June
2007, Volume 11, Number 3
Feature
Article
Totect™: A New Agent for Treating Anthracycline Extravasation
Lisa Schulmeister,
RN, MN, APRN-BC, OCN®, FAAN
Anthracycline chemotherapy agents bind to DNA and cause cell death when they extravasate into healthy tissue. Although many approaches
to managing extravasations have been studied and reported, data from two
prospective clinical trials suggest that Totect™ (dexrazoxane for injection, TopoTarget
USA, Inc.) is an effective anthracycline extravasation treatment. Only 1 of 54 patients with
doxorubicin or epirubicin biopsy-confirmed
extravasations treated with Totect developed tissue
necrosis. Because nurses are on the forefront of extravasation
prevention and management, they need to be knowledgeable about this new agent
and how it is administered.
At A
Glance
·
Totect™ (dexrazoxane for injection, TopoTarget
USA, Inc.) is indicated for the treatment of anthracycline
extravasation.
·
Totect is
administered via IV daily for three days into a large vein that is not in or
near the extravasation area. Topical cooling and
other extravasation treatment (e.g., dimethyl sulfoxide) should not be
used during treatment with Totect.
·
Totect must be
administered as soon as possible and within six hours of the anthracycline extravasation.
Extravasation of vesicant chemotherapy agents causes varying degrees of
tissue damage and a variety of complications. The extent of damage is
influenced by the type of vesicant that extravasates
(e.g., DNA binding or nonbinding), the concentration and amount of the vesicant
in the tissue, the location of the extravasation, and
various patient factors. Vesicants that bind to nucleic acids in DNA (e.g., anthracyclines) bind to DNA in the cells of healthy tissue
when they extravasate from the vein and promptly and
directly cause cell death. DNA-anthracycline
complexes released from dead cells in the tissue spread to adjacent healthy
cells by endocytosis. This process of cellular uptake
of extracellular substances creates a continuing
cycle of tissue damage as the DNA-binding vesicant remains in the tissue for a
prolonged period of time and is essentially “recirculated”
in the surrounding healthy tissue (Luedke, Kennedy,
& Rietschel, 1979; Mross,
van der Vijgh, Gall, Boven, & Pinedo, 1988).
Consequently, these extravasation injuries become
larger in size, deeper in depth, and more painful over time.
Vesicants
that do not bind to DNA (e.g., plant alkaloids) have an indirect rather than a
direct effect on the cells in healthy tissue when they extravasate.
Non–DNA-binding vesicants eventually are metabolized in the tissue and are
neutralized more easily than DNA-binding agents (Ener,
Meglathery, & Styler,
2004). This type of extravasation injury generally
remains localized, is mildly to moderately painful, and improves on its own
over time.
Vesicant
extravasation injuries in areas of flexion, such as
the wrist and elbow, or in areas with minimal overlying tissue, such as the
dorsum of the hand and wrist, tend to be greater in their severity when
compared to extravasation injuries in other areas,
such as the forearm. Vesicant extravasations from deeply implanted ports may
cause significant damage to the anterior chest wall and breast tissue (see Figure 1). Patient factors, such as older or
very young age, comorbidity (e.g., diabetes), and immunosuppression, may influence the severity of extravasation injuries and patients’ response to treatment
of these injuries (Ener et al., 2004; Goolsby & Lombardo, 2006; Sauerland,
Engelking, Wickham, & Corbi, 2006; Schulmeister & Camp-Sorrell,
2000).
Vesicant
extravasations may cause partial- or full-thickness skin loss.
Partial-thickness tissue injuries penetrate the epidermis and may extend into
the dermis. The injuries often heal by epithelialization,
whereby epithelial cells migrate from the wound edges to resurface the wound.
The wounds usually are moist and painful because of the loss of skin covering
and exposure and irritation of nerve endings. Full-thickness tissue injuries
extend beyond the dermis into the subcutaneous tissue. They may involve
muscles, tendons, and sometimes bone and take longer to heal than
partial-thickness tissue injuries. The wounds may heal by filling with
granulation tissue, contraction, and epithelialization
from the wound edges but may require surgical intervention (see Figure 2). Some patients have required
extensive surgical debridement necessitating skin
grafting or myocutaneous flap placement. In a few
cases, vesicant extravasation has led to septicemia,
permanent nerve loss, joint stiffness and contractures, and the development of
compression syndrome (Ener et al., 2004; Schulmeister & Camp-Sorrell, 2000).
