has been injected into pigs given [1). doxorubicin
`with significant (80%) reductions in the average size
`of skin ulcers.95 In this study, a 10-fold molar ratio of'
`DHM32doxoruhicin was required for maximally effi-
`cacy. Importantly, DHM3 alone was non—toxic in the
`ID. pig skin model.95
`In addition to doxorubicin, DHM3 can also reduce
`skin ulcers in pigs given other I.D. vesicants, includ-
`ing daunorubicin, menogaril, idarubicin, epirubicin,
`5-irninodaunorubicin, aclarubicin and mitomycin
`
`
`
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`46 ANTIDOTES T0 VESICANT CHEMOTHERAPY EXTRAVASA'I'IONS
`
`C.“ DHM3 has also been shown to be effective
`against doxorubicin-induoed skin ulcers in the mouse
`model (Dorr, unpublished observations). However,
`the radical dimer DHM, is not active against some
`vesicant drugs including vinblastine and mitoxan—
`trone.
`
`Mechanistic studies with anthracycline extravasa-
`tions in pigs further suggest that skin toxicity with
`quinone-containing agents like doxorubicin may in-
`deed be associated with the reductive formation of
`
`highly reactive quinone methide radicals at critical
`cellular sites of damage.“ Thus, an agent such as
`DHM3 may rapidly reduce anthracyclines to inactive
`aglycones.” Cellular alkylation by quinone methides
`may explain the greater degree of skin toxicity seen
`with anthracyclines such as 5—iminodaunorubicin
`which do not form oxygen free-radicals, but which do
`form quinone-methide intermediates much more
`easily than other vesicant anthracyclines.“
`These novel radical dimers have demonstrated con-
`
`sistent antidotal activity against experimental doxo-
`rubicin skin ulcers. They appear to produce little
`intrinsic toxicity.
`Importantly, unlike other ‘anti-
`dotes’, the radical dimers have a well defined specific
`mechanism of action, namely chemical reduction of
`vesicant quinone anticancer agents to inactive meta-
`bolites. DHM3 should be considered for immediate
`
`clinical testing as orphan drugs with indications in the
`emergency treatment of common vesicant extravasa-
`tions.
`
`Dimethylsuéfoxide
`
`Dimethylsulfoxide (DMSO) has a number of biologic
`characteristics which make it an attractive potential
`local antidote to doxorubicin. First, DMSO is known
`to enhance skin permeability which might facilitate
`systemic absorption of an extravasated vesicant
`drug.91 Second, DMSO has free-radical scavenging
`activities. This can prevent DNA damage from oxy-
`gen free-radicals which might be produced by drugs
`such as doxorubicin.” Several experimental and clini-
`cal trials have tested this hypothesis.
`
`Experimental DMSO Studies
`
`Desai et al have reported complete protection against
`doxorubicin-induced skin ulcers using DMSO in both
`Sprague Dawley rats and in Yorkshire piglets.”
`DMSO was applied topically for 1’ days (0.6 ml of a
`100% solution). In this trial,
`topical DMSO also
`prevented ulcers from developing at distal, untreated
`doxorubicin injection sites. In another study using
`Sprague-Dawley rats, a combination of DMSO and
`10% alpha-tocopherol decreased doxorubicin skin
`ulcers by almost 70%.“ The maximally efl'ective
`regimen involved topical administration of 0.] ml of
`the vitamine EJDMSO mixture for 2 days. While
`alpha-tocopherol sutxzinate was shown to be more
`active than the acetate or alcohol forms, no Vitamin E
`
`preparations were active in the absence of DMSO.“
`In guinea pigs. topical DMSO and 50% alpha-toen-
`pherol were effective at reducing but not preventing
`I.D. doxorubicin skin ulcers.“Jo The dose of doxo-
`rubicin was shown to be critical in this study since
`topical DMSO with alpha-toeopherol could not sub-
`stantially reduce lesion sizes from doxorubicin doses
`greater than 0.05 mg.
`In contrast to these studies, several negative trials
`of DMSO audior alpha-tocopheryl are also reported.
`In the Yorkshire piglet, DMSO did not significantly
`reduce doxorubicin ulceration.101 In this same study
`alpha-toeopherol (50 units 1.0.) was shown to actu-
`ally enhance doxorubicin skin ulcers. Similarly, Har-
`wood et a1 could not demonstrate efficacy for a 7-day
`topical DMSO regimen as an antagonist to doxorubi-
`cin skin ulcers in pigs.102 A 14-day topical DMSO
`regimen had limited efficacy but was inferior to simply
`cooling the site with ice.”2 Finally, no antidotal
`effects were noted in mice receiving topical DMSO
`andfor alpha-tocopherol in a mouse model.“
`
`Clinical DMSO Reports
`
`The use of DMSO in the clinic has been described
`
`anecdotaliy in several cases in which different poten-
`tial antidotes were combined. In 1 case, a 10mg
`daunorubicin extravasation in a 42-year-old man was
`treated with sodium bicarbonate, dexamethasone
`{4 mg), ice packs and topical DMSO?” The DMSO
`regimen used 1.5 ml of a 70% solution which was
`applied to the site every 3—4h for 10 days (a total
`dose of 90 m1). Pain relief and the prevention of ulcer
`formation were described for this patient. In another
`case, a 4—6 mg doxorubicin extravasation in a 49-
`year-old man was treated with 5 ml of 8.4% sodium
`bicarbonate, ice packs and DMSO (99%, analytical
`grade).103 The DMSO was applied daily for E4 days
`and while ulceration did not occur, a 3x25 cm
`indurated area limiting elbow extension remained.
