Ifosfamide
Ifosfamide is associated with an encephalopathy thought to result from one of its
metabolites, chloroacetaldehyde. The incidence ranges from 10% to 20%; it presents
hours to days after initiation of treatment with confusion and disorientation and is
generally self-limiting. Methylene blue, albumin, and thiamine have been used for
both prevention and treatment. Conclusive evidence to promote routine prophylaxis
is not available.
158 Reported risk factors for this complication include a history of
ifosfamide-induced encephalopathy, prior cisplatin exposure, concomitant opioids,
concomitant CYP2B6 inhibitors, renal dysfunction, low serum albumin, increased
hemoglobin, and abdominal disease.
159,160
CASE 94-6, QUESTION 2: What is the most likely medication causing A.L.’s numbness?
Peripheral Neuropathy
Paresthesia (numbness and tingling) involving the feet and/or hands is an early
subjective symptom of vincristine neurotoxicity, which often appears within the first
days to weeks of therapy. Because A.L. received vincristine on days 1 and 8, it is
reasonable to assume that her presentation of numbness in her extremities is
secondary to her vincristine. This peripheral nerve toxicity commonly is bilateral and
symmetric and is often referred to as a “stocking-glove” neuropathy. Symptoms
initially consist of paresthesias, loss of ankle jerks, and depression of deep tendon
reflexes. Areflexia (absent reflexes) typically occurs in about 50% to 70% of
patients treated with a cumulative dose greater than 6 to 8 mg. Although older
patients appear to be more susceptible to paresthesias than younger ones, almost all
complain of paresthesias after combination chemotherapy that incorporates
vincristine or vinblastine. Pain and temperature sensory loss are usually more
pronounced than vibration and proprioception sensory loss. Patients also may display
motor weakness with a foot drop or muscle atrophy. Motor weakness, which can
become the most disabling symptom associated with vincristine neurotoxicity, can
occasionally cause muscle wasting. Although some patients exhibit muscle atrophy,
true muscle weakness seldom occurs after treatment with vincristine. Stumbling and
falling that can occur with this peripheral neuropathy is not usually caused by muscle
weakness; instead, it occurs in the dark when patients lose proprioception because
they lack visual orientation. These complications are either partially or completely
reversible, but recovery often takes several months.
161
Other agents that often share the peripheral nerve toxicity of vincristine include
vinblastine, vinorelbine, cisplatin, etoposide, oxaliplatin, paclitaxel, docetaxel,
cabazitaxel, ixabepilone, bortezomib, thalidomide, and lenalidomide among others.
147
Unlike the vinca alkaloids, most of these agents cause numbness only and not a loss
of reflexes, or weakness. Patients may report sensory loss and pain, however. The
incidence may be related to cumulative doses as well as individual risk factors such
as history of diabetic neuropathy.
162–164 Many preventive strategies have been
evaluated including amifostine, glutamine, glutathione, vitamin E, and others, but
many of the studies are limited by small sample sizes and are lacking placebocontrolled randomized designs.
165 The serotonin–norepinephrine reuptake inhibitor
(SNRI), venlafaxine, was evaluated for the prevention of neuropathy in a
randomized, double-blind, placebo-controlled Phase III trial of 48 patients receiving
an oxaliplatin-based regimen. The primary endpoint was the percentage of patients
with no acute neurotoxicity, which was significantly higher in the venlafaxine-treated
group compared with patients receiving placebo (31.3% vs. 5.3%, respectively; p =
0.03). Due to the small study population and ongoing concerns about compromise of
chemotherapy efficacy, this preventive strategy is not routine practice. Treatment
strategies are only palliative and include adjuvant pain medications such as tricyclic
antidepressants, anticonvulsants (pregabalin and gabapentin), and topical agents.
Peripheral neuropathy is usually reversible, although resolution may take months.
Several reviews provide detailed references for this information.
165–167
Oxaliplatin causes peripheral neuropathies that differ from other anticancer agents.
Oxaliplatin-induced neurotoxicity manifests as an acute neurosensory complex as
well as a cumulative sensory neuropathy. Hyperexcitability of peripheral nerves
causes an 85% to 95% incidence of paresthesia and dysesthesias of the hands, feet,
and the perioral region. Laryngeal dysesthesias have been described as well. These
effects are precipitated by exposure to cold. The cumulative dose-limiting chronic
neuropathy is described as a sensory neuropathy that is reversible several months
after completion of therapy. Dose modifications for patients with persistent
neurotoxicities have been developed and typically involves delaying therapy until
their condition improves.
168,169 Prevention of these toxicities with infusions of
magnesium and calcium has been evaluated in a prospective, randomized doubleblind study of patients (n = 102) with colon cancer receiving adjuvant therapy with
oxaliplatin, fluorouracil, and leucovorin. Patients received either calcium gluconate
1 g IV and magnesium sulfate 1 g IV 15 minutes before and immediately after
completion of
p. 1986
p. 1987
the oxaliplatin administration or placebo infusions. Calcium and magnesium
infusions reduced the incidence of grade 2 of greater sensory neurotoxicity
significantly over placebo (22% vs. 41%, respectively).
170 An additional Phase III
randomized trial of 353 patients randomly assigned to receive calcium and
magnesium pre-and postoxaliplatin showed no statistically significant differences in
the incidence of peripheral neuropathy compared to placebo.
171 Decreased efficacy
of this anticancer regimen has been reported with use of the calcium and magnesium
infusions.
172 Therefore, the use of calcium and magnesium infusions remains
controversial.
CASE 94-6, QUESTION 3: What is the significance of A.L.’s lid lag?
Cranial Nerve Toxicity
Cranial nerve toxicity occurs in 1% to 10% of patients receiving vinca alkaloids, and
most patients present with ptosis or ophthalmoplegia,
173,174 probably related to
damage to the third cranial nerve. Toxicity to other cranial nerves can cause
trigeminal neuralgia, facial palsy, depressed corneal reflexes, and vocal cord
paralysis—and may occur in the first few days to weeks after administration.
175 Other
nerve toxicities associated with the vinca alkaloids include jaw pain, which can
occur as early as after the first or second injection
176
; the pain usually resolves
spontaneously and does not recur with subsequent doses. Several of the cranial nerve
toxicities, especially with vincristine, may be dose-limiting because evidence shows
an increased prevalence with increasing doses. A.L.’s eyelid lag probably is caused
by vincristine.
Ifosfamide, vinblastine, and cisplatin have been reported to cause cranial
neuropathies. Intra-arterial administration of chemotherapy agents such as carmustine
may increase the risk of encephalopathy and cranial neuropathies.
