Cytotoxic chemotherapy and radiation therapy can also damage the mucosal lining of
the esophagus. Although dysphagia is a common symptom reported by patients with
esophagitis, other causes of dysphagia should be excluded. Because patients
receiving myelosuppressive cytotoxic therapy may exhibit infectious esophagitis,
bacterial, viral, and fungal cultures should be completed to search for infectious
causes before starting treatment for esophagitis. Symptomatic management of
esophagitis is similar to the management of mucositis. Other treatment modalities,
including behavioral modifications (e.g., elimination of acidic and irritating foods)
and other medications (e.g., histamine-2 [H2
] receptor antagonist, antacids, and
proton pump inhibitors), may help reduce esophageal irritation and improve comfort.
Patients with severe esophagitis should be carefully monitored to ensure adequate
oral hydration and nutritional intake, and instructed to avoid acidic or irritating
foods. Symptoms should resolve in 1 to 2 weeks as myelosuppression resolves.
LOWER GASTROINTESTINAL TRACT COMPLICATIONS
Lower GI tract complications associated with anticancer therapy include
malabsorption, diarrhea, and constipation. These complications may be related to
structural changes that occur to the GI tract after cytotoxic or radiation therapy.
Several investigators noted villus atrophy and cessation of mitosis within GI crypts
in patients and animals treated with combination cytotoxic therapy.
investigators noted swelling and dilation of mitochondria and endoplasmic reticulum
and shortening of the microvilli. These or other changes to the small and large bowel
can cause decreased absorption of medications that are primarily absorbed in the
upper portion of the small intestine.
Cytotoxic-induced intestinal changes also may be responsible for diarrhea, which
frequently occurs with regimens containing
irinotecan, high-dose cytarabine, or fluorouracil. Unlike diarrhea, constipation is
rare. The vinca alkaloids, which produce colicky abdominal pain, constipation, and
adynamic ileus caused by autonomic nerve dysfunction (see Neurotoxicity section),
can cause chemotherapy-induced constipation. Additionally, constipation is a
problematic side effect of therapy with thalidomide. Constipation should be treated
prophylactically with stool softeners and mild stimulants. The true incidence of
diarrhea and constipation associated with chemotherapy is difficult to discern,
because many medications (e.g., opioid analgesics, antiemetics, antacids) and
clinical conditions (e.g., immobility, spinal cord compression) commonly associated
with cancer and anticancer therapies can cause these symptoms as well.
QUESTION 1: B.G., a 60-year-old woman with recurrent colorectal cancer refractory to FOLFOX
Diarrhea is a common toxicity seen during cancer treatment. It is most prevalent in
patients treated with fluoropyrimidines and irinotecan. In addition, it is one of the
most common side effects seen with new targeted therapies. A recent review
provides an excellent summary of targeted therapy-induced diarrhea.
toxicity in which patient education is paramount. Patients who do not recognize
potentially serious symptoms, understand the role of self-management, or understand
when to contact their provider are at risk of life-threatening consequences. The
mechanism of diarrhea is not completely understood, is likely multifactorial, and
varies depending on the therapy. Diarrhea may result from direct effects on the GI
mucosa, secretory factors, dysmotility, and immunotherapy-related (ipilimumab) and
parasympathetic (irinotecan) effects. Irinotecan can cause severe diarrhea, both early
and late, in the course of therapy. The early-onset diarrhea and late-onset diarrhea
appear to be mediated by different mechanisms. Unique to irinotecan, the early-onset
diarrhea (within 24 hours after treatment) may be mediated by parasympathetic
stimulation. Patients often report other cholinergic symptoms, such as rhinitis,
increased salivation, miosis, lacrimation, diaphoresis, flushing, and abdominal
cramping as well. These symptoms can be prevented or managed with atropine IV or
SC 0.25 to 1 mg. Late-onset diarrhea (generally occurring >24 hours after treatment)
can be prolonged leading to dehydration, electrolyte imbalances, and significant
morbidity. In irinotecan-induced diarrhea, patients should promptly receive
loperamide 4 mg with the first episode of diarrhea and repeat doses of 2 mg every 2
hours until 12 hours have passed without a bowel movement.
loperamide (16 mg in 24 hours) does not apply for irinotecan-induced diarrhea. Fluid
and electrolyte replacement should also be administered, if necessary. With the
potential severe complications associated with chemotherapy-associated diarrhea,
prompt treatment cannot be overemphasized.