One
aspect of vesicant extravasation management that has
received little attention in the literature is the effect of extravasation injury on patients’ emotional health and
well-being. Most patients who experience an extensive extravasation
injury become distressed at some point during extravasation
treatment. In many cases, further chemotherapy treatment must be delayed. Some
patients are worried that their cancer will recur or progress while their
chemotherapy is on hold, which is a legitimate concern. In several cases,
patients who experienced a severe extravasation
injury changed healthcare providers and some pursued legal action (Schulmeister, 2005; Schulmeister
& Camp-Sorrell, 2000).
The
cost of treating extravasation injuries is unknown.
Direct costs, such as those associated with multiple hospitalizations, home
health care, physical therapy, and care provided by specialists (e.g., plastic
surgeons), in one case were estimated to exceed $450,000 (Westlaw, 2006).
Indirect costs, such as lost work revenue, payments for in-home assistance, and
costs associated with traveling for specialized wound care, also may be
significant.
Extravasation
Management
In
many cases, vesicant extravasation is preventable (Sauerland et al., 2006; Schrijvers,
2003). However, despite nurses’ best efforts, extravasations sometimes occur.
Nurses play a major role in preventive efforts because they are responsible for
vesicant administration in most treatment settings. Nurses therefore must be
knowledgeable about vesicant chemotherapy administration and extravasation prevention, detection, and management.
Vesicant
extravasation management recently has been reviewed
by several authors (Ener et al., 2004; Goolsby & Lombardo, 2006; Schrijvers,
2003; Wickham, Engelking, Sauerland, & Corbi, 2006).
The literature that forms the basis of the reviews is mostly comprised of
anecdotal reports and small clinical study findings; consequently, evidence is
lacking to guide extravasation management. As noted
by Wickham et al., “Most suggestions to use local
comfort measures, local antidotes, debridement, or
other surgical interventions remain empirical and controversial” (p. 1143).
Anthracycline Extravasation
Although
extravasation of any vesicant has the potential to
cause tissue damage, anthracycline extravasations
seem to have the most potential to cause severe damage. Case reports of doxorubicin
extravasation injuries were first reported in 1976
(Rudolph, Stein, & Pattillo, 1976). At that time,
doxorubicin typically was administered via steel winged (“butterfly”) needles
inserted into peripheral veins, often in the dorsum of the hand. Early reports
noted that doxorubicin infiltration into subcutaneous tissues caused “ulcers
filled with shaggy necrotic yellowish debris” (Rudolph et al., p. 1093), which
often were accompanied by an intense local inflammatory response that
progressed to full-thickness skin loss and irreversible damage to underlying
tendons and neurovascular structures (Reilly, Nei-feld,
& Rosenberg, 1977). In 1978, Bowers and Lynch observed that doxorubicin extravasation injuries “develop at a slow rate, continue to
increase in severity for several weeks, and do not heal in the usual manner”
(p. 86).
Additional
case reports documented that spontaneous healing rarely occurred and surgical
excision of the involved tissues usually was required (Barden,
1980; Mehta & Najar, 1978; Reilly et al., 1977).
Split-thickness skin grafting often was needed as well, especially if tissue
necrosis extended down to the extensor tendons of the hands. The periosteum overlying the metacarpals frequently was
involved, which presented a treatment dilemma because a skin graft is unable to
survive on bare cortical bone. In those instances, pedicle skin flaps were
required to cover the area of injury (Bowers & Lynch, 1978; Laughlin, Landeen, & Habal, 1979).
Since
the late 1970s, researchers have studied various treatments and antidotes for
managing anthracycline extravasations and clinicians
have reported their anecdotal experiences with various treatment modalities.
