Febrile neutropenia leads to increased hospital admissions and lengths of stay as
well as greater morbidity and mortality, so the optimal indication for CSFs is as
prophylaxis; however, CSFs have been studied as part of the treatment of neutropenic
fever. Because the duration of neutropenia is the most significant prognostic factor in
patients with established febrile neutropenia, the major benefit of CSFs is their
ability to reduce the duration of neutropenia. CSFs accelerate hematopoiesis by
expanding the mitotic pool of committed progenitor cells and shortening the time
spent in the postmitotic pool from 6 days to 1 day. If CSFs reduce the duration of
neutropenia in patients who present with febrile neutropenia, then morbidity,
mortality, and cost should be significantly reduced.
The ability of CSFs to reduce the duration of neutropenia in patients with
filgrastim and sargramostim reveal minimal-to-moderate benefit in reducing hospital
stays and no differences in mortality. Furthermore, questions have been raised as to
whether all patients with febrile neutropenia require hospitalization. Several studies
have shown equal efficacy and safety with increased cost effectiveness of outpatient
treatment of febrile neutropenia.
12–14 Although CSFs do appear to hasten neutrophil
recovery, the true cost–benefit ratio associated with the use of these products in
established febrile neutropenia remains to be determined. The ASCO guidelines
currently do not support routine use of CSFs in patients with febrile neutropenia,
although they do recognize that certain patients with febrile neutropenia and high-risk
features predictive of clinical deterioration (e.g., age >65 years, pneumonia, fungal
infection, hypotension, sepsis syndrome, uncontrolled primary disease) may benefit
The reduction in platelets is another common myelosuppressive toxicity seen with
chemotherapy. Most commonly, thrombocytopenia is managed via the use of platelet
transfusions and modifications to the chemotherapy dosing scheme. Although
oprelvekin, a thrombopoietic growth factor, is indicated to prevent severe
thrombocytopenia and reduce the need for platelet transfusions after
myelosuppressive chemotherapy in patients with nonmyeloid malignancies at high
risk for developing severe thrombocytopenia, it is rarely utilized in clinical practice
due to limited efficacy and potential adverse effects.
15,16 The majority of clinicians do
use of thrombopoietin receptor agonists, romiplostim and eltrombopag, is being
investigated. These agents are both approved for the treatment of idiopathic
thrombocytopenia purpura (ITP), but only case reports and Phase I trials have looked
at the use of these agents for chemotherapy-induced thrombocytopenia
Anemia usually is not a dose-limiting toxicity commonly associated with cytotoxic
chemotherapy, because RBCs survive approximately 120 days. Chemotherapy
predominantly affects RBCs by causing anisocytosis and macrocytosis. These effects
are related to inhibition of DNA synthesis, and they predominantly occur after
treatment with antimetabolites, including folic acid analogs, hydroxyurea, purine
antagonists, and pyrimidine antagonists. Anemia commonly does not accompany these
changes in RBC size. In addition, chemotherapy-induced effects on RBCs are rarely
the sole factor contributing to the low Hgb levels that necessitate an RBC transfusion.
See Chapter 92, Anemias, for additional information on anemias and their treatment.
Patients with cancer can exhibit bleeding secondary to chemotherapy-induced
thrombocytopenia or thrombosis after chemotherapy. Bleeding can occur after
treatment with asparaginase or the pegylated formulation, pegaspargase, due to
inhibition of the synthesis of fibrinogen and other specific coagulation factors
produced by the liver under the influence of vitamin K.
widespread effect on protein synthesis, and many plasma protein factors are
depressed shortly after treatment. A patient receiving asparaginase can often exhibit a
prolonged prothrombin time (PT) and partial thromboplastin time (PTT). Bleeding or
thrombosis occurring as a direct result of changes in coagulation factors has not been
frequently reported or conclusively documented. Coagulation factors may return to
normal levels with continued administration of the agent, which suggests that the
impairment of protein synthesis created by asparaginase is partially overcome by the
liver. Specific treatment of prolonged PT and PTT with coagulation factors,
fibrinogen, or vitamin K is not indicated.
The risk of venous thrombotic events is markedly elevated in patients with cancer.
