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US Pharm. 2008;33(1):10-18.
ABSTRACT: Despite
advancements in chemotherapy treatments, dermatologic complications continue
to be associated with chemotherapeutic agents. These adverse effects include
alopecia, hyperpigmentation, nail changes, palmar-plantar erythrodysesthesia,
extravasation, and radiation reactions. This article reviews the general
dermatologic adverse effects of chemotherapeutic agents and discusses their
pharmacologic and nonpharmacologic management.
Chemotherapy has been proven
efficacious for the treatment of cancer; however, these treatments are often
associated with serious toxicities. Chemotherapeutic agents generally target
rapidly dividing cells and consequently are toxic to organ systems with high
metabolic rates, such as bone marrow, hair, nails, skin, and the
gastrointestinal mucosa. Adverse effects associated with chemotherapy such as
myelosuppression, chemotherapy-induced emesis, diarrhea, mucositis, and
stomatitis are well appreciated in the literature. However, there is a paucity
of data and guidelines for the management of dermatologic toxicities. Despite
much advancement in chemotherapy, dermatologic complications continue to be
associated with both older and newer chemotherapeutic agents. The dermatologic
toxicities may be the most psychologically detrimental and have been shown to
have a major negative impact on quality of life, specifically when treating
women's cancers.1 Dermatologic toxicities of chemotherapy often
include alopecia, pigment and nail changes, palmar-plantar erythrodysesthesia
(PPE), chemotherapy-induced extravasation (CIE), radiation recall, and
photosensitivity.
Chemotherapy-Induced
Alopecia
Terminal hair follicles with the
most rapid hair matrix formation, such as those on the scalp, are affected
more than slower growing hair such as eyebrows, eyelashes, axillary, and pubic
hair.2 Hair growth occurs in three separate phases during the hair
life cycle: the anagen, telogen, and catagen phases. During the anagen phase,
hair undergoes mitotic changes and rapid cell growth. In the telogen phase,
hair is dormant and mitotic activity is arrested. The telogen phase lasts from
three to six months. In the final catagen phase, the hair root is separated
from the hair bulb, pigment storage is terminated, and the club-shaped root
end is pushed out from the bulb. Less than 1% of hair is in the catagen phase
at any time.2,3 Chemotherapy-induced alopecia frequently occurs
during the anagen phase, which results in suppression of cell production and
thinner, more brittle hair. This affect is typically seen within two to three
weeks of therapy and resolves within two to three months of discontinuation of
treatment, often noted with a change of hair color and texture.4,5
Another mechanism by which chemotherapy can induce alopecia involves the
transition between anagen and telogen. Hair breakage is caused by the hair
being prematurely forced into the telogen phase. Examples of chemotherapeutic
agents that are associated with hair loss are listed in TABLE 1.
Minoxidil:
Topical minoxidil 2% is the only pharmacologic agent that has been studied in
the treatment of chemotherapy-induced alopecia. Minoxidil is a pyrimidine
N-oxide used as an antihypertensive agent when administered orally and for
male-pattern baldness when used topically. Minoxidil modifies hair cycle
dynamics, by prolonging the anagen phase as demonstrated in the animal model.
6 Minoxidil 2% was ineffective for the treatment of chemotherapy-induced
alopecia in past studies.5,7 However, a randomized,
placebo-controlled study of 43 female cancer patients receiving
doxorubicin-based chemotherapy investigated the use of topical minoxidil 2%
applied twice daily starting 24 hours before the first course of chemotherapy.
8 Minoxidil 2% did not prevent alopecia; however, it significantly
decreased the duration of alopecia.8 Clinicians may use topical
minoxidil prophylactically to reduce the length of time that patients are
exposed to this aesthetically displeasing effect of chemotherapy.
Scalp Tourniquets:
Scalp tourniquets temporarily occlude, by pressure, superficial blood vessels
that supply the scalp, which can minimize drug contact with hair follicles.