`Another patient treated with sodium bicarbonate, ice
`and DMSO had only residual pigmentation in the
`extravastion area with no functional impairment. In
`this trial the DMSO was applied every 6 hours for 1
`week, then twice daily for another week. A similar
`outcome was described in a third patient receiving
`only ice and the identical DMSO regimen.‘°"
`These observations presaged a larger non-random-
`ized clinical
`trial
`in 20 patients receiving topical
`DMSO for doxorubicin extravasations.1°5 In this
`trial, 99% DMSO was applied twice to the apparent
`extravasation area, 6 times daily for 2 weeks. Doxo-
`rubicin (l8 cases) or daunorubicin (2 cases) were the
`vesicant anthracyclines studied at 2 institutions. No
`open ulcers were described following DMSO treat-
`ment although initial swelling, erythema and pain
`were evident in 85%, 75% and 60% of this popula-
`tion, respectively. At least 3 months of follow-up were
`available for 16 patients and there were no symptoms
`in 6 (38%) and only pigmented induration in 10
`
`
`
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`BLOOD REVIEWS 47
`
`(63%). DMSO toxicities primarily involved a [ran-
`sient burning sensation with urticaria and erythema
`during application. In addition, 6 patients described
`the characteristic garlic odor on their breath.
`These results suggest that topical DMSO may have
`antidotal activity against anthracycline-induced skin
`ulceration. It
`is still unclear what pharmacologic
`mechanism is involved. The inactivity of DMSO in
`some studies using both rodents and pigs, cautions
`that DMSO’s antidotal efficacy may be limited, or
`even artifactual. In this regard,
`the low degree of
`toxicity and the recently reported clinical trial clearly
`argue for broader studies of topical DM 50 in treating
`anthracycline extravasations. However, the lack of a
`medically approved topical DMSO dosage form is a
`problem. Currently, only the formulation available is
`a 50% (vollvol) DMSO solution in water. This prod-
`uct has an official indication limited to the intravesi-
`
`cular treatment of recurrent cystitis {Package Insert
`Rimso-SO, Research Industries. Salt Lake City). This
`is unfortunate since the enhancement in percutaneous
`drug absorption by DMSO is only produced with
`highly concentrated DMSO solutions
`(generally
`390%). Nonetheless, it is possible that DMSO may
`be acting as a vesicant antidote by other mechanisms
`such as free-radical scavenging or by anti-inflamma-
`tory or vasodilatory effects.“ Certainly the most
`attractive hypothesis is enhanced percutaneous ab-
`sorption of anthracyclincs since it
`is known that
`anthracycline skin ulcers are associated with pro—
`longed local drug retention.‘51 Pharmacokinetic
`studies of doxorubicin disposition in skin tissues
`treated with topical DMSO could test this hypothesis
`and might additionally suggest better topical regi-
`mens for the clinic.
`
`Hear Versus Cold
`
`Chemical phlebitis is often managed by the applica-
`tion of warm compresses to the effected area. The
`rationale for this treatment involves increased blood
`flow to the area with a resultant enhanced resolution
`
`of pain and a resorption of local swelling. In contrast,
`topical cooling can act to shunt blood flow away from
`an area and reduce cellular metabolism. Local hypo-
`thermia is now well recognized as
`technique to
`prevent
`doxombicin-induccd
`scal
`alopecia
`in
`patients with solid tumorsms'm" Thus,
`there are
`divergent rationale for the use of local heating or
`cooling to manage doxorubicin extravasations.
`In a controlled trial of heating versus cooling in
`mice, topical skin cooling from a normal of 38°C to
`l?°C produced marked reductions in doxorubicin~
`induced ulceration. “’3 In contrast, mild heating of the
`skin to 43—44°C resulted in a significant increase in
`doxorubicin-induced skin ulcersma Indeed, the ad-
`dition of heat to intraderrnal doxoruhicin resulted in
`
`lethality from otherwise non—lethal doses of the
`drugm‘ Similar synergistic efi'ects from heat and
`doxorubicin are also described in tumor cells.1°E"m9
`
`these eli'ects are not limited to the
`Importantly,
`mouse model. In the pig, topical cooling was found to
`be much more effective than DMSO as a local
`
`doxorubicin extravasation antidote.”2 In addition,
`many of the ‘positive‘ clinical anecdotes regarding
`doxorubicin extravasation management have in-
`volved the application of topical cooling with other
`agents-251102.104
`Topical cooling does not appear to reduce doxo-
`rubicin skin concentrations in vivo.108 Rather,
`the
`antidotal effect may relate to critical phase transition
`states in cell membrane lipids.1 1° For example, the in
`vitro studies have shown that tumor cell cytotoxicity
`from doaorubicin is markedly reduced when temper-
`atures are less than 25°C. This effect appears to be due
`to a change in the fluidity of the plasma membrane
`rendering cells insensitive to doxorubicin lethality. ‘ '0
`In summary, cooling clearly provides significant pro-
`tection from doxorubicin cytotoxicity and this should
`comprise a mainstay of doxorubicin extravasation
`management.
`
`Daunorubiciu
`
`Like doxorubicin, daunorubicin is a well known
`ia'esic‘artt.9“”'26 Most clinical reactions are not