Possible pathophysiologic mechanisms include hypercoagulability marked by
abnormalities in clotting factors and the coagulation cascade, vessel wall damage,
and vessel wall compression by tumor masses. Many risk factors for thromboembolic
events include the type of cancer, stage of cancer, comorbidities, mobility, and type
of systemic anticancer therapy received, among others. Pancreatic, stomach, kidney,
lung, brain, and uterine cancers are associated with the highest risk.
anticancer therapy has been associated with a 2.2-fold increased risk compared with
patients not using these treatment modalities.
first reported an increased incidence of venous thrombosis in patients
with cancer, and many investigators have since confirmed the relationship of multiple
or migratory venous thrombosis in patients with cancer. Up to one-third of apparently
healthy adults who exhibit otherwise unexplained deep vein thrombosis eventually
are proved to have a malignancy.
Initiating treatment for acute promyelocytic leukemia (APL) commonly is
associated with disseminated intravascular coagulation (DIC).
process that results from a large activation of the clotting cascade and presents as
overlapping bleeding and thrombotic events. These events can result in end-organ
damage. The lysed tumor cells in patients with APL appear to release procoagulant
materials after anticancer therapy causing both hemorrhagic and thrombotic events.
The foundation of treatment for DIC is to treat the underlying disease. Use of heparin
and antifibrinolytics to minimize risk of coagulation is controversial. Other treatment
is primarily supportive with blood products including platelets and cryoprecipitate.
Several anticancer agents have been associated with an increased thrombosis risk,
including cytotoxic chemotherapy (cisplatin, fluorouracil), hormonal targets
(tamoxifen, aromatase inhibitors), antiangiogenic therapies (bevacizumab), and the
immunomodulatory agents, thalidomide and lenalidomide.
lenalidomide, in combination with other agents including dexamethasone and
doxorubicin, have been associated with venous thromboembolic events when used in
the treatment of multiple myeloma and other diseases.
30–32 Prophylaxis is warranted
when these combinations are used. There are several guidelines and reviews
discussing both prophylaxis, including the use of low-molecular-weight heparin or
warfarin, and treatment in this patient population.
30 The use of direct-acting oral
anticoagulants such as rivaroxaban or apixaban is not well studied nor currently
recommended for prophylaxis in this population. Bevacizumab is associated with
both arterial thrombosis and bleeding events. A retrospective analysis of five trials
of patients receiving chemotherapy for colorectal, breast, or NSCLC showed a 3.8%
incidence of arterial thrombosis in patients receiving chemotherapy and bevacizumab
versus 1.7% in chemotherapy alone.
33 Most bleeding events associated with
bevacizumab are minor. However, severe major bleeding events have been reported
in patients with metastatic colorectal and lung cancer.
34 Different types of thrombotic
events have been identified in patients receiving bevacizumab for other types of
Other factors can cause patients to experience thrombosis. Many patients receiving
cancer chemotherapy often have other illnesses that may predispose them to
exhibiting thrombosis. In addition, surgical procedures and bed rest can increase the
risk of thrombosis. Clinicians should maintain a high index of suspicion when a
patient with cancer presents with signs or symptoms of thrombosis. Several reviews
summarize risk factors and recommendations and provide further insight for specific
Gastrointestinal Tract Toxicities
The GI tract may be second only to bone marrow in its susceptibility to toxic effects
produced by cytotoxic chemotherapy. GI toxicities include nausea and vomiting, oral
complications, esophagitis, and lower bowel disturbances.
Nausea and vomiting are common and serious toxicities associated with many
cytotoxic and targeted anticancer agents. Anticancer agents or their metabolites may
stimulate dopamine or serotonin receptors in the GI tract, the chemoreceptor trigger
zone, or the CNS, which ultimately act on the vomiting center. Emesis most
commonly occurs on the first day of chemotherapy and often persists for several days
38 Most patients who receive traditional cytotoxic chemotherapy agents
require antiemetics before and after chemotherapy for several days to control these
symptoms. The most appropriate antiemetic regimen is based on patient-specific and
agent-specific factors. Some of the targeted therapy agents carry some risk of
emetogenicity, although it is generally milder. Guidelines are beginning to
incorporate these targeted agents into their emetogenic classification schema based
on incidence of nausea and vomiting in clinical trials (see Chapter 22, Nausea and
Vomiting, for antiemetic algorithms and emetogenic potential of the cancer agents).