Treatments that have been studied or reported include topical cooling, saline lavage and suction, hyperbaric oxygen, topical negative
pressure, and administration or application of growth factors, free radical
scavengers (e.g., dimethyl sulfoxide
[DMSO], ginkgo biloba extract, alpha-tocopherol), and various pharmacologic agents. Current
practice for managing anthracycline extravasation varies; from 1976–2007, early surgery with debridement, saline lavage and
suction, and topical application of DMSO reportedly have been used more often
than other treatments. Topical cooling with ice is recommended and frequently
used as an initial treatment for anthracycline extravasation (Ener et al., 2004;
Goolsby & Lombardo, 2006; Schrijvers;
2003; Wickham et al., 2006).
Antidotes
and Treatments
Much of
the research on anthracycline extravasation
treatment has focused on the efficacy of antidotes. In an early study, local
injections of alpha-tocopherol (vitamin E), cimetidine, diphenhydramine,
heparin, hyaluronidase, lidocaine,
and N-acetylcysteine were found to be ineffective in
reducing doxorubicin-induced ulceration in mice. Two opposing beta-adrenergic
compounds, the antagonist propranolol and agonist isoproterenol reduced but did not prevent ulceration,
suggesting that the beta-adrenergic receptor played a role in mediating
doxorubicin-induced tissue necrosis (Dorr & Alberts,
1981). When alpha-tocopherol, amifostine,
merbarone (a catalytic inhibitor of topoisomerase II), aclarubicin
(an antitumor antibiotic), ethylenediamine
tetra-acetic acid (a chelating agent), dexrazoxane,
and ADR-925 (a product of dexrazoxane hydrolysis)
were studied as antidotes for doxorubicin extravasation
injuries in mice, only dexrazoxane was found to be
effective in preventing tissue necrosis (Langer, Sehested,
& Jensen, 2001).
Dexrazoxane is a metal ion chelator that
protects against the free radical toxicity induced by formation of anthracycline-iron complexes. Dexrazoxane
is believed to provide protection from free radical damage by binding and thus
concealing iron from oxygen. Another proposed mechanism of action is that it is
a catalytic inhibitor; anthracyclines increase levels
of topoisomerase II–mediated cleavage, which cause
DNA strand breaks (Andoh & Ishida, 1998;
Hellmann, 1998). Dexrazoxane’s activity in protecting
tissue from anthracycline extravasation–induced
injury may be because of its ability to scavenge free radicals, its effect on
the catalytic cycle of topoisomerase II, a combined
effect, or additional mechanisms (Langer et al., 2000a).
When
mice were subcutaneously injected with 2 mg/kg of doxorubicin and treated with
varying doses of dexrazoxane (125, 250, or 375 mg/kg)
at varying times (concurrent with doxorubicin or three or six hours afterward),
concurrent dexrazoxane treatment reduced the number
of mice with wounds from 88% to 21% (Langer et al., 1999). In another study,
mice were injected with the anthracyclines daunorubicin, doxorubicin, and idarubicin
and various doses of dexrazoxane were either infused
via IV or injected into the intraperitoneal space at
various times (immediately following, three or six hours later, or on days 1
and 2). Significant reduction in ulcer frequency, size, and duration was
observed when dexrazoxane was administered up to six
hours after injection. Triple treatment (administered at the time of anthracycline injection and repeated three and six hours
later) prevented ulcers from occurring. The results led to the following
clinical practice changes at the researchers’ hospital (National University
Hospital, Copenhagen, Denmark): (a) Administration of anthracyclines
via a central venous access device now is optional rather than mandatory, and
(b) anthracycline extravasations are treated with
prompt surgical evaluation, and dexrazoxane 1,000
mg/m2 IV is administered within six hours of the extravasation
and repeated on day 2. On day 3, a dexrazoxane dose
of 500 mg/m2 is given (Langer et al., 2000b).
