Table 94-10

Chemotherapy-Induced Pulmonary Toxicity

Drug Histopathology Clinical Features Treatment/Outcome

Aldesleukin

241 Capillary leak,

pulmonary edema

Clinical presentation: ↓ BP,

fever, SOB, anorexia, rash,

mucositis

Stop infusion; provide

supportive care to cause a

quick resolution of symptoms

Bleomycin

243,251 Interstitial edema and

hyaline membrane

formation, mononuclear

cell infiltration

pneumonitis with

progression to fibrosis,

eosinophilic infiltrations

seen in patients with

suspected

hypersensitivity-type

reactions

Cumulative dose-related

toxicity with risk increasing

substantially with total dose

>450 mg or 200 units/m

2

;

may occur during or after

treatment

Clinical presentation: cough,

fever, dyspnea, tachypnea,

rales, hypoxemia, bilateral

infiltrates, dose-related ↓ in

diffusing capacity

Recovery if bleomycin is

discontinued while symptoms

and radiologic changes still

minimal; progressive and

usually fatal if symptoms

severe. Avoid cumulative

doses >200 mg/m

2

; monitor

serial pulmonary function

tests. Discontinue therapy if

diffusing capacity ≤40% of

baseline, FVC <25% of

baseline, or if any signs or

symptoms suggestive of

pulmonary toxicity occur.

Steroids may be helpful if

toxicity is result of

hypersensitivity

Busulfan

238 Pneumocyte dysplasia;

mononuclear cell

infiltrations, fibrosis

Does not appear to be doserelated, but no cases reported

with total doses <500 mg

Clinical presentation:

insidious onset of dyspnea,

dry cough, fever, tachypnea,

rales, hypoxemia, diffuse

linear infiltrate, ↓ in diffusing

capacity

Fatal in most patients;

progressive despite

discontinuation of busulfan.

High-dose steroids (50–100

mg prednisone daily) have

been helpful in a few cases

Carmustine

242 Dose-related; usually occurs

with doses >1,400 mg/m

2

Clinical presentation:

dyspnea, tachypnea, dry

hacking cough, bibasilar

rales, hypoxemia, interstitial

infiltrates; spontaneous

pneumothorax has been

reported

May continue to progress after

carmustine discontinued. No

evidence that steroids improve

or alter incidence. High

mortality rate if symptoms

severe. Serial pulmonary

function studies

recommended. Total

cumulative dose should not

exceed 1,400 mg/m

2

Chlorambucil

240 Pneumocyte dysplasia,

fibrosis

Usually occurs after at least

6 months of treatment with

total cumulative doses of >2

g

Clinical presentation:

dyspnea, dry cough, anorexia,

fatigue, fever, hypoxemia,

bibasilar rales, localized

infiltrates progressing to

diffusing involvement of both

lung fields

Fatal in most cases despite

discontinuation of chlorambucil

and treatment with high-dose

steroids

Cyclophosphamide

239 Endothelialswelling,

pneumocyte dysplasia,

Does not appear to be

schedule-related or doseClinical recovery reported in

about 50% of patients within

lymphocyte infiltration,

fibrosis

related and may occur after

discontinuation

Clinical presentation:

progressive dyspnea, fever,

dry cough, tachypnea, fine

rales, ↓ diffusing capacity

and restrictive ventilatory

defect, bilateral interstitial

infiltrates

1–8 weeks if therapy stopped.

Some of these patients

received steroid therapy;

however, others have died

despite steroid therapy.

Occasionally, therapy has

been restarted without

recurrence

Cytarabine

244 Pulmonary edema,

capillary leak

Clinical presentation:

tachypnea, hypoxemia,

interstitial or alveolar

infiltrates

Not always fatal

Gemcitabine

245 Pulmonary edema, rare

interstitial pneumonitis

Dyspnea was reported in

23% of patients; severe

dyspnea in 3%; dyspnea

occasionally accompanied by

bronchospasm (<2% of

patients); rare reports of

parenchymal lung toxicity

consistent with drug-induced

pneumonitis

Treatment is supportive care

measures. Symptoms resolve

and are usually not seen with

rechallenge

p. 1994

p. 1995

Fludarabine

240 Interstitial infiltrates,

alveolitis, centrilobular

emphysema

Clinical presentation: fever,

dyspnea, cough, hypoxia; onset

3–28 days after third or fourth

course; bilateral infiltrates and

effusions

Resolves spontaneously during

several weeks with or without

corticosteroids

Melphalan

238 Pneumocyte dysplasia Not dose-related

Clinical presentation: dyspnea,

dry cough, fever, tachypnea,

rales, pleuritic chest pain,

hypoxemia

Most patients die because of

progressive pulmonary disease.