COMPLICATIONS OF THE ORAL CAVITY
Complications of the oral cavity include mucositis (or stomatitis), xerostomia (dry
mouth), infection, and bleeding. The incidence of severe oral mucositis varies with
the anticancer therapies given. Doxorubicin and continuous-infusion fluorouracil are
among the agents at highest risk for causing severe mucositis. Virtually, all patients
who receive myeloablative hematopoietic cell transplantation (HCT) or have
radiation therapy to the head and neck experience oral complications.
toxicities occur because of the nonspecific effects of chemotherapy on cells
undergoing rapid division, including the cells of the mouth that undergo rapid
renewal with a turnover time equal to 7 to 14 days. Cytotoxic therapy reduces the
renewal rate of the basal epithelium and can cause mucosal atrophy, as well as
glandular and collagen degeneration.
39,10 Radiation therapy to the head and neck also
causes mucosal atrophy by decreasing cell renewal. Radiation can also cause
fibrosis of the salivary glands, muscles, ligaments, and blood vessels, and damage to
40 The combined effects of chemotherapy and radiation therapy on the
oral mucosa can also cause infection and bleeding in the oral cavity. Infection and
bleeding occurs when treatment causes bone marrow suppression, including
thrombocytopenia and neutropenia. Because the oral mucosa is highly vascular and
frequently traumatized, bleeding occurs commonly with thrombocytopenia. In
addition, cytotoxic chemotherapy and neutropenia can alter the extensive microbial
flora harbored in the oral cavity, thus leading to oral infections. Oral complications
often compound one another. For example, xerostomia can accelerate the
development of mucositis as well as the formation of dental caries and local
infection. Mucositis can clearly predispose the oral cavity to local bleeding and
infection, as well as systemic infections leading to sepsis. These oral complications
can also cause varying degrees of discomfort and adversely affect the patient’s
ability to eat, which potentially may lead to a compromised nutritional status.
Topical treatments of oral complications are reviewed extensively in guidelines.
J.B. is at high risk for several of the oral complications previously described.
Xerostomia, one of the most frequent side effects of radiation therapy to the head and
neck, occurs secondary to radiation-induced changes to the salivary glands.
Evidence supports a direct relationship between the dose of radiation to the salivary
glands and the extent of glandular changes.
In most patients treated with less than
6,000 rad (radiation absorbed dose), radiation-induced changes to the salivary
glands are reversible within 6 to 12 months after the end of therapy. J.B. will also be
receiving chemotherapy agents (i.e., cisplatin) that can cause xerostomia and enhance
the toxicity to the salivary glands. Clinically, xerostomia has been caused by as little
as two to three radiation doses of 200 rad.
Damage to the salivary glands causes various effects, including a loss of salivary
buffering capacity, lower salivary pH, no mechanical flushing, decreased salivary
immunoglobulin A, and reduction of saliva production. In addition, xerostomia can
alter the sense of taste, causing some patients to lose their ability to differentiate
between sweet and salty foods and others to report a bitter taste. Xerostomia also
commonly causes caries. Caries and decalcification may become sufficiently severe
to compromise tooth integrity and cause fracture. Because saliva is no longer
available to help clear bacteria from the mouth, xerostomia also predisposes patients
to infection secondary to the increases in oral bacteria.
Amifostine, an organic thiophosphate chemoprotectant agent, is approved to reduce
the incidence of moderate-to-severe
xerostomia in patients having postoperative radiation treatment for head and neck
cancer. Guidelines published by ASCO support the use of amifostine to reduce the
incidence of acute and late xerostomia in patients receiving fractionated radiation
therapy without concurrent chemotherapy for head and neck cancer.
amifostine is not widely used due to its cost and adverse effect profile. If xerostomia
occurs, treatment strategies can include stimulation of existing salivary flow and
replacement of lost secretions. Relatively low doses of systemically administered
pilocarpine (5–10 mg orally 3 times daily) may stimulate salivary flow and produce
clinically significant benefits in patients with postradiation xerostomia.
demonstrating pilocarpine’s benefit are inconsistent. Dose-related adverse effects
include cholinergic effects, such as sweating, rhinitis, headache, nausea, and
abdominal cramps. A review on the oral complications of cancer therapy suggests
that cevimeline (30 mg orally 3 times daily) and bethanechol (25 mg orally 3 times
daily) may have fewer side effects than those seen with pilocarpine.
hard candy and sugar-free chewing gum can also stimulate salivation, but these
treatments are typically considered oral comfort agents. Saliva substitutes can also
provide oral comfort to patients with xerostomia. Commercially available saliva
substitutes generally are recommended for use before meals and at bedtime. They are
available in several formulations, including sprays, rinses, and chewing gums.