In 2000,
Langer, Sehested, Jensen, Buter,
and Giaccone published a letter to the editor in the Journal
of Clinical Oncology in which they described the efficacy of dexrazoxane in treating two anthracycline
extravasations. A woman with breast cancer experienced an extravasation
of an estimated doxorubicin dose of 149 mg, which occurred as a result of
needle displacement from an implanted port, and was treated with the dexrazoxane protocol previously mentioned. A second patient
with breast cancer had a 7 x 11 cm epirubicin extravasation (verified by fluorescence microscopy, which
confirms that an extravasation did occur) in her
forearm and was treated with dexrazoxane. Tissue
necrosis did not develop in either patient, and both were able to resume
chemotherapy after a one-week delay. Both patients experienced mild leukopenia (Common Toxicity Criteria grade 2) and transient
elevation of liver transaminases (twice the upper
limit of normal for < 7 days). No sequelae were
observed at the three-month follow-up examinations of the patients (Langer et
al., 2000). In 2003, oncologists in
In a
case report from
In
Although
DMSO was applied concurrently to the extravasations that were reported in
From
July 2001–August 2005, 79 patients with 80 peripheral anthracycline
extravasations were enrolled in two prospective, open-label clinical trials of dexrazoxane (one patient had two extravasations occur in an
eight-day period). The first study enrolled patients from 10 cancer centers in
Denmark, and the second study enrolled patients from 24 centers in Denmark,
Germany, Italy, and the Netherlands. Anthracycline extravasation was verified by fluorescence microscopy of
patients’ tissue biopsies. Fifty-four patients were evaluable;
13 of the 25 patients who could not be evaluated had negative biopsies (which
indicate that although an extravasation was
suspected, it did not occur), 4 did not have biopsies performed, and 8 others
were excluded for protocol violations, cases that could not be reviewed,
patients who received concurrent treatment, and late enrollments in the study.
Patients ranged in age from 34–81 years (mean = 56 years). Seventeen of the
patients were male (31%), and 37 were female (69%). The most common cancer
diagnosis among the patients was breast cancer (50%), followed by lymphoma
(39%), and other types of cancer (9%). Patients experienced extravasations of
doxorubicin (n = 23) or epirubicin (n = 31). The mean
extravasation area was 23.6 cm2 in the
first study and 39 cm2 in the second study. Eleven patients had
areas of extravasation exceeding 75 cm2.
Symptoms experienced by the patients in both studies are listed in Table 1. All patients received dexrazoxane for three consecutive days, with a dose of
1,000 mg/m2 on days 1 and 2 and a dose of 500 mg/m2 on
day 3. None of the 18 evaluable patients in the first
study and only one of the 36 evaluable patients in
the second study had tissue necrosis occur (overall efficacy = 98%). A
doxorubicin extravasation prior to and following dexrazoxane treatment is shown in Figure 3. In the clinical trial studies, the
patient who developed tissue necrosis had a very large area of doxorubicin extravasation measuring 253 cm2. Tissue necrosis
began to occur nine days following the extravasation
and was surgically excised. Most of the patients (71%) were able to receive
further chemotherapy treatment on schedule. Treatment sequelae
included mild pain (19%) and mild sensory disturbances (17%) at the extravasation site (Giaccone,
2006; P. Knoblauch, December 22, 2006, personal
communication; Mouridsen et al., 2006a, 2006b).
Marketing authorization of dexrazoxane (Savene™, TopoTarget A/S) as a
treatment for anthracycline extravasation
in
Totect
Administration
Totect is indicated for the treatment of anthracycline
extravasation. It is packaged in a kit that contains
10 vials of Totect powder and 10 vials of Totect diluent solution. Each
vial of Totect powder contains 500 mg of dexrazoxane hydrochloride. After reconstitution with Totect diluent, supplied in the
kit in 50 ml vials, the concentration of Totect is 10
mg/ml. Totect is administered once daily for three
consecutive days. The first infusion needs to be initiated as soon as possible
and within six hours of the anthracycline extravasation. The patient’s body surface area is used to
calculate the dose of Totect, and a single dose of Totect should not exceed 2,000 mg. The dose of the first
infusion (day 1) is 1,000 mg/m2. On day 2, as close as possible to
24 hours following the time the day 1 dose was given, a second dose of 1,000
mg/m2 is administered. On day 3, a dose of 500 mg/m2 is
given. The Totect dose should be reduced 50% in
patients with creatinine clearance values less than
40 ml per minute. Totect has a
biphasic elimination; the mean initial elimination half-life is
approximately 30 minutes, and the mean terminal elimination half-life is 2.8
hours. In in vitro studies, none of
the five major cytochrome P450 isoenzymes
was inhibited by Totect, which suggests that
significant metabolism via this cytochrome is
not likely. Detailed administration guidelines are described in Figure 4 (TopoTarget
USA, Inc., 2007).