9 The scalp tourniquet is inflated 10 mm Hg above the patient's systolic
blood pressure to occlude superficial scalp circulation. The tourniquet should
be applied when plasma drug levels are highest, e.g., during the last 10
minutes of infusion and for 10 minutes after it is stopped. Scalp tourniquets
are not recommended for use in leukemias or lymphomas, due to the risk of
metastases. The most common adverse effect is scalp numbness. A randomized,
controlled study investigating the use of tourniquets found that they were
ineffective in treating chemotherapy-induced alopecia.10
Scalp Hypothermia:
Scalp hypothermia prevents chemotherapy-induced alopecia by two mechanisms:
1) it causes vasoconstriction and reduces the blood flow to hair follicles
during peak plasma concentrations of the chemotherapeutic agents, thus
reducing cellular uptake; and 2) it reduces biochemical activity, which makes
hair follicles less susceptible to the damage of chemotherapeutic agents.
11 Scalp cooling procedures are done by use of an ice or cold gel cap.
The most common adverse effects are headaches, complaints of coldness, and/or
uncomfortable sensations. Scalp cooling is contraindicated in cases of cold
sensitivity, cold agglutinin disease, cryoglobulinemia, cryofibrinogenemia,
and hematological malignancies. Cancers with a high prevalence of scalp
metastases (i.e., leukemia and lymphoma), carry a risk of cancer recurrence on
the scalp, when using cooling methods to prevent hair loss.12,13†
This is due to a reduction of drug delivery to the scalp, which allows cancer
cells to thrive.
Several randomized controlled
studies have shown that scalp cooling resulting in a reduction of alopecia is
both statistically and clinically significant.14-17 No distinct
method of scalp cooling has been described; however, a cooling time of
approximately 90 minutes postinfusion has been suggested.17 Liver
dysfunction or the presence of liver metastasis was related to less benefit in
several nonrandomized trials.18-20 Although more efficacious, scalp
cooling is associated with more adverse effects than scalp tourniquets. Prior
to using scalp tourniquets or scalp hypothermia therapy, careful screening
must be conducted by clinicians to prevent any long-term adverse effects.
Chemotherapy-Induced
Hyperpigmentation and Nail Changes
Pigment
Changes: Hyperpigmentation is a common cutaneous adverse effect
of cancer chemotherapeutic agents. Hyperpigmentation can occur locally at the
site of infusion or diffusely.2 The nails, mucous membranes, and
teeth have all been reported sites of discoloration.2 Some of the
mechanisms of chemotherapy-induced hyperpigmentation that have been postulated
include: 1) drug deposition in certain areas that subsequently lead to
increased pigmentation; 2) direct skin toxicity caused by secretion of drug in
sweat with accumulation of drug on the skin; 3) endocrinologic abnormalities
with increased adrenocorticotrophic hormone and melanocyte-stimulating hormone
causing hyperpigmentation as a result of suppressed adrenal function; 4)
depletion of tyrosinase inhibitors resulting in increased pigmentation; and 5)
direct toxic effects on epidermal melanocytes stimulating increased melanin
production.17 Some hyperpigmentation may be irreversible, but often
resolves after discontinuation of the chemotherapeutic agent. The pigment
changes are mainly a cosmetic concern as they have not been associated with
any negative clinical sequelae. There is no treatment available for this
adverse effect. Patients should be counseled about the risk of developing
pigment changes when starting the chemotherapeutic agents listed in TABLE 2
.
Nail Changes:
The nail plate is made up of the hard keratin cover of the dorsal portion of
the distal phalanx and as it grows the distal part of the nail matrix
generates the deeper layers of the plate.21 The epithelium of the
nail matrix is made up of rapidly proliferating cells that differentiate and
keratinize to generate the nail plate, making it susceptible to the toxicities
of chemotherapy.22 Nail changes seen with the use of chemotherapy
are both cosmetically displeasing (nail discoloration) and can result in
onycholysis (separation of the nail plate from the nail bed)--which can be
painful and may lead to infection.21 Taxanes (e.g., docetaxel and
paclitaxel) are most notorious for causing onycholysis.22 These
nail changes have been attributed to a cessation of mitotic activity in the
nail matrix, which produces a horizontal depression of the nail plate or
complete separation of the nail plate from the nail bed (Figure 1).23
After several weeks of chemotherapy, Beau's lines (darkened horizontal lines)
or Mees' lines (horizontal white lines) appear on the nail bed. Beau's and
Mees' lines move with normal nail growth and disappear within six months.