Ototoxicity, characterized by a progressive, high-frequency, sensorineural hearing
loss, commonly occurs with cisplatin,
177,178 most likely as a result of a direct toxic
effect on the cochlea. Ototoxicity occurs more frequently at higher dosages, worsens
with concurrent cranial radiation therapy, and appears to be more pronounced in
children. The reversibility of cisplatin ototoxicity is questionable. At some centers,
routine audiometric tests are performed in patients receiving cisplatin; as a result,
these centers have a greater percentage of patients with documented decreases in
audio acuity than others. Early cessation of cisplatin may result in greater hearing
improvement. Although ototoxicity appears to be a major toxicity associated with
cisplatin, it has been reported in patients receiving carboplatin.
178
If ototoxicity is
suspected, a hearing test should be performed and therapy discontinued if alternate
treatments are available.
Autonomic Neuropathy
CASE 94-6, QUESTION 4: What is the cause of A.L.’s constipation, and how might this problem have been
prevented?
Vincristine, as well as vinblastine, commonly causes an autonomic neuropathy. The
earliest symptoms (colicky abdominal pain with or without constipation) are
reported by one-third to one-half of patients receiving these agents.
147,173 Because
severe constipation can progress to or include adynamic ileus, prophylactic laxatives
are recommended on a regular basis for patients receiving vincristine and
vinblastine. Stimulant laxatives such as the senna derivatives or bisacodyl are
believed to be the most effective agents, and stool softeners also may be used
concurrently. No compelling evidence suggests, however, that laxatives prevent
constipation. Other less frequent manifestations of autonomic dysfunction associated
with vinca alkaloids include bladder atony with urinary retention, impotence, and
orthostatic hypotension.
179,180 Patients should be monitored carefully for these signs or
symptoms and receive appropriate management after diagnosis.
CARDIOTOXICITY
Cardiomyopathy
Doxorubicin
CASE 94-7
QUESTION 1: D.A., a 35-year-old man with stage IV Hodgkin lymphoma, is receiving ABVD (doxorubicin
25 mg/m
2
IV days 1, 15, bleomycin 10 units/m
2
IV on days 1, 15, vinblastine 6 mg/m
2
IV on days 1, 15, and
dacarbazine 375 mg/m
2
IV on days 1 and 15) and concurrent radiation therapy to a large mediastinal mass. He
comes to the clinic to receive his fifth cycle of ABVD and complains of tachycardia, SOB, and a nonproductive
cough. Physical examination reveals neck vein distension, pulmonary rales, and ankle edema. Past medical
history is significant for controlled hypertension. What is the most likely cause of D.A.’s current symptoms?
D.A. is experiencing symptoms of congestive heart failure (CHF) most likely
caused by doxorubicin therapy. Doxorubicin, an anthracycline, can cause a dosedependent cardiomyopathy that generally occurs with repeated administration.
Doxorubicin causes myocyte damage by a mechanism that differs from its cytotoxic
effect on tumor cells. Because myocytes stop dividing in infancy, they presumably
would not be affected by an agent whose cytotoxicity relies on actively cycling cells.
Many mechanisms have been proposed to explain the cardiac toxicity associated with
anthracyclines including the formation of reactive oxygen species.
181–184 The
association of anthracycline-induced cardiotoxicity with other agents administered
concomitantly, monitoring techniques, and therapies to prevent and treat this
condition have been reviewed.
181,185,186
D.A.’s presentation is fairly typical of doxorubicin-induced cardiomyopathy,
although he has no significant risk factors usually associated with CHF. The total
cumulative dose of doxorubicin is the most clearly established risk factor for CHF.
187
Patients, such as D.A., who are receiving bolus doses of doxorubicin at the standard
3-week interval face little risk of CHF until a total dose of 450 to 550 mg/m2 has
been reached. After a patient has received a total dose greater than 550 mg/m2
, the
risk of CHF rises rapidly. Patients receiving less than 550 mg/m2 of doxorubicin face
a 0.1% to 1.2% risk of experiencing CHF. Comparatively, patients receiving greater
than 550 mg/m2
face a risk that rises more or less linearly; the probability of CHF in
patients receiving a total dose of 1,000/m2 may be nearly 50%.
187
Other factors that could increase D.A.’s risk of experiencing doxorubicin
cardiomyopathy include mediastinal radiation therapy, preexisting cardiac disease,
and hypertension. Young children, as well as older patients, are likely to experience
CHF at a lower cumulative dose. Concurrent chemotherapy agents (e.g.,
cyclophosphamide, etoposide, mitomycin, melphalan, trastuzumab, paclitaxel,
vincristine, bleomycin) may also potentiate doxorubicin cardiac toxicity.
181,185 When
patients receive paclitaxel and doxorubicin, the risk of cardiac toxicity appears to be
related to the sequence and proximity of the infusions. In a pharmacokinetic study,
paclitaxel increased the AUC of doxorubicin and its active metabolite,
doxorubicinol, when paclitaxel administration immediately preceded doxorubicin.
Therefore, doxorubicin should be given at least 30 minutes before paclitaxel. The
relationship between risk factors and the total cumulative dose of doxorubicin is
sufficiently strong to warrant guidelines restricting the total cumulative dose of
doxorubicin to 450 mg/m2
in patients with one or more identified risk factors
including mediastinal radiation, elderly age, and preexisting cardiovascular
p. 1987
p. 1988
disease (high-risk patients) and to 550 mg/m2
in patients without any of these
aforementioned risk factors (low-risk patients).
It is unusual that D.A., a 35-year-old man who has received a cumulative dose of
only 200 mg/m2 of doxorubicin, would be presenting with symptoms of CHF.
Mediastinal radiation therapy, or an undiagnosed cardiac disease may, however,
have contributed to this event. In addition, Hodgkin lymphoma involving the
myocardium may be responsible for this presentation.
Cardiac Monitoring
CASE 94-7, QUESTION 2: Should D.A. receive routine cardiac monitoring while he is receiving
doxorubicin?
Doxorubicin
Prevention of cardiomyopathy is achieved primarily by limiting the total cumulative
dose. Limiting the total dose, however, cannot entirely prevent the cardiomyopathy
for two reasons. First, individual tolerance to doxorubicin varies such that
cardiotoxicity may occur before the arbitrary dose limit; second, some clinical
situations warrant exceeding the dose limit to achieve positive chemotherapeutic
outcomes.
Early efforts to prevent cardiomyopathy focused on monitoring systolic time
intervals, QRS voltage loss, or ST-T segment changes on an electrocardiogram.
These changes were too nonspecific or occurred too late to be useful; however,
serial echocardiography (ECHO) has been useful. Current monitoring for
anthracycline cardiomyopathy includes assessment of a patient’s left ventricular
ejection fraction (LVEF), which is a measure of the heart’s systolic function by
ECHO, radionuclide cardiac angiography (multiple gated acquisition [MUGA]), or
endomyocardial biopsy. The use of MUGA for early detection of doxorubicininduced cardiac dysfunction has been investigated extensively.