Most reported cases occurred

while patients were receiving

concomitant prednisone therapy

Usually progresses rapidly

Methotrexate

247

Delayed

Nonspecific changes,

occasional fibrosis

No evidence that it is doserelated; daily or weekly

schedules more likely to cause

toxicity than monthly dosing

Clinical presentation: headache,

malaise prodrome, dyspnea, dry

cough, fever, hypoxemia,

tachypnea, rales, eosinophilia,

cyanosis in up to 50% of

patients, interstitial infiltrates, ↓

diffusing capacity, restrictive

ventilatory defect

Most patients recover within 1–

6 weeks (some may have

persistent infiltrates or ↓

pulmonary function

parameters). Steroids may

produce more rapid resolution.

May resolve despite

continuation of methotrexate,

but discontinuation may speed

resolution. Rarely fatal

Noncardiac

pulmonary

edema

Acute pulmonary edema Occurs very rarely 6–12 hours

after PO or IT methotrexate

May be fatal

Pleuritic chest

pain

Not related to other

methotrexate toxicities or serum

levels; may not occur with each

course of therapy

Clinical presentation: right-sided

chest pain, occasional pleural

effusion or collapse of lung,

thickened pleural densities

Usually resolves within 3–5

days

Mitomycin

273 Similar to bleomycin Clinical presentation: dyspnea,

dry cough, basilar rales,

hypoxemia, bilateral interstitial

or finely nodular infiltrates, ↓

diffusing capacity

Fatal in ∼50% of cases.

Complete resolution reported in

some patients, including some

who received steroid therapy

BP, blood pressure; FVC, forced vital capacity; IT, intrathecal; PO, oral; SOB, shortness of breath.

CASE 94-10, QUESTION 3: Why are routine pulmonary evaluations indicated in patients such as J.A. who

receive bleomycin or other pulmonary toxic agents?

Dose-related decreases in diffusing capacity can occur before the onset of clinical

symptoms; therefore, routine baseline and serial pulmonary function studies are

recommended.

243 Bleomycin therapy should be withheld if the diffusing capacity falls

to less than 40% of the baseline value, if the forced vital capacity falls to less than

75% of the baseline value, or if patients exhibit any signs or symptoms of pulmonary

damage.

238,251 Some practitioners also recommend limiting the total cumulative

lifetime dose to less than or equal to 450 units. Specific screening is not routinely

recommended for patients receiving other pulmonary toxic agents; however, if

patients exhibit any symptoms or clinical findings, therapy should be withheld until

the cause can be determined. J.A. received pulmonary function tests before his first

cycle of ABVD. Further tests are usually not completed, unless the patient shows

signs or symptoms of SOB or difficulty breathing. J.A. did not receive any further

studies during his chemotherapy courses because he had no pulmonary symptoms

until 6 months after his six cycles of ABVD.

Management

CASE 94-10, QUESTION 4: How should J.A.’s agent-induced pulmonary toxicity be managed?

If pulmonary toxicity becomes evident, all suspected agents should be discontinued

and the patient should receive symptomatic support based on their physical condition.

As illustrated by J.A., other treatable causes of pulmonary infiltrates (e.g., infection)

also should be eliminated. Often, pulmonary toxicity is irreversible and progressive,

and effective treatments are unavailable. Corticosteroids are administered but

probably are effective only in cases of hypersensitivity-associated pulmonary

damage. Nevertheless, because other effective treatments are lacking, a trial of

steroids

p. 1995

p. 1996

generally is indicated for all patients; if steroids are discontinued, they must be

tapered carefully to avoid clinical deterioration.

HEPATOTOXICITY

CASE 94-11

QUESTION 1: J.D., a 56-year-old man, has received two courses of therapy with cytarabine for acute

myeloid leukemia. Before his therapy was started, his liver function tests (LFT) and coagulation studies were

within normal limits. His current laboratory values on day 10 of his second cycle of high-dose cytarabine include

the following:

Aspartate aminotransferase, 204 units/L

Alanine aminotransferase, 197 units/L

Lactate dehydrogenase, 795 units/L

Alkaline phosphatase, 285 units/L

Bilirubin, 1.2 mg/dL

Why could J.D.’s cytarabine be responsible for these laboratory abnormalities?