Patients who find one product or formulation unacceptable or unsuccessful may
benefit from experimenting with other formulations or product lines. Studies have
shown that salivary substitutes containing carboxymethyl cellulose or hydroxyethyl
cellulose are more effective in relieving dryness than water-based or glycerin-based
Prevention of radiation-induced cavities is best accomplished by aggressively
48 Generally, acidulated fluorides are the most effective, although
neutral fluorides may be more acceptable to patients with mucositis. Patients are
instructed to rinse daily for 1 minute with 5 to 10 mL of a fluoride rinse. Stannous
fluoride gels 0.4% or sodium fluoride gel 1.1% tooth brushing agents may also be
used by patients to minimize their risk of caries. Meticulous attention to oral hygiene
with regular dental checkups and avoidance of sucrose is essential to minimize the
In general, a dentist should see patients who will be receiving radiation therapy to
the head and neck or chemotherapy agents with a high risk of oral complications
before starting therapy. This includes patients with hematologic malignancies who
will most likely experience severe myelosuppression for prolonged periods. Oral
evaluation before therapy, intervention to eliminate potential sources of infection or
irritation before therapy, and preventive measures taken during therapy can
dramatically decrease the frequency of oral complications.
factors, including the dose of radiation he will receive and concomitant therapy with
cisplatin, a dental examination is indicated before initiating therapy.
CASE 94-2, QUESTION 2: J.B. successfully completed his first 2 weeks of combined chemotherapy and
likely explanation for J.B.’s new onset of symptoms? What treatment is indicated at this time?
Mucositis occurs as a nonspecific effect of chemotherapy and radiation therapy on
the basal epithelium of the mouth. Nonkeratinized mucosa is affected most often.
Thus, the buccal, labial, and soft palate mucosa, the ventral surface of the tongue, and
the floor of the mouth are the most common sites of involvement. Although lesions
are usually discrete initially, they often progress to produce large areas of ulceration.
The lesions typically do not progress outside the mouth, but they may extend to the
esophagus and involve the entire GI tract. The terms of stomatitis and oral mucositis
may be used interchangeably. Mucositis may occur anywhere along the full GI tract.
Signs and symptoms generally occur about 5 to 7 days after chemotherapy or at
almost any point during radiation therapy. The antimetabolites (e.g., methotrexate,
fluorouracil, capecitabine, and cytarabine) and the antitumor antibiotics are the
chemotherapy agents that most commonly produce direct effects on the epithelial
cells of the GI tract. Lesions generally regress and resolve completely in
approximately 1 to 3 weeks, depending on their severity. Unlike oral toxicity seen
with conventional chemotherapy, aphthous-like mucositis or stomatitis is a prevalent
toxicity distinctly seen with mTOR (mammalian target of rapamycin) inhibitor
therapy. Lesions typically appear during the first cycle of therapy, within the first
week. Management often consists of supportive care measures and dose reductions.
In severe cases, mucositis may require parenteral opioid analgesics for relief.
Other signs or symptoms include decreased ability to eat and speak. Mucositis may
be confused with an oral infection (particularly thrush), or mucositis and oral
infections may occur concurrently. Local and systemic bacterial, fungal, or viral
infections can occur and can cause a characteristic lesion; however, the lesion’s
appearance usually does not always correlate with the infectious agent. This
particularly occurs in patients with neutropenia who cannot mount a full inflammatory
response. In these individuals, the clinical appearance of an infected lesion may be
muted relative to the presence or number of pathogens. Under normal conditions, the
mucosa provides a natural barrier to the entry of normal oral flora, but the ulcerated
mucosa allows pathogens access to the bloodstream. The patient could experience
life-threatening infection or sepsis in addition to a local infection.
Treatment of mucositis is palliative. Topical anesthetics, including viscous lidocaine
or dyclonine hydrochloride 0.5% or 1%, are often recommended. Equal portions of
lidocaine, diphenhydramine, and magnesium-containing or aluminum-containing
antacids can be used for their anesthetic and astringent properties. Many institutions
compound mouthwash products containing these ingredients as well as antibiotics,
nystatin, or corticosteroids. Corticosteroids provide anti-inflammatory properties,
and the antibiotics and antifungals provide antibacterial or antifungal properties.
Another topical agent, sucralfate, may provide some benefit by coating the lesion and
reducing discomfort. All of these topical products provide symptom control only, and
data supporting superior efficacy of one product over another in relieving pain are
lacking. Furthermore, these topical products are only effective in oral and throat
lesions because lesions lower in the GI tract are not reached with these local
All the topical anesthetic-containing preparations are recommended for use as
“swish-and-spit” preparations. Generally, 5 to 10 mL is used three to 6 times a day.