Totect is only effective for treating anthracycline extravasation. It is not effective, nor indicated, for
treating other types of extravasations, such as extravasation
of plant alkaloids (e.g., vinblastine, vincristine, vinorelbine), taxanes (e.g., paclitaxel, docetaxel), or alkalating agents
(e.g., mechlorethamine [commonly known as nitrogen
mustard], platinum analogs).
Implications for Practice
Nurses
are integral in preventing and managing anthracycline
extravasation. They usually are the first to detect that
an extravasation may have occurred and need to be
well informed about how to best proceed once an extravasation has been identified. With the introduction of
Totect, healthcare providers have yet another option
for treating anthracycline extravasations.
Although
the efficacy data are compelling, both of the clinical trials of the agent were
conducted on patients with peripheral anthracycline
extravasations. In the published clinical trials report, none of the evaluable patients in either trial had an extravasation from an implanted port or central venous
catheter (CVC) (Mouridsen et al., 2006b). Published
data on response in patients with extravasations from implanted ports are
limited to two case reports. As noted previously, neither patient developed
tissue necrosis (El-Saghir et al., 2003; Langer et
al., 2000).
Nurses
will be instrumental in collecting further data about the efficacy of Totect, especially in patients with extravasations from
implanted ports or CVCs. Nurses also need to be
familiar with this new agent and able to respond to questions they may be asked
about it (see Figure 5). Because Totect is a nurse-administered treatment, nurses have an
instrumental role in ensuring that it is given safely and correctly. Totect must be administered as soon as possible and within
six hours following the extravasation. Totect is an IV treatment; therefore, in most cases, nurses
will insert an IV device to administer the agent. Nurses also need to check the
expiration date (Totect is an agent that hopefully
will rarely—or never—be used) and calculate or verify the doses of Totect that need to be administered daily for three days.
Depending on the institution, nurses may be responsible for reconstituting and
preparing Totect in addition to administering it or
may need to develop policies and procedures with pharmacy staff to ensure that Totect is promptly prepared and the first dose is
administered within six hours of extravasation.
Nurses also need to teach patients about Totect and
monitor response to treatment. Lastly, nurses must document the extravasation and its management and coordinate patient
follow-up.
Nurses
must continue to administer anthracyclines with great
care. The availability of Totect to treat anthracycline extravasation does
not negate the need for extravasation prevention
efforts. When confronted by situations in which the placement or patency of an IV device is questionable, nurses should not
proceed with anthracycline chemotherapy simply because
an extravasation treatment is available. In addition,
patient monitoring should not be any less vigilant. Instead, nurses need to
continue to use due diligence when administering anthracyclines
(and all other vesicants) and monitoring patients receiving vesicant
chemotherapy.
Summary
Vesicant
extravasations are best prevented; however, prevention is not always possible. Anthracycline extravasations historically have been, for
the most part, managed by topical cooling and a variety of other measures, such
as early surgery, saline lavage, and DMSO
application. Unfortunately, none of these measures has clearly demonstrated
efficacy. Totect, introduced in 2007, is packaged as
an extravasation management kit. Clinical trial data
support the efficacy of Totect as an anthracycline extravasation
treatment. Nurses need to be aware of this new treatment and prepared to safely
administer it if an anthracycline extravasation
inadvertently occurs.
The
author gratefully acknowledges Poul Knoblauch and TopoTarget A/S,
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Lisa Schulmeister,
RN, MN, APRN-BC, OCN®, FAAN, is an oncology nurse consultant in
River Ridge, LA. No financial relationships to
disclose. Mention of specific products and opinions related to those products
do not indicate or imply endorsement by the Clinical Journal of Oncology Nursing or the Oncology Nursing
Society. (Submitted December 2006. Accepted
March 2, 2007.)
Author
Contact: Lisa Schulmeister, RN, MN, APRN-BC, OCN®, FAAN, can
be reached at LisaSchulmeister@hotmail.com,
with copy to editor at CJONEditor@ons.org.
Digital Object Identifier: 10.1188/07.CJON.387-395