188 A MUGA can
accurately detect functional cardiac status, but it is not particularly sensitive in
detecting patients who have early myocyte damage. Augmenting the MUGA with
exercise appears to give a more accurate picture of functional cardiac reserve.
Because myocyte damage usually occurs days to weeks after treatment with
doxorubicin, the MUGA should be obtained just before, rather than just after, a
course of the agent. Although guidelines vary, most suggest regular cardiac function
assessment by evaluation of LVEF by either ECHO or MUGA.
185
D.A. should have received a baseline assessment of his LVEF either by ECHO or
MUGA before his first cycle of ABVD. During courses of therapy, LVEF monitoring
for D.A. would not have been routinely recommended unless he was approaching his
lifetime cumulative dose or there were clinical signs or symptoms of CHF. Because
D.A. presented before his fifth cycle of ABVD with symptoms of CHF, another
ECHO should be performed, and his doxorubicin should be discontinued.
Additional assessments should be obtained when a patient shows signs or
symptoms of CHF or when low-risk patients receive cumulative doxorubicin doses
greater than 450 mg/m2 or high-risk patients receive greater than 350 mg/m2
, if
additional doses are planned. Most guidelines recommend stopping doxorubicin or
obtaining an endomyocardial biopsy when there is an absolute decrease in the LVEF
of greater than 10% to 20%, the LVEF is less than 40%, or the LVEF fails to increase
greater than 5% with exercise. Endomyocardial biopsies, along with a quantitative
assessment of morphologic changes, provide the most specific evaluation of
myocardial damage induced by anthracyclines. Progressive myocardial pathology is
graded on a scale (the Billingham score) of 0 (no change from normal) to 3 (diffuse
cell damage in >35% of total number of cells with marked change in cardiac
ultrastructure).
189 Abnormal MUGA findings and the appearance of signs and
symptoms of CHF correlate with biopsy scores. Usually, a significant change in
cardiac function is not seen with scores less than 2 to 2.5. Several investigators have
evaluated the predictive value of this technique. With a score of 2, a patient has less
than a 10% chance of experiencing heart failure if 100 mg more of doxorubicin is
given.
190 The most significant risk associated with endomyocardial biopsy is
perforation of the right ventricle with associated tamponade; this occurs rarely and
depends largely on the experience of the individual performing the biopsy.
Other Anthracyclines
Daunorubicin differs structurally from doxorubicin only by hydroxylation of the
fourteenth carbon. Cardiac toxicities are similar for both drugs, although somewhat
higher cumulative doses of daunorubicin are typically tolerated.
191 Although
idarubicin appears less cardiotoxic than doxorubicin in animal models and
daunorubicin in some early clinical trials, other studies show equivalent
myelosuppressive doses can cause cardiotoxicity comparable to that of doxorubicin
and daunorubicin.
192–194 Epirubicin also has an incidence of demonstrated CHF.
195
For all of the agents in the anthracycline class, risk factors for CHF appear to be the
same, and similar assessments should be undertaken to monitor for cardiotoxicity.
Mitoxantrone is an anthracenedione that is structurally similar to the anthracyclines.
Guidelines for monitoring doxorubicin-induced cardiotoxicity should also be
followed with mitoxantrone therapy to minimize the risk for CHF.
185
Prevention
CASE 94-7, QUESTION 3: Could D.A.’s CHF be prevented by the use of a different dose or dosing
schedule or by an agent that protects the myocardium?
Altering the dose schedule of doxorubicin to more frequent, smaller doses while
maintaining dose intensity has consistently resulted in reduction of cardiotoxicity
without obvious compromise of antitumor effects.
196–200 Several reports suggest that
peak plasma levels, as well as cumulative dose, have an important relationship to
doxorubicin cardiotoxicity. Low doses of doxorubicin administered weekly or
prolonged continuous IV infusions (48–96 hours) can be relatively cardiac sparing,
allowing higher cumulative doses to be administered. In a retrospective, uncontrolled
study of 1,000 patients receiving weekly doxorubicin, a total dose of 900 to 1,200
mg/m2 of doxorubicin given in weekly fractions had the equivalent cardiotoxicity of
550 mg/m2 given in every-3-week fractions.
197 Although well-designed studies
comparing cardiac toxicity after bolus doses with fractionated therapy or continuous
infusion are lacking, treatment that incorporates these alternative schedules should be
considered in patients with preexisting risk factors who will be receiving doses
greater than 450 mg/m2 or in patients without risk factors who will be receiving
doses greater than 550 mg/m2
. In patients with preexisting CHF or those who have
exhibited CHF, a continuous-infusion schedule of anthracyclines rather than bolus
doses may be considered. The concurrent use of drugs that might minimize the risk of
cardiotoxicity without compromising efficacy can be considered as well.
Dexrazoxane is a chemoprotectant that reduces the incidence and severity of
cardiomyopathy. It is indicated in women with metastatic breast cancer who have
received a cumulative doxorubicin dose of 300 mg/m2
. The recommended dosing
ratio of dexrazoxane to doxorubicin is 10:1 slow IV push 30 minutes before starting
doxorubicin. Currently, the ASCO guidelines do not support the routine use of
dexrazoxane in patients unless a
p. 1988
p. 1989
plan exists to continue doxorubicin beyond a total cumulative dose greater than
300 mg/m2
.
44 Clinical trials have evaluated the benefits of dexrazoxane in children
and patients receiving other anthracyclines. A meta-analysis including 10 trials with
a total of 1,619 patients evaluated the use of dexrazoxane in anthracycline therapy
and observed a decreased risk of clinical HF (relative risk 0.18, CI 0.1–0.32, p <
0.001), but there was no effect on overall survival.
201 Despite data suggesting
cardioprotection with the use of dexrazoxane, it is not used routinely. Concerns exist
about a possible decrease in efficacy of anthracyclines with its use as well as the
potential for an increase in secondary leukemias. In the meta-analysis, there was no
difference in tumor response rate reported and toxicities attributed to dexrazoxane
only included an increased frequency of risk of neutropenia that resolved with count
recovery.
201
To reduce cardiotoxicity, doxorubicin that is encapsulated in liposomes can be
given instead. A Phase III trial of women (n = 509) with metastatic breast cancer
showed that efficacy with liposomal pegylated doxorubicin may be similar to
conventional doxorubicin with decreased cardiotoxicity.
202 A review and metaanalysis of 55 randomized control trials in patients receiving anthracyclines showed
that the risk of cardiotoxicity was significantly decreased with liposomal
doxorubicin versus conventional doxorubicin (odds ratio, 0.18; 95% confidence
interval, 0.08–0.38).