If a patient fails to respond to adequate doses of loperamide, the somatostatin
analog, octreotide, can be used to manage the diarrhea. Randomized trials comparing
loperamide with octreotide in patients with acute leukemia or those undergoing HCT
found loperamide to be more effective.
61,62 Nevertheless, some evidence shows that
octreotide may be used to successfully manage diarrhea associated with fluorouracil
and other high-dose chemotherapy regimens.
63,64 These findings have been
inconsistent. Several trials in patients with colorectal cancer receiving
chemoradiation or chemotherapy failed to show benefit of decreasing diarrhea with
64,65 Octreotide produces antisecretory activity in the gut and
promotes the absorption of sodium, chloride, and water from luminal content.
Patients should receive doses ranging from 100 to 2,000 mcg SC 3 times daily or 20
to 40 mg of long-acting octreotide.
64,65 Although responses seem to correlate with
octreotide dose, more studies are needed to determine the optimal dose. Based on
current evidence, octreotide should be limited to second-line therapy for cytotoxic
therapy-associated diarrhea. Other treatment options, including antibiotics, opioids,
and corticosteroids, have been evaluated and are summarized in review articles.
B.G. should be counseled on the diarrhea that is often seen with irinotecan. She
should be instructed to call her clinic if she starts experiencing any diarrhea within
24 hours after administration of irinotecan so she can receive prompt atropine
therapy. Additionally, she should be given a prescription and instructions for
loperamide administration and oral hydration recommendations for diarrhea
occurring beyond the initial 24 hours after chemotherapy.
Dermatologic toxicities associated with anticancer therapies include alopecia,
hyperpigmentation, radiation recall, photosensitivity, nail changes, hand-foot
syndrome, acneiform rashes, hypersensitivity reactions, and extravasations. Several
reviews serve as excellent references and provide detail related to dermatologic
toxicities of targeted agents.
QUESTION 1: C.W. is a 45-year-old woman with recently diagnosed breast cancer, who underwent lymph
receive the first of four cycles of doxorubicin and cyclophosphamide (AC). Although C.W. had minimal
most common toxicities by reviewing the likelihood and management of myelosuppression, nausea, and
C.W.’s concern regarding hair loss is typical of cancer patients starting
chemotherapy. In fact, several investigators have reported that hair loss ranks second
only to nausea and vomiting as a patient’s greatest fear. Because hair bulb cells
replicate every 12 to 24 hours, the cells are susceptible to various cytotoxic
chemotherapy agents. Normally, hair follicles independently move cyclically through
phases of growth (anagen), involution or transition (catagen), and rest (telogen).
Although most persons normally lose about 100 scalp hairs a day, patients with
cancer can lose substantially more. Because approximately 85% to 90% of hair
follicles are in the anagen phase, chemotherapy agents may partially or completely
inhibit mitosis or impair metabolic processes in the hair matrix. These effects can
cause a thinned or weakened hair shaft or failure to form hair. Even mild trauma,
such as normal hair grooming or rubbing the head on a pillow, can fracture the
thinned hair shaft and cause hair loss. Hair loss usually begins 7 to 10 days after one
treatment, with prominent hair loss noted within 1 or 2 months.
Other terminal hairs, such as beards, eyebrows, eyelashes, and axillary and pubic
hair, can be affected; however, these effects are somewhat variable, depending on the
rate of mitosis and the percentage of hairs in the anagen phase.