23,24 Chemotherapeutic agents that cause nail changes include
5-fluorouracil, bleomycin, cyclophosphamide, daunorubicin, docetaxel,
doxorubicin, epirubicin, hydroxyurea, and paclitaxel.2
Treatment:
No current pharmacological therapies are available for the treatment of
chemotherapy-induced nail changes and only one nonpharmacological therapy is
available. The Elasto-Gel (84400 APT Cedex, Akromed, France) frozen glove (FG)
is a glycerin-containing glove with thermal properties, allowing its use in
hot or cold therapies.25 The FG causes vasoconstriction of the
blood vessels that supply the hand, which then minimizes the amount of
chemotherapy reaching the nail matrix. In a phase II, multicenter, matched
case-control study, patients wore the frozen FG for 90 minutes starting 15
minutes prior to receiving chemotherapy. Overall, skin toxicity was reduced by
approximately 50% with the use of the FG.25 Persons who should not
receive FG therapy include those with Raynaud's phenomenon, distal metastases,
ungual pathology, arteriopathy, cold intolerance, or peripheral neuropathy.
25 Excluding any contraindications, one can initiate FG therapy,
especially with the use of taxanes for cancer therapy.
Chemotherapy-Induced
Palmar-Plantar Erythrodysesthesia (PPE)
PPE, also termed
hand-foot syndrome or chemotherapy-associated acral erythema, is a common
adverse effect of 5-fluorouracil, capecitabine, and liposomal doxorubicin.
26 Chemotherapeutic agents that have sustained blood levels are more
likely to cause this reaction.26 PPE typically presents with
dysesthesia and tingling in the hands and feet, which usually appear 2 to 12
days after the administration of chemotherapy. These symptoms may progress,
three to four days later, into symmetrical edema and erythema of the palms and
soles. Erythematous plaques with violaceous and edematous patches in the
palms, soles, and other high-pressure areas are usually mild and resolve in
one to two weeks. However, PPE may evolve into blistering desquamation,
crusting, ulceration, and epidermal necrosis.27 PPE results from
the rupture of small capillaries in the palms of the hands and soles of the
feet with increased pressure from walking or use, leading to the extravasation
of chemotherapy which creates an inflammatory reaction.26 The
treatment of PPE depends on the severity of ulceration; however, there is a
paucity of data discussing the management of capecitabine and
5-fluorouracil-induced PPE. Guidelines for the management of
doxorubicin-induced PPE include dose reduction and delay of chemotherapy (
TABLE 3).
Nonpharmacologic
Treatment: A nonpharmacological method of preventing PPE is
hypothermia treatment. In a retrospective study, regional cooling was
performed by applying ice packs around the patients' wrist and ankles during
chemotherapy and 24 hours postchemotherapy treatment.28 Patients
were also instructed to avoid direct sunlight, hot foods and liquids, hot
water contact, and undue friction to the hands and feet for 72 hours
postchemotherapy. The regional cooling protocol was found to be effective in
significantly reducing the frequency and severity of PPE.28 The
greatest obstacle in this method of treatment would be patient compliance with
the protocol.