The longer the patient can hold the solution in the mouth, the longer the contact, and,
theoretically, the better the symptom relief. Therefore, patients should be advised to
hold and swish the solution around the mouth for as long as possible before spitting it
systemic effects from topical anesthetic preparations is slim if patients were to
swallow them; however, large quantities swallowed could induce sedation and
possible arrhythmias. Other palliative treatment options include topical benzocaine
and ice chips. For small localized lesions, ointments such as benzocaine may be
applied after the affected area has been dried with a sponge. Patients may also find
ice chips soothing by allowing them to melt in their mouth. Most patients, however,
require systemic analgesics to alleviate the pain. Table 94-1 provides guidelines to
Gelclair is a bioadherent oral gel containing polyvinylpyrrolidone, hyaluronic
acid, and glycyrrhetinic acid (but no alcohol or anesthetic agent). It provides an
adherent barrier over the mucosal surfaces, thereby shielding oral lesions from the
effect of food, liquids, and saliva.
51 Controlled clinical data are lacking. In a study of
20 patients with head and neck cancer undergoing radiation therapy presenting with
mucositis, Gelclair was compared with standard of care, including sucralfate and
lidocaine. No significant difference was found between the Gelclair and standard of
care in relieving general pain.
J.B. appears to have a mild case of stomatitis or mucositis at this time. J.B. should
be encouraged to maintain good mouth care by keeping his mouth clean. Additionally,
topical anesthetics are indicated for J.B. Topical lidocaine or a mixture of topical
lidocaine with diphenhydramine and an antacid, 5 to 10 mL swish and spit 3 to 6
times/day, should be recommended. If the lesions progress during the next several
days, systemic opioids may be necessary. J.B. should also be carefully assessed for
local infections within his mouth.
CASE 94-2, QUESTION 3: Could J.B.’s mucositis have been prevented?
Historically, treatment of chemotherapy-induced and radiation-induced mucositis
has been aimed at reducing symptoms once they occur and avoiding further trauma to
the oral mucosa. Cryotherapy has been marginally effective in reducing the severity
of chemotherapy-induced mucositis.
Ice chips are placed in the mouth 5 minutes
before chemotherapy begins and retained for 30 minutes. Theoretically, this will
reduce blood flow to the mouth, thereby protecting the dividing cell population from
toxins. Chlorhexidine gluconate 0.12% also may reduce the frequency and severity of
54,55 although not all studies have shown a benefit. This solution
should be used twice daily as a rinse. Side effects include occasional burning
(thought to be caused by the product’s alcohol content, which can be reduced by
diluting it with water) and superficial brown tooth staining, which polishes off
easily. Chlorhexidine may reduce the frequency and severity of mucositis by
eliminating microorganisms in the oral cavity.
Guidelines for the Management of Mucositis
An oral care protocol which may include the following:
Remove dentures to prevent further irritation and tissue damage
Maintain gentle brushing of teeth with a soft toothbrush
Avoid mouthwashes or rinses that contain alcohol because they may be painful and cause drying of the
mucosa. Consider normalsaline or sodium bicarbonate oralswishes
associated with severe mucositis. Acetaminophen is often avoided because it may mask fevers in
Ensure that adequate hydration and nutrition are maintained:
Eat a bland diet, avoiding spiced, acidic, and salted foods
Avoid rough food; process in a blender if necessary
Use sugar-free gum or sugar-free hard candy to stimulate salivation and facilitate mastication
If necessary, provide intravenous (IV) nutritionalsupport
Avoid extremely hot or cold foods
Use shakes with nutritionalsupplements or ice cream
Despite these prophylactic measures, none of these aforementioned methods have a
definitive benefit. To date, the only medication with proven efficacy is palifermin, a
keratinocyte growth factor, approved for patients with hematologic malignancies
undergoing HCT to reduce the incidence and duration of severe oral mucositis. For
further discussion, see Chapter 101, Hematopoietic Cell Transplantation.
Other methods for decreasing the incidence and severity of mucositis symptoms
include reducing the dose of radiation or cytotoxic therapy, but doing so comes at the
risk of compromising treatment outcomes. Mucositis remains the dose-limiting
toxicity for several anticancer regimens. Unfortunately, there are no prevention
strategies that would reduce the chance of J.B. experiencing mucositis from his
chemotherapy and radiation, and thus, treatment for J.B. is targeted toward relief of
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