203 The majority of patients were women with advanced breast
cancer. Despite reduced cardiotoxicity, liposomal doxorubicin has not replaced
standard doxorubicin in current treatment regimens secondary to high cost and lack of
evidence showing equivalency. An established equivalent dose of liposomal
preparations to conventional doxorubicin is not confirmed and is variable depending
on the disease state and regimen.
D.A.’s CHF may have been prevented with continuous-infusion doxorubicin or the
use of dexrazoxane; however, because he had not approached a cumulative dose that
warranted alternative strategies, this would not have been part of the standard
management plan for a patient receiving their first several cycles of ABVD.
Management
CASE 94-7, QUESTION 4: How should D.A.’s doxorubicin-induced CHF be managed clinically?
Anthracycline-induced CHF presents similarly to other forms of biventricular CHF
and occurs between 0 and 231 days after the last dose of doxorubicin (mean, 33
days). Anthracycline-induced CHF should be treated with a similar approach to
cardiomyopathy induced by other means. Often these measures are ineffective. The
clinical course varies, with some patients showing stable disease and others showing
improvement. Before cardiotoxicity was a widely recognized toxicity, the course of
anthracycline-induced CHF was characterized by a rapid progression that generally
led to death in a few weeks. The clinical outcome is better now, likely because
anthracycline therapy is promptly discontinued after initial presentation and there are
better treatments for CHF. These include the use of spironolactone, β-blockers,
angiotensin-converting enzyme (ACE) inhibitors, angiotensin II receptor blockers,
and diuretics, which have decreased morbidity and mortality in non-anthracyclineinduced CHF. Enalapril was evaluated to determine whether it would prevent
cardiac function decline in a randomized, double-blind, placebo-controlled study of
pediatric cancer patients who were at least 2 years out from treatment with
anthracyclines and had evidence of CHF. Patients received enalapril at 0.05
mg/kg/day and this dose was progressively escalated to 0.10 mg/kg/day, and finally
0.15 mg/kg/day if there were no side effects. Although enalapril did not increase
exercise intolerance, it did increase left ventricular end-systolic wall stress in the
first year of treatment. Side effects included dizziness, hypotension, and fatigue.
204,205
An additional trial evaluated 201 patients with anthracycline-induced
cardiomyopathy. Enalapril and carvedilol were initiated as tolerated as soon as
LVEF impairment was observed. Complete resolution of CHF was observed in 85
(42%) of patients, and an additional 26 (13%) demonstrated a partial response.
Patients who had heart failure therapy initiated closer to the time of observation of
their LVEF impairment had better response. No responses were observed in patients
who had heart failure therapy initiated greater than 6 months from the end of their
anthracycline regimen.
206 D.A.’s cardiomyopathy should be managed conservatively
with an ACE inhibitor such as enalapril and fluid restriction with the addition of
diuretics as necessary.
183
Trastuzumab
In addition to anthracyclines, trastuzumab has also been associated with increased
cardiotoxicity, likely through a different mechanism. Signs and symptoms of CHF
(e.g., dyspnea, increased cough, peripheral edema, S3 gallop, and reduced ejection
fraction) have been reported in 3% to 7% of patients receiving trastuzumab singleagent therapy. Of these patients, 5% had New York Heart Association (NYHA) class
III or IV heart failure. The use of trastuzumab in combination with chemotherapy in
patients (n = 469) with metastatic breast cancer was associated with a 27%
incidence of cardiotoxicity compared with an overall 8% incidence in the
anthracycline-alone arm. In these same patients, the incidence of NYHA class III or
IV heart failure was 16% in the trastuzumab and chemotherapy arm versus 3% in
patients receiving anthracyclines alone. Additionally, heart failure occurred in the
combination paclitaxel and trastuzumab arm with an overall incidence of 13% and
2% (classes III and IV, respectively) versus a 1% incidence in the paclitaxel-alone
arm.
207 A meta-analysis of five randomized trials of adjuvant trastuzumab also
showed a 2.5 higher risk of cardiotoxicity following trastuzumab administration.
208
The toxicity seems to be direct and not dependent on cumulative dose or treatment
duration. Trastuzumab-associated cardiac toxicity usually responds to standard
medical treatment or discontinuation of the drug.
181 Before, and periodically during
treatment with trastuzumab, patients should undergo cardiac evaluation to assess left
ventricular ejection fraction. Therapy should be discontinued if patients exhibit a
clinically significant decrease in left ventricular function.
Multitargeted Tyrosine Kinase Inhibitors
The multitargeted tyrosine kinase inhibitors exhibit a range of cardiovascular
toxicities. Because these agents are dosed chronically, toxicities may develop
relatively late in the course of therapy. Imatinib has been associated with the
development of CHF. A single-institution series reviewed all patients ( n = 1,276)
who had received imatinib within their institution. Twenty-two patients (1.2%)
exhibited CHF. Eleven patients continued imatinib with the addition of diuretics, βblockers, and ACE inhibitors. Five of those who continued therapy with imatinib had
dose reductions. The remaining eleven discontinued imatinib (3 secondary to disease
progression, 6 secondary to CHF, and 2 were deaths).
209 Patients receiving imatinib
should be monitored for symptoms and signs of heart failure.
210 Dasatinib has also
been associated with heart failure and ventricular dysfunction.
211 Sorafenib and
sunitinib have been associated with a decline in cardiac ejection fraction in 5% and
14%, respectively, in 86 patients treated for metastatic renal cell cancer.
212 A decline
in cardiac function has also been reported in a pooled analysis of 3,689 patients with
breast cancer receiving lapatinib. The incidence was 1.6% (60 patients). Twelve of
the patients had prior anthracyclines and fourteen had received prior
p. 1989
p. 1990
trastuzumab.
213 There have been additional oral oncolytic agents associated with
CHF including pazopanib and vemurafenib.
185 Patients experiencing cardiomyopathy
on targeted agents are treated similarly to those patients with anthracycline-induced
cardiomyopathy. Discontinuation of the offending agent or reduction of dose with
concurrent pharmacologic management of CHF is warranted. Two reviews of
proposed mechanisms and reported incidence of targeted therapy-induced
cardiomyopathy therapies provide a summary of current evidence.
181,214
Arrhythmias
Electrocardiographic (ECG) changes have been observed during or after treatment
with doxorubicin, other anthracyclines, cisplatin, etoposide, paclitaxel,
cyclophosphamide, mechlorethamine, and arsenic. ST-T segment changes, decreases
in voltage, T-wave flattening, and atrial and ventricular ectopy are most common.
Arrhythmias may occur in 6% to 40% of patients receiving bolus doxorubicin.