Pharmacologic Treatment:
The pharmacologic agents used to prevent and treat PPE include
pyridoxine, dexamethasone, amifostine, celecoxib, Bag Balm, and dimethyl
sulfoxide (DMSO).29-33
Pyridoxine:
Pyridoxine (vitamin B6) has been investigated because of the similarities
between PPE and acrodynia (chronic mercury poisoning that results in
irritability, photophobia, pink discoloration of hands and feet, and
polyneuritis).28 In a phase I, observational study investigating
the use of pyridoxine in 23 cancer patients with solid tumors, pyridoxine 50
mg orally three times daily was given on days 2 to 21 of each cycle in
patients taking cisplatin and paclitaxel. No cases of grade 3/4 PPE were
observed and grade 1/2 PPE occurred in four of 18 patients.29
Randomized, placebo-controlled trials that would provide more robust findings
are lacking. However, pyridoxine is inexpensive and relatively nontoxic,
therefore, supplemental pyridoxine 150 to 200 mg daily can be recommended to
patients on chemotherapy for prevention of PPE.
Dexamethasone:
Corticosteroids have been investigated for the management of PPE due to their
anti-inflammatory properties. Kollmannsberger et al studied high-dose
dexamethasone 8 mg twice daily in combination with pyridoxine 100 mg twice
daily given on days 1 through 5 of each cycle. Only 12 of the 27 patients
studied had grade 3 or higher PPE.30 Drake et al conducted a
randomized, placebo-controlled trial in which the use of dexamethasone alone
prevented further delay of chemotherapy or dose reduction when compared to
patients who did not receive dexamethasone.31 Therefore,
dexamethasone 8 mg twice daily, with or without pyridoxine or an equivalently
dosed corticosteroid, may be used in patients to reduce the frequency and
severity of PPE. However, the many adverse effects of corticosteroids (e.g.,
hyperglycemia, psychosis, electrolyte imbalances, hypertension) may limit its
use.
Amifostine:
Amifostine, a cytoprotective adjuvant used in cancer chemotherapy, has been
reported to reduce the incidence of grade 3/4 PPE.32 In a crossover
study of 22 patients with solid tumors, intravenous amifostine 500 mg was
administered on days 1, 3 or 4, and 8 during treatment with pegylated
liposomal doxorubicin.32 Although in this study and in clinical
trials amifostine did not interfere with the clinical efficacy of
chemotherapy, it is not recommended to be used in patients receiving
chemotherapy or radiotherapy for other malignancies in which chemotherapy or
radiotherapy can produce a significant survival benefit or cure (e.g., certain
malignancies of germ cell origin), due to the risk of the reduced antitumor
efficacy of chemotherapy.33 Other serious adverse effects of
amifostine include hypotension, hypersensitivity reactions with anaphylaxis,
and hypocalcemia.33 Due to its many toxicities and limited efficacy
data, amifostine should only be reserved for patients who are refractory to
all other therapies and can tolerate treatment.
Celecoxib:
Celecoxib, a COX-2 inhibitor known to attenuate the inflammatory response, has
also been studied in the prevention of capecitabine-induced PPE. A
retrospective study comparing the incidences of hand-foot syndrome in 67
patients with metastatic colorectal cancer was undertaken. The study found
that celecoxib given at 400 mg twice daily reduced the incidence and frequency
of capecitabine-induced PPE.34 The drawback is that chronic use of
celecoxib at high doses increases the risk of serious adverse cardiovascular
thrombotic events, in patients who may already have underlying
hypercoagulability. In the Prevention of Sporadic Colorectal Adenomas with
Celecoxib trial, the relative risk for the composite endpoint of
cardiovascular death, mycardial infarction, or stroke was 3.4 (95% CI, 1.4 to
8.5) for celecoxib 400 mg twice daily and 2.5 (95% CI, 1.0 to 6.4) for the
celecoxib 200 mg twice daily compared to placebo.35 Although there
is data that suggest positive outcomes, further studies should be conducted
before using such a high-risk medication in this subset of patients.