C.W. should be informed about the expected onset of hair loss, and she should be
reassured that alopecia caused by cytotoxic chemotherapy is reversible. She can
expect her hair to begin regenerating 1 to 2 months after therapy is completed. The
color and texture of her hair may be altered; the new hair may be lighter, darker, or
Several interventions have been proposed to prevent scalp hair loss during
chemotherapy. These procedures attempt to prevent chemotherapy agents from
circulating to the hair follicles with either an occlusive scalp tourniquet or an ice cap
that produces a localized hypothermia and vasoconstriction. Recognizing that such
devices create a refuge for tumor cells, these procedures are contraindicated in
patients with hematologic malignancies and in others at risk for scalp metastases.
Concerns regarding the efficacy and safety of these devices have prevented them
from availability in the US market.
72,73 Topical minoxidil has been studied with
C.W.’s concern is a legitimate one expressed by many patients with cancer, not
just patients with breast cancer. C.W. is likely to experience near or complete hair
loss, depending on the thickness of her hair and its growth rate. She should be told
how to minimize the effect of alopecia on her appearance through the use of hair
pieces or stylish head scarves, turbans, or hats. She also should be referred to
volunteer groups and organizations that can help her through this difficult time. Hair
pieces are tax deductible as a medical expense and are covered by some health
insurance policies. If C.W. thinks she will use a hair piece, she should be advised to
select a wig before hair loss begins.
CASE 94-4, QUESTION 2: Besides alopecia, what other skin or nail changes should C.W. anticipate?
Several skin and nail changes have been associated with cytotoxic and targeted
anticancer agents, which C.W. may find disturbing.
The major consequences of these toxicities are cosmetic, however, and they
usually resolve within 6 to 12 months after discontinuing or completing therapy.
The growth of fingernails and toenails is arrested in a manner similar to hair growth.
A reduction or a cessation of mitotic activity in the nail matrix causes a horizontal
depression of the nail plate. Within weeks, these pale horizontal lines (Beau lines)
begin to appear in the nail beds. They are most commonly seen in patients receiving
chemotherapy for more than 6 months. These growth arrest lines move distally as the
nail grows and normally disappears from the fingernails in approximately 6 months.
Nail changes including hemorrhagic onycholysis, discoloration, and acute exudative
paronychia are seen in approximately 40% of patients receiving paclitaxel and
67,75 Some other nail pigmentation changes that can occur after therapy with
cyclophosphamide, fluorouracil, daunorubicin, doxorubicin, and bleomycin are less
76,77 Brown or blue lines deposit as horizontal or vertical bands in
the nails. These lines are seen more commonly in dark-skinned patients. As with
Beau lines, these pigmentation lines generally grow out with the nail. Standardized
treatment recommendations for nail-related adverse events do not exist. Oral
antibiotics and corticosteroids may be considered.
occasionally in patients receiving cytotoxic therapy, but hyperpigmentation is more
frequently reported. Usually, hyperpigmentation is not associated with an identifiable
cause or systemic toxicity. It usually occurs after treatment with a wide variety of
cytotoxic agents, including anthracyclines, alkylating agents, and antimetabolites.
Most agents cause a diffuse, generalized hyperpigmentation, but the pigmentation
changes can also be localized, involving only the mucous membrane, hair, or nails.
Busulfan, cyclophosphamide, fluorouracil, dactinomycin, and hydroxyurea are
examples of specific agents that can cause widespread cutaneous
Various chemotherapy agents can cause diverse patterns of hyperpigmentation. A
peculiar serpiginous hyperpigmentation can occur over veins used to administer
78,79 Some investigators have attributed this phenomenon
to a subclinical phlebitis. Hyperpigmentation has also been noted over pressure
points after the use of bleomycin. Thiotepa has been reported to cause
hyperpigmentation in areas of skin occluded by bandages, which may be caused by
secretion of thiotepa in sweat.