215
Paclitaxel also caused significant arrhythmias and conduction defects in Phase I and
II trials
216
; most patients experienced sinus bradycardia. Doxorubicin and paclitaxel
are used in many outpatient regimens, so this toxicity is seen frequently. Arsenic,
used in the treatment of APL, can cause QT interval prolongation and complete
atrioventricular block. Dasatinib, nilotinib, lapatinib, pazopanib, and sunitinib have
also demonstrated QT prolongation.
185 The underlying mechanisms for these
prolongations are not yet understood. Nilotinib, with a reported incidence of 1% to
10%, carries a black box warning regarding prolongation of the QT interval. The
package insert gives specific recommendations for monitoring of ECGs; baseline, 7
days after initiation, after any change of dose, and routinely thereafter.
217 QT
prolongation can lead to a torsade de pointes-type ventricular arrhythmia. Before
initiating therapy, an ECG should be performed, and serum electrolytes, including
potassium and magnesium, should be assessed and corrected. Additionally, all
medications, both anticancer and other supportive care medications that are known to
prolong the QT interval, should be discontinued.
185 Many other anticancer agents not
mentioned previously occasionally cause a rhythm disturbance, but these are limited
to a few scattered reports and should not be considered clinically significant.
Therapy should not be discontinued unless the patient experiences a serious cardiac
arrhythmia.
Hypertension
An increased incidence of hypertension has been observed in patients receiving
VEGF-targeted therapy including bevacizumab, sunitinib, sorafenib, axitinib,
regorafenib, and pazopanib among others. Bevacizumab-related hypertension may be
dose-related; it can occur at any time during therapy and is reported to have a 22% to
32% incidence. Hypertension is usually grade 3 or less and can be controlled with
antihypertensive medications.
218 An increased risk of myocardial ischemia and
infarction has been observed with the use of sorafenib in patients with metastatic
renal cell cancer in a Phase III study.
219 Patients receiving these agents should be
routinely monitored for hypertension and antihypertensives promptly initiated. In
patients with uncontrolled hypertension, anticancer therapy medication may need to
be dose-reduced or discontinued. Several consensus statements and guidelines have
been published to assist in the hypertension management of patients in VEGF
inhibitors.
220,221
Angina and Myocardial Infarction
Fluorouracil and capecitabine have been associated with angina pectoris and
myocardial infarction. In a systematic review including 30 studies, symptomatic
cardiotoxicity occurred in 0% to 20% of the patients treated with fluorouracil and in
3% to 35% with capecitabine. The most common symptom was chest pain (0%–
18.6%) followed by palpitations (0%–23.1%), dyspnea (0%–7.6%), and
hypotension (0%–6%). It appears to occur more frequently in patients receiving
multiple-day continuous infusions.
222 Direct myocyte damage is observed from
animal studies; however, human studies suggest that coronary artery spasm is the
most likely cause of angina. Because the chest pain associated with fluorouracil
responds to nitrates, this problem, theoretically, could be managed prophylactically
or therapeutically with long-acting nitrates or calcium-channel blockers.
221 Other
agents have been associated with myocardial ischemia (including, but not limited to
temsirolimus, docetaxel, paclitaxel, and imatinib) based on case reports in the
literature.
185
NEPHROTOXICITY
Cisplatin
CASE 94-8
QUESTION 1: T.J., a 58-year-old man with nonresectable head and neck cancer, is being treated with
cisplatin 100 mg/m
2
IV on day 1 and fluorouracil 1 g/m
2
/day IV on days 1 to 4. He received 1 L of normal
saline (NS) before and 1 L of NS after his cisplatin on day 1. He presents today for the third cycle of this
regimen. T.J.’s labs reveal an estimated creatinine clearance (CrCl) of 75 mL/minute, decreased from 110
mL/minute at baseline. Other abnormalities include serum magnesium of 1.2 mEq/L; all other electrolyte values
are within normal range. Is cisplatin responsible for T.J.’s decreased glomerular filtration rate (GFR) and serum
magnesium levels?
Cisplatin, a platinum heavy metal complex, is active against many solid tumors and
remains as part of first-line therapy for lung, head and neck, and testicular cancers.
The major dose-limiting toxicity of cisplatin is nephrotoxicity, and various renal and
electrolyte disorders, both acute and chronic, have been associated with cisplatin. In
the early 1970s, before the need for vigorous hydration was recognized, cisplatin
often caused acute renal failure. Today, with the use of vigorous hydration, acute
renal failure is uncommon; however, tubular dysfunction and decreased GFR remain
problematic.
Morphologic damage is greatest in the straight segment of the proximal renal
tubules where the highest concentration of platinum occurs. Acute and cumulative
renal tubular damage has been demonstrated by increased urinary excretion of
proximal tubular enzymes, such as β2
-microglobulin, alanine aminopeptidase, and Nacetyl glucosamine. Acute renal failure occurs from acute proximal tubular damage
and presents as polyuria in the first 24 to 48 hours when urine osmolality declines,
but GFR is normal. Polyuria will decline, and then 72 to 96 hours later polyuria
increases again, urine osmolality declines, and the GFR declines as well and is
persistent. Increases in proximal tubular enzymes correlate well with urinary
excretion of protein and magnesium as well as decreased reabsorption of salt and
water in the proximal tubules. T.J. has hypomagnesemia, which is the most common
electrolyte abnormality caused by cisplatin. Hypomagnesemia appears to be doserelated and may occur after a single treatment. Despite replacement with oral
magnesium, renal losses of magnesium and decreased serum magnesium levels can
persist for months or even years after completion of cisplatin therapy. Hypocalcemia,
hyponatremia, and hypokalemia occur less frequently. The cause of these electrolyte
abnormalities is thought to be similar to that of hypomagnesemia in that a proximal
tubular defect occurs that interferes with reabsorption of these electrolytes.
223,224
p. 1990
p. 1991
Chronic renal toxicity associated with cisplatin presents as a decrease in the GFR.
Published reports suggest that the GFR decreases by 12% to 25% in most patients
receiving multiple courses.
224 The decrease appears to be persistent and only
partially reversible. An increase in serum creatinine or a decrease in CrCl does not
necessarily reflect the decline in GFR. T.J. is at risk for chronic renal toxicity
because he has previously received two other cycles. The renal function of patients
receiving cisplatin therapy should be evaluated, because dosage reductions of
cisplatin may be necessary if the CrCl decreases. T.J.’s decreased GFR and low
serum magnesium likely are caused by repeated cycles of cisplatin therapy. Although
a dose reduction of cisplatin generally is not recommended for creatinine clearances
that are greater than 60 mL/minute, the clinician should provide T.J. with adequate
and aggressive hydration to prevent cisplatin nephrotoxicity. Despite preventive
methods, many patients will still experience declines in GFR as seen in T.J. In
addition, T.J. should receive an oral magnesium supplement. When large doses of
magnesium are necessary, diarrhea often limits the use of oral supplementation. IV
administration should be used if higher magnesium doses are required. Patients
should undergo frequent measurements of their electrolytes, including magnesium, to
minimize potential complications.