Elevated LFTs occur frequently in cancer patients and their causes are listed in

Table 94-11. Other signs and symptoms of hepatotoxicity include jaundice, nausea,

vomiting, abdominal pain, and, rarely, encephalopathy. Patients should receive an

extensive workup to determine whether they require immediate attention for tumor

involvement of the liver or possible infection. In addition, patients should

discontinue any nonessential medications that can potentially cause hepatotoxicity.

The clinician may also discontinue chemotherapy if this is the suspected cause.

Several anticancer agents, including cytarabine, have been associated with

hepatocellular damage (Table 94-12).

252–263 Some agents commonly associated with

hepatotoxicity include asparaginase, carmustine, cytarabine, mercaptopurine,

methotrexate, irinotecan, oxaliplatin, clofarabine, and imatinib. A review of 537

cancer patients with tyrosine kinase-associated liver enzyme elevations observe that

clinically significant abnormalities were unusual and transient.

264 Multiple agents

have black box warnings regarding potential hepatotoxicity. The onset of

hepatotoxicity with these drugs is usually within 2 months of treatment initiation and

is reversible in the majority of cases. Although death from hepatotoxicity in these

cases is uncommon, there have been reports of cirrhosis.

264 All of these drugs come

in contact with the liver by entering the liver’s blood supply; the liver uniquely

receives a dual blood supply from the portal and superior mesenteric veins. The liver

detoxifies or inactivates noxious substances and metabolizes many anticancer agents.

The exact mechanisms by which cytotoxic and targeted agents cause hepatotoxicity

are unknown, but most agents probably cause it by (a) interfering with the

mitochondrial function of the hepatocyte, (b) depleting hepatic glutathione stores, (c)

eliciting hypersensitivity reactions, (d) decreasing bile flow, or (e) causing phlebitis

of the central hepatic vein to produce sinusoidal obstructive syndrome (also known

as veno-occlusive disease). Several articles serve as excellent resources for

anticancer therapy-induced hepatotoxicity.

252,253

Table 94-11

Common Causes of Elevated Liver Function Tests in Patients with Cancer

Primary or metastatic tumor involvement of the liver

Hepatotoxic drugs (e.g., cytotoxics, hormones [estrogens, androgens], antimicrobials [trimethoprim–

sulfamethoxazole, voriconazole])

Infections (e.g., hepatic candidiasis, viral hepatitis)

Parenteral nutrition

Portal vein thrombosis

Paraneoplastic syndrome

History of liver disease (including hepatitis B and hepatitis C)

Table 94-12

Hepatotoxicity From Select Antineoplastic Drugs

Drug Type

Asparaginase

254 Hepatocellular fatty metamorphosis

Busulfan

255 Veno-occlusive disease

Carmustine

252 Hepatocellular

Clofarabine

257 Hepatocellular

Cytarabine

258 Cholestatic

Etoposide

259 Hepatocellular

Imatinib

253 Hepatocellular

Mercaptopurine

261 Cholestatic and hepatocellular

Methotrexate

262 Hepatocellular

Streptozocin

263 Hepatocellular

Several laboratory tests can serve as indicators of liver structure and function.

Serum transaminases, alkaline phosphatase, and bilirubin levels should be monitored

routinely in patients receiving hepatotoxic chemotherapy. Although these laboratory

indices are sensitive, they are nonspecific for the type of liver disease and do not

necessarily correlate with hepatic function. Serum levels of proteins produced by the

liver (e.g., ferritin, albumin, pre-albumin, or retinol-binding protein) also may be

helpful in assessing liver function. The decision to continue or discontinue

chemotherapy in patients with apparent hepatic dysfunction can be difficult. If the

chemotherapy is the suspected cause, therapy should be withheld until LFTs are

within normal ranges. The clinician should also consider alternative

(nonhepatotoxic) chemotherapy for future treatment. In addition, agents that are

cleared predominantly via the liver may require dosage adjustments and should be

administered cautiously (Table 94-13). J.A.’s cytarabine is likely responsible for his

elevated liver enzymes. Therefore, costly workup should be deferred to allow