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

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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