Interestingly, skin contact with thiotepa and
mechlorethamine has been reported to cause hypopigmentation.
hyperpigmentation reactions commonly affect the skin, some rare reactions are noted
in hair. Methotrexate can cause hyperpigmented banding of light-colored hair. This
phenomenon has been described in a patient receiving intermittent high-dose
methotrexate and has been referred to by some investigators as the “flag sign” of
83 Alternatively, depigmentation of hair has been seen with several
tyrosine kinase inhibitors including sunitinib, imatinib, and pazopanib. This adverse
effect is attributed to c-KIT signal inhibition leading to decreased melanin
84 To minimize a patient’s concern regarding these pigment changes, they
should receive counseling before treatment.
As previously stated, pigment changes that occur in patients receiving cytotoxic
chemotherapy are basically a cosmetic concern. It is important to anticipate these
distressing side effects and educate patients in appropriate cases. At this time, C.W.
should receive counseling, explaining that these side effects may occur because she
will be receiving several agents that have been implicated in producing diffuse, as
well as localized, cutaneous nail hyperpigmentation. She should be reassured that
pigment changes usually resolve with time.
Some patients receiving chemotherapy may exhibit tender, erythematous skin on the
palms of their hands and sometimes on the soles of their feet. Patients may also
complain of tingling, burning, or shooting sensations in their hands or feet usually not
described as painful. These signs and symptoms may resolve after several days, or
they may progress to bullous lesions that can desquamate. This reaction is referred to
as chemotherapy-associated acral erythema or the palmar-plantar erythrodysesthesia
syndrome. Agents most commonly reported to cause this reaction include cytarabine,
fluorouracil, doxorubicin, liposomal doxorubicin, docetaxel, capecitabine, sorafenib,
sunitinib, pazopanib, regorafenib, axitinib, and vemurafenib.
that the application of urea-based cream may be effective in prevention of hand-foot
syndrome based on study results in patients receiving capecitabine and sorafenib.
Both study populations utilized 10% urea-based cream 3 times daily for 6 to 12
weeks and saw a decrease in the incidence of hand-foot syndrome.
primarily focused on symptom control, and discontinuation of the medication or
treatment interruption will help to resolve the reaction. After resolution, the
medication may be initiated at a lower dose.
The most common toxicities reported with the epidermal growth factor receptor
(EGFR) inhibitors and EGFR monoclonal antibodies are skin related and are
probably due to inhibition of the tyrosine kinase pathways in EGFR-dependent
tissues, including keratinocytes in the skin. Erlotinib, gefitinib, afatinib, and lapatinib
are small-molecule tyrosine kinase inhibitors that target the intracellular domain of
the EGFR, and cetuximab and panitumumab are monoclonal antibodies that target the
extracellular domain of EGFR. These agents are associated with skin toxicities. Skin
effects occur in greater than 50% of patients who receive these treatments and are
dose-dependent. A pustular or maculopapular eruption typically appears on the upper
body, face, and scalp in the first 1 to 2 weeks of treatment.
The rashes are predominantly grade 1 or 2 in severity, may be associated with dry
skin and itching, and completely resolve without sequelae when the drug is
69,89 Evidence suggests that the severity of the skin rash is associated
with increased efficacy of this class of agents. In a retrospective analysis of a Phase
III trial in patients with NSCLC receiving erlotinib, those who experienced a rash
had a significantly longer survival time than those who did not. Survival was
reported to be 1.5 months in patients with no development of skin rash versus 8.5
months in those with grade 1 rash, and 19.6 months in patients exhibiting a grade 2 or
90 Evidence of a correlation between skin rashes and higher response rates has
also been observed in patients receiving cetuximab for colorectal cancer.
therapies have been studied in hopes of reducing or preventing this bothersome side
effect. Patients should be advised to minimize sun exposure and to keep the rash
moist with lotions and creams, avoiding drying agents.