Prevention
CASE 94-8, QUESTION 2: What measures should be taken to prevent further cisplatin nephrotoxicity in
T.J.?
Several measures are used to minimize or prevent cisplatin- induced
nephrotoxicity, including hydration with saline and prophylactic magnesium.
Incorporation of hydration with saline and magnesium is the standard of care for all
patients receiving cisplatin. The patient should be vigorously hydrated with 2 to 3 L
of normal saline over 8 to 12 hours to maintain a urine output of 100 to 200 mL/hour
for at least 6 hours after treatment with cisplatin.
223–225 A loop diuretic (e.g.,
furosemide) may be required in elderly patients to eliminate excess sodium or in
patients with compromised cardiac reserve, but these diuretics should not be used
routinely to prevent nephrotoxicity. Additionally, mannitol (25–50 g) may be
administered just before chemotherapy to prevent cisplatin-induced renal artery
vasoconstriction, which can increase the concentration of platinum in the renal
tubules. The use of mannitol is controversial and is not given in all practice settings.
Most patients may also benefit from prophylactic magnesium supplementation.
Patients who received prophylactic magnesium 16 mEq IV daily during a 5-day
course of cisplatin followed by 60 mEq orally (20 mEq 3 times daily) between
courses experienced less nephrotoxicity compared with those who received no
supplements in a prospective trial of 16 patients with testicular carcinoma.
226 T.J.
should be encouraged to increase his oral hydration to 2 to 3 L/day for several days
after this cycle of chemotherapy. Additionally, he should take oral magnesium
supplementation between courses. For cycle 4 of his chemotherapy, he should
receive 3 to 4 L of saline the day of cisplatin administration. He may also receive 25
to 50 g of IV mannitol before cisplatin to reduce his risk of further nephrotoxicity.
Patients who experience renal dysfunction commonly have the dose of cisplatin
reduced. Guidelines to modify the dosage of cisplatin in patients with decreased
renal function are available. Most suggest a 50% dosage reduction when the GFR
decreases to 30 to 60 mL/minute and discontinuation when the GFR falls to less than
10 to 30 mL/minute. Percentage dose reductions are relative to the recommended
dose for a specific cancer in a given combination chemotherapy regimen.
227 Because
the cisplatin dose ranges from 50 to 120 mg/m2
, the precise dose for a patient with a
GFR of less than 60 mL/minute must be individualized to the situation. T.J. should
have another SCr drawn to estimate CrCl before his next cycle. As long as his CrCl
is maintained above 60 mL/minute, then no dose reductions of his cisplatin are
necessary. If a tumor type is known to be responsive to carboplatin and efficacy will
not likely be compromised, substitution of carboplatin should be considered because
it does not cause nephrotoxicity. Carboplatin is excreted primarily by the kidneys and
the dose is calculated by the Calvert equation,
228 which accounts for decreased GFR
(discussed further in Chapter 98, Lung Cancer). Therefore, patients who have
decreased renal function receive lower doses than those with normal function. Other
agents requiring dose adjustments or omission for renal dysfunction are shared in
Table 94-9.
Other Nephrotoxic Agents
Proximal Tubule Dysfunction
Other agents reported to cause renal tubular defects include lomustine, carmustine,
ifosfamide, pemetrexed, and azacytidine.
223,225 Nephrotoxicity appears to be related
to the total cumulative dose for carmustine and lomustine, but not necessarily for
ifosfamide. Renal abnormalities associated with high doses of bolus ifosfamide have
led to the use of fractionated doses and a reduced incidence of toxicity.
223 Most
patients show signs and symptoms consistent with proximal tubular dysfunction.
The primary renal lesion associated with each of these agents occurs in the
proximal renal tubule and patients experience several electrolyte imbalances, such as
loss of protein, glucose, bicarbonate, and potassium. Serum creatinine, bicarbonate,
potassium, urinary pH, protein, and glucose should be monitored closely in patients
receiving these agents. Because the reversibility of the lesions is reported to be
highly variable and a significant number of patients who exhibit severe renal toxicity
with these agents require dialysis,
223 patients should discontinue treatment with these
agents if they show any changes in serum creatinine or electrolytes.
Proteinuria
Bevacizumab, an anti-VEGF monoclonal antibody, is associated with proteinuria and
the reported incidence ranges from 21% to 46% of patients.
229 While bevacizumab is
the anti-VEGF agent most noted with this toxicity, oral tyrosine kinase inhibitors that
affect the VEGF receptor such as axitinib have also been associated with
proteinuria.
230 Mechanisms for this toxicity include microcirculatory angiogenesis
and inhibition of nitric oxide synthesis. This may lead to an increase in peripheral
resistance and endothelial dysfunction. Glomerular injury from VEGF inhibition may
also lead to renal thrombotic microangiopathy and glomerulonephritis. Severe
nephrotic syndrome has been observed in 1% to 2% of patients.
221,229,231 Patients
receiving bevacizumab should be monitored routinely for proteinuria by dipstick
urinalysis. The manufacturer recommends that patients with a 2+ or greater urine
dipstick reading undergo further assessment with a 24-hour urine collection.
Additionally, it is recommended to delay further administration of bevacizumab when
greater than 2 g of proteinuria in 24 hours is observed. Therapy may be reinitiated
when the proteinuria observed is less than 2 g in 24 hours. Proteinuria is most often
mild in patients and is usually reversible upon discontinuation of the agent. The
highest incidence of severe proteinuria requiring permanent discontinuation has been
seen in patients with metastatic renal cell carcinoma.
232
Table 94-9
Anticancer Agents Requiring Dosage Modifications or Dosage Omissions in
Renal Insufficiency
Bleomycin Lenalidomide
Capecitabine Lomustine
Carboplatin Melphalan
Carmustine Methotrexate
Cisplatin Mitomycin
Cytarabine Pemetrexed
Dacarbazine Pentostatin
Fludarabine Topotecan
Ifosfamide
Sources: Kintzel PE, Dorr RT. Anticancer drug renal toxicity and elimination: dosing guidelines for altered renal
function. Cancer Treat Rev. 1995;21:33; Launay-Vacher V et al. Prevalence of renal insufficiency in cancer
patients and implications for anticancer drug management: the renal insufficiency and anticancer medications
(IRMA) study. Cancer. 2007;110:1376; Li YF et al. Systemic anticancer therapy in gynecologic cancer patients
with renal dysfunction. Int J Gynecol Cancer. 2007;17:739.
p. 1991
p. 1992
CASE 94-9
QUESTION 1: J.R., a 15-year-old boy with osteogenic sarcoma of the right knee, is to be treated with
chemotherapy consisting of high-dose methotrexate with leucovorin rescue, doxorubicin, and cisplatin. The dose
of methotrexate is 12 g/m
2
IV administered over 4 hours. What precautions are necessary to prevent the renal
and other toxicities associated with high-dose methotrexate therapy in J.R.?