Topical Treatments:
Topical agents used to treat PPE include emollients, aloe vera lotion,
and moisturizing creams such as Bag Balm, a topical petroleum-lanolin-based
ointment with the antiseptic ingredient 8-hydroxyquinoline sulfate, to
maintain skin integrity.28 In a nonrandomized trial of 39 cancer
patients, Bag Balm was evaluated for its effects on PPE.36 Bag Balm
was applied three times daily to the affected areas at the first signs and
symptoms of PPE; this therapy was associated with an improvement in skin
appearance and resulted in no delays or reduction of chemotherapy.36
This study did not mention the use of concomitant therapies (e.g., routine
wound care and topical antibiotics); therefore, one cannot definitively
conclude that the use of Bag Balm alone is effective. Due to its low toxicity,
Bag Balm may be recommended in patients with the initial signs and symptoms of
PPE.
Dimethyl Sulfoxide:
Dimethyl sulfoxide (DMSO), a potent free-radical scavenger, has been
investigated for the treatment of PPE. In a small observational study, 99%
DMSO applied four times daily to the affected areas for 14 days resulted in
symptom resolution over one to three weeks.37 Large randomized
trials are lacking in investigating DMSO for the treatment of PPE. However,
the initial findings in this pilot study do show promising results, making
DMSO a drug that may be considered for use in the treatment of PPE.
Chemotherapy-Induced
Extravasation
Extravasation
occurs when there is an inadvertent leaking of intravenous fluid during
medication administration which, in turn, leads to tissue damage.23
The accidental extravasation of intravenous drug occurs in approximately 0.1%
to 6% in patient receiving chemotherapy.23,38,39 Risk factors for
extravasation include the size and type of vein chosen for administration of
drug, recent venipuncture, and limited vein selection.39 Steps that
can be taken to minimize the incidence of extravasation include the use of the
forearm as the preferred site of infusion, performing only one venipuncture,
taping the needle in place, and testing the IV site.24
Extravasation results in local reactions ranging from local irritation to
severe tissue necrosis of the skin, surrounding vasculature, and supporting
structures.40 More severe reactions are seen with vesicants (i.e.,
cisplatin, dactinomycin, daunorubicin, idarubicin, mechlorethamine,
mithramycin, mitomycin-C, mitoxantrone, paclitaxel, vinblastine, vincristine,
and vinorelbine) as compared to irritants (i.e., carmustine , dacarbazine,
etoposide, and streptozocine).2 Vesicants are highly reactive
chemicals that combine with proteins, DNA, and other cellular components,
which result in cellular changes immediately after exposure. Irritants produce
irritation after exposure to tissue but do not combine with proteins and
tissue DNA.2 Treatment modalities for extravasation include
immediate discontinuation of chemotherapy and cooling of the site (TABLE
4). To reduce the
morbidity associated with extravasation, it is vital that clinicians focus on
prevention and develop expertise in its management.
Radiation Recall and
Sensitivity
Radiation reactions
can be subdivided into four categories: radiation enhancement, radiation
recall, photosensitivity reaction, and sunburn reactivation.1
Radiation reactions are varied and range from a maculopapular rash to a
generalized exfoliative, ulcerative dermatitis. Enhanced radiation effects
that occur with chemotherapy may be caused by an agent's ability to interfere
with enzyme-mediated radiation repair. Chemotherapy agents are known to
inhibit some of the enzymes and synthetic mechanisms needed to repair tissue.
24 Enhancement reactions may occur when chemotherapy is given
concomitantly with radiation or within one week of radiation.24 In
contrast, the recall phenomenon may develop over several weeks to years after
radiation therapy, when a chemotherapy agent causes an inflammatory reaction
in tissues previously treated with radiation.2,24 Chemotherapy may
also interact with ultraviolet (UV) light to produce similar effects.
Reactivation of sunburn is a variation of the recall phenomenon and is most
commonly associated with methotrexate.24 Chemotherapy agents that
have reactions to radiation or UV light are listed in TABLE 5. Patients
should be counseled on the appropriate use of sunscreens and cautioned to
avoid unnecessary sun exposure.2
Conclusion
Dermatological toxicities associated
with chemotherapy are common. However, the dearth of information available
makes the management of these dermatological toxicities difficult. Clinicians
should become more cognizant of the dermatological adverse effects of oncology
drugs and radiation in order to minimize the morbidity associated with these
devastating toxicities.
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