Association of Supportive Care in Cancer (MASCC) has developed an EGFR
information and clinical practice guidelines for the prevention and treatment of
EGFR inhibitor-associated dermatologic toxicities. Because of the prevalence and
significant discomfort associated with the rash, prevention is recommended in the
majority of patients in the first 6 to 8 weeks of therapy and consists of hydrocortisone
1% cream with moisturizer, sunscreen, and either minocycline or doxycycline
Many cytotoxic anticancer agents (especially bleomycin, hydroxyurea, and
fluorouracil) and several targeted therapies (EGFR inhibitors) can cause dry skin
with fine scaling on the surface. Normally, sebaceous and sweat glands provide
lipids, lactates, and other products that contribute to the pliability and moisture
retention of the stratum corneum. In patients receiving cytotoxic therapy, the dry skin
may be caused by the cytostatic effect of agents on sebaceous and sweat glands.
Topical application of emollient creams may provide some symptomatic relief of this
INTERACTIONS WITH RADIATION THERAPY
C.W. should take, or signs and symptoms of toxicity that she should know about?
The interactions between cytotoxic therapy and radiation therapy or ultraviolet
(UV) light (from both external beam and natural sources) can be divided into
radiation sensitization, radiation recall, photosensitivity reactions, and sunburn
Chemotherapy-Associated and Radiation-Associated Reactions
Radiation Sensitivity Reactions
Bleomycin Doxorubicin Hydroxyurea
Dactinomycin Fluorouracil Methotrexate
Vinblastine Epirubicin Capecitabine
Etoposide Paclitaxel Oxaliplatin
Reactions with Ultraviolet Light
Dacarbazine Thioguanine Methotrexate
Fluorouracil Vinblastine Mitomycin
therapy. Curr Opin Oncol. 2002;14:212.
Several excellent reviews are available that describe each of these interactions in
detail. A discussion of the important principles of the interaction between radiation
therapy and cytotoxic therapy follows.
96–98 A synergistic interaction between a small
number of cytotoxic agents and radiation therapy results in an enhanced radiation
effect. This may be caused by an agent’s ability to interfere with radiation repair.
Radiation therapy can alter the molecular structure of DNA, but excision repair
allows cells to remove small, damaged portions of one strand of DNA and insert new
bases using the other strand as a template. This repair mechanism requires several
enzymes, including DNA polymerase. Cytotoxic therapy agents can interfere with
some of the enzymes and synthetic mechanisms needed to repair damaged cells.
Although the synergistic effects of radiation therapy and cytotoxic therapy are often
exploited therapeutically for the treatment of solid tumors, these reactions can
inadvertently cause undesirable reactions in nontumor tissues, such as the skin,
esophagus, lung, and GI tract. The skin is the most common target of radiation
These reactions can produce severe tissue necrosis, which can compromise organ
function and delay or mandate discontinuation of future treatment courses. These
reactions may be further classified as either radiation sensitivity or radiation-recall
reactions. The primary distinction between radiation sensitivity reactions and
radiation-recall reactions lies in the temporal relationship between radiation therapy
and chemotherapy. Generally, sensitivity reactions occur when chemotherapy is
given concurrently or within 1 week of radiation therapy. In comparison, recall
reactions occur several weeks to years after radiation therapy, when the
administration of chemotherapy induces an inflammatory reaction in tissues
previously treated with radiation. Radiation recall is independent of previous,
clinically apparent radiation damage. Not surprisingly, the chemotherapy agents that
radiation-recall reactions are the same as those that cause radiation sensitivity
reactions. Management of reactions is supportive and consists primarily of topical
agents including corticosteroids.
Because UV light has sufficient energy to cause photochemical changes in biologic
molecules, cytotoxic agents can interact with it. The subsequent reactions are usually
less severe than reactions that occur with radiation therapy, and they may be caused
by a different mechanism. Photosensitivity reactions, defined as enhanced erythema
responses to UV light, have been reported with specific agents (Table 94-2).
Methotrexate can also reactivate sunburns, causing a similar, but less severe reaction
compared with the radiation-recall reactions described previously. The reaction can
be more severe than the initial sunburn, resulting in severe blisters, and it usually
occurs only in patients who receive large doses of methotrexate. Although the precise
incidences of photosensitivity reactions caused by chemotherapy agents are unknown,
they may be more common than generally believed. For example, photosensitivity
may account for many of the erythematous periodic rashes attributed to allergy.