Methotrexate normally is not nephrotoxic, although 90% of the agent is excreted
unchanged in the urine; however, acute tubular obstruction can occur with high-dose
methotrexate if appropriate precautions are not taken. Acute tubular obstruction is
caused by tubular precipitation of methotrexate, which is poorly soluble at a pH less
than 7.0. To prevent this, J.R. should receive hydration and brisk diuresis to produce
urine output of 100 to 200 mL/hour for at least 24 hours after administration. A urine
pH greater than 7.0 usually can be ensured by administration of 25 to 150 mEq/L
sodium bicarbonate within the hydration fluid. J.R.’s urine output and pH must be
monitored closely to prevent acute tubular obstruction during this period.
233
In
addition, intrapatient and interpatient variability in methotrexate clearance is
considerable, particularly with high doses of methotrexate therapy. Renal excretion
of methotrexate is a complex process involving glomerular filtration, tubular
reabsorption, and secretion. Acute tubular obstruction associated with high-dose
methotrexate therapy can be prevented only by appropriate attention to optimal
urinary output before, and for at least 24 hours after, high-dose methotrexate
administration and urinary alkalization.
233
If J.R. has existing renal insufficiency, methotrexate excretion will be decreased,
leading to higher systemic exposure. As a result, myelosuppression and mucositis can
become more problematic. Leucovorin (folinic acid) is a reduced form of folic acid
given after methotrexate administration to selectively rescue normal cells from
adverse effects such as myelosuppression and mucositis. Because leucovorin is
already in reduced form, it can bypass the action of dihydrofolate reductase and not
interfere with methotrexate’s inhibition of this enzyme. Therefore, it is important that
leucovorin rescue is initiated 24 hours after the high-dose methotrexate infusion.
Blood concentrations of methotrexate obtained within 24 hours after the infusion
often are not predictive of concentrations at 48 hours. Therefore, methotrexate
concentrations between 24 and 48 hours after infusion must be monitored in J.R. and
in all patients receiving high-dose therapy. Methotrexate levels are necessary to
guide leucovorin dosing. Leucovorin rescue does not affect the renal clearance of
methotrexate. A rescue agent, glucarpidase, is indicated for the treatment of toxic
methotrexate concentrations in patients with delayed methotrexate clearance due to
impaired renal function. Glucarpidase is a recombinant bacterial carboxypeptidase
enzyme that converts methotrexate to its inactive metabolites, and provides an
alternative route for methotrexate elimination in patients with renal dysfunction and
signs or symptoms of methotrexate toxicity.
234
ion in patients with renal dysfunction and
signs or symptoms of methotrexate toxicity.
234
HEMORRHAGIC CYSTITIS
Ifosfamide
CASE 94-9, QUESTION 2: After J.R.’s surgery, it is decided to add ifosfamide to his treatment. What
bladder toxicity occurs with ifosfamide that requires attention before its administration?
Pathogenesis
Ifosfamide is a structural analog of cyclophosphamide belonging to the
oxazaphosphorine class of antitumor alkylating agents, which must be hydroxylated
and activated by the cytochrome P-450 3A4/3A5 and 2B6 enzymes in the liver. The
4-hydroxy metabolite spontaneously liberates acrolein, which is excreted in high
concentrations in the urine. Acrolein is responsible for urotoxicity causing a direct
irritation of the bladder mucosa. Both ifosfamide and cyclophosphamide can produce
cystitis, which ranges from mild-to-severe bladder damage and hemorrhage. Cystitis
is characterized by tissue edema and ulceration followed by sloughing of mucosal
epithelial cells, necrosis of smooth muscle fibers and arteries, and culminating in
focal hemorrhage.
Clinical Presentation
Patients with acrolein-induced hemorrhagic cystitis initially go through an
asymptomatic stage characterized by complaints of brief episodes of painful
urination, frequency, and hematuria. The symptoms may subside over a period of
several days or weeks after discontinuing the agent. The course of acrolein-induced
hemorrhagic cystitis usually is relatively benign, although death from massive
refractory hemorrhage has occurred.
235 The primary factors that may predispose J.R.
to hemorrhagic cystitis include the dose of ifosfamide he is receiving.
Prevention
Historically, forced hydration was the primary method used to prevent hemorrhagic
cystitis in patients treated with cyclophosphamide therapy. Theoretically, hydration
flushes the toxic acrolein metabolite out of the bladder so that insufficient contact
time is available to set up the tissue reaction. The more urotoxic agent, ifosfamide,
was introduced to the market with a uroprotective agent, mesna. This agent contains a
free thiol group, which can neutralize acrolein in the bladder. When administered in
an appropriate dosing schedule, mesna can prevent the bladder toxicity completely,
and thus use of mesna is the current standard of care.
225,235
The ASCO guidelines recommend a parenteral mesna dose of 20% of the
ifosfamide dose given at zero, 4, and 8 hours after ifosfamide (for a total mesna dose
of 60% of the ifosfamide dose).
44 The goal is to maintain prolonged mesna
concentrations within the urinary tract that are uroprotective. Repeated administration
is required because mesna has a much shorter elimination half-life (<1 hour) than
ifosfamide. If patients receive a continuous infusion of ifosfamide, a different dosing
strategy for mesna is required. To prolong mesna’s protective effects, ASCO
guidelines recommend an IV bolus mesna dose that is 20% of the ifosfamide dose,
followed by a mesna continuous infusion that is an additional equivalent of 40%
given during and for 12 to 24 hours after the end of the ifosfamide infusion.
46 This
regimen ensures that mesna remains
p. 1992
p. 1993
in the bladder for an extended amount of time after the end of the ifosfamide
infusion.
Various other mesna dosing schedules are clinically used, but no trials have
compared the different regimens. Many clinicians use a 1:1 mg dose of mesna to
ifosfamide when administered by continuous infusion. The dosing guidelines become
less well defined, however, when patients receive higher dosages of ifosfamide
(>2.5 g/m2
). The lack of data and the unique pharmacokinetic properties of
ifosfamide have caused some concerns about the current dosing guidelines. The
pharmacokinetics of ifosfamide are nonlinear. For example, the elimination half-life
associated with doses of 2.5 g/m2
is 6 to 8 hours, whereas with doses of 3.5 to 5
g/m2
, it is 14 to 16 hours. The current recommendations for mesna administration
enable protection for approximately 12 hours after an IV bolus; thus, with higher
dosages of ifosfamide, mesna should be infused beyond the recommended 8 hours
after ifosfamide to maintain bladder protection.