C.W. received doxorubicin which can interact with radiation therapy. Although not
commonly reported, doxorubicin also can cause some increased erythema in the
specific area of skin treated with radiation. Because C.W. may have an increased
risk for a photosensitivity reaction, she should be advised to avoid direct exposure to
the sunlight for several days to a week after chemotherapy. Although no data exist
regarding the efficacy of sunscreens in this patient population, C.W. should be
advised to use a protective sunscreen with a high sun protective factor when she
cannot avoid sun exposure. Protective clothing and a hat can provide additional
protection for C.W. Furthermore, she should periodically assess her skin’s reaction
to the sun with intermittent periods of rest and observation throughout the day.
CASE 94-4, QUESTION 4: How will C.W. know whether she has a radiation reaction? How should she be
treated if such a reaction occurs?
If C.W. has a radiation reaction, she will experience “easy burning” and erythema
or redness, followed by dry desquamation. With a more severe reaction, small
blisters (vesicles) and oozing can develop. Necrosis with persistent painful
ulceration can also occur in severe cases. Postinflammatory hyperpigmentation or
depigmentation may follow. Treatment options vary, depending on reaction severity.
Milder cases can be treated with topical steroids in an emollient cream base and
cool wet compresses. Necrosis and ulcers are notoriously difficult to treat, however,
because radiated skin does not heal well. Ulcers are often treated with surgical
debridement to keep the ulcer clean. Even when the ulcers are clean, exudation and
bacterial contamination can be persistent. Radiation reactions that occur in tissues
other than the skin (e.g., the lungs, esophagus, GI tract) often are treated with oral
corticosteroids, although data regarding the efficacy of these agents in ameliorating
the symptoms or reducing the extent of damage are lacking. If C.W. experiences any
of these signs or symptoms, she should immediately seek medical attention.
IRRITANT AND VESICANT REACTIONS
reactions can occur after the administration of chemotherapy?
Several distinct types of local reactions (ranging from transient local irritation to
severe tissue necrosis of the skin, surrounding vasculature, and supporting structures)
have been reported after cytotoxic chemotherapy
reactions are characterized by immediate local burning, itching, and erythema. Some
patients may also experience a “flare” reaction along the length of the vein used for
treatment. More severe reactions, including irritation of the vein (or phlebitis) caused
by the irritant properties of an agent or a diluent, and possibly extravasation, can
occur after cytotoxic chemotherapy.
68,103 Extravasation, a potentially serious local
reaction, is seen in approximately 1% of chemotherapy administration and occurs
when IV medications are accidentally administered into the surrounding tissue, either
by leakage or by a needle puncturing the vein, causing direct exposure and damage to
Reactions resulting from the extravasation of agents with vesicant or irritant
properties are more severe. All agents with vesicant properties potentially can
produce devastating reactions. Agents known to bind to DNA (i.e., the
anthracyclines) have the propensity to produce the most severe damage. Treatment
with a cytotoxic agent with these properties can produce phlebitis and pain; however,
extravasations can cause severe local irritation or soft tissue ulcers, depending on the
agent and the amount and concentration of the extravasated drug. In addition, no clear
agreement exists regarding the vesicant potential of many cytotoxic chemotherapy
agents, and various references may categorize agents differently based on their
vesicant or irritant properties. Initially, it may be impossible to distinguish a local
irritant reaction from a vesicant extravasation; therefore, if an agent with vesicant or
irritant properties has been administered, the reaction should be treated as a potential
Patients who experience an extravasation can show a range of different signs or
symptoms. Infiltration of a vesicant into tissue often produces a severe burning
sensation that may persist for hours. In some cases, no immediate symptoms or signs
are evident. However, in the days to weeks that follow, the skin overlying the
extravasation site may become reddened and firm. The redness may gradually
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