235 Also, concern exists that the 4-hour
dosing interval used with lower doses may be inadequate to maintain sufficient
mesna concentrations within the bladder. To ensure maximal protection against
urotoxicity, ASCO currently recommends more frequent or prolonged mesna dosage
regimens to account for its short half-life.
44
Ifosfamide and mesna are compatible in
solution; therefore, they can be infused together, offering greater patient convenience.
Because mesna works in the bladder, frequent urination may diminish its efficacy.
Patients may be reminded to try to empty their bladder every few hours. Although
forced hydration has been the mainstay for prevention of cyclophosphamide-induced
hemorrhagic cystitis, it is unnecessary and potentially disadvantageous when mesna
is used. This is because forced hydration can increase urination and thus the
evacuation of mesna from the bladder.
Mesna is usually given IV but an oral formulation is available. The oral
bioavailability of mesna is approximately 50%; therefore, patients should receive
twice the standard IV dose (e.g., oral mesna 40% of the IV ifosfamide dose) 2 hours
before and 4 and 8 hours after ifosfamide.
236 Others have recommended that an oral
dose also be given with the ifosfamide dose. Many centers administer the first dose
of mesna IV followed by oral doses at 4 and 8 hours, particularly in the outpatient
clinic setting.
44 All patients receiving cyclophosphamide should receive saline
diuresis or forced saline diuresis to protect urothelial tissue. When patients receive
cyclophosphamide for an HCT, it is at high dose; therefore, they receive mesna and
hydration. Other practices to prevent this complication include hyperhydration and
the use of continuous bladder irrigation. Data comparing these methods are
controversial and report varying rates of hematuria and severe hemorrhagic cystitis.
These recommendations are currently supported by the ASCO consensus guideline
44
(see Chapter 101, Hematopoietic Cell Transplantation). J.R. will receive mesna at a
dose of 20% of the ifosfamide dose given immediately before ifosfamide, and at 4
and 8 hours after ifosfamide (for a total mesna dose of 60% of the ifosfamide dose).
Treatment
CASE 94-9, QUESTION 3: If J.R. exhibits hemorrhagic cystitis, how should it be treated?
Once hemorrhagic cystitis develops, the agent causing the disorder must be
discontinued and vigorous hydration started. If gross hematuria occurs, a large-bore
urinary catheter should be inserted to avoid obstruction of the urethra by clots. Some
clinicians also use continuous silver nitrate irrigation, local instillation of formalin
or alum, or electrocauterization of bladder blood vessels to control bleeding. There
is no consensus as to which of these methods is superior. If these measures fail,
surgical intervention may be necessary to divert urine flow away from the
bladder.
235,237
PULMONARY TOXICITIES
Bleomycin and Other Agents
CASE 94-10
QUESTION 1: J.A., a 54-year-old man with stage III Hodgkin lymphoma, has received ABVD (doxorubicin
25 mg/m
2
IV days 1 and 15, bleomycin 10 units/m
2
IV on days 1 and 15, vinblastine 6 mg/m
2
IV on days 1 and
15, and dacarbazine 375 mg/m
2
IV on days 1 and 15) for six cycles. He presents to the clinic 6 months after his
last cycle with dyspnea, a nonproductive cough, and fever. Chest radiograph showed diffuse bilateral infiltrates;
his respiratory rate was 36 breaths/minute; and his arterial blood gases (ABG) were as follows:
pH, 7.50
PO2
, 62 mm Hg
PCO2
, 28 mm Hg
O2
saturation, 92%
What are the possible causes of his new pulmonary findings?
J.A. is at risk for several processes that could produce diffuse pulmonary
infiltrates and dyspnea. He is immunosuppressed secondary to his lymphoma and the
therapy; therefore, J.A. has an increased risk for infection and may have pneumonia.
In addition, the infiltrates may represent a relapse of his disease. Pulmonary
infiltrates also may represent toxicity from one or more of the cytotoxic agents he
received. Further diagnostic workup is necessary to establish the cause.
CASE 94-10, QUESTION 2: A bronchoscopy with bronchoalveolar lavage and a biopsy with pathologic and
microbiologic evaluations were performed. Bacterial, fungal, and viral cultures were negative, and the biopsy
revealed inflammation and fibrosis with no evidence of lymphoma. These results are highly suggestive of
chemotherapy-induced pulmonary damage. Which of the agents that J.A. received is associated with pulmonary
toxicity?
J.A. has received bleomycin and that places him at risk for pulmonary toxicity. As
part of initial workup before initiating chemotherapy with ABVD, J.A. had
pulmonary function tests, which were normal. Many chemotherapy agents have been
associated with pulmonary toxicity and the varying types of mechanisms and clinical
presentations have been reviewed (Table 94-10).
238–250 Several reviews discuss the
different types of pulmonary toxicities associated with anticancer agents.
238–240,250
Among all chemotherapy agents, bleomycin is associated with the highest
incidence of pulmonary toxicity. Although several types have been reported, the most
frequent is interstitial pneumonitis followed by pulmonary fibrosis.
238,243,251 Patients
generally present with a nonproductive cough and dyspnea. Clinicians may detect
only fine crackling bibasilar rales that often progress to coarse rales. The chest
radiograph may be normal in the early stages, but patients can exhibit bilateral
alveolar and interstitial infiltrates. Arterial blood gases show hypoxia and pulmonary
function tests generally reveal a progressive fall in the diffusing capacity without a
significant decrease in the forced vital capacity.
243,251 The most significant factor
associated with the development of pulmonary toxicity is the cumulative dose of
bleomycin. At total doses less than 400 units, fewer than 10% of patients may
experience pulmonary toxicity. When the cumulative dose reaches 450 to 500 units,
the incidence is higher. A rarer, hypersensitivity reaction produces fever,
eosinophilia, and diffuse infiltrates, and this pulmonary toxicity is not dose-related.
The mortality associated with bleomycin pulmonary toxicity is about 50%.
238,251
If
bleomycin is discontinued while symptoms are minimal and before pulmonary
function has decompensated significantly, the damage may not progress. In contrast,
patients with prominent physical and radiographic findings generally die because of
pulmonary complications. Other anticancer agents can potentially exacerbate the
pulmonary toxicity associated with bleomycin. J.A.’s pulmonary findings are most
likely suggestive of bleomycin toxicity. Unfortunately, there are no methods for
reversing the pulmonary toxicity seen with bleomycin and treatment consists of
supportive measures such as oxygen and steroids.
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p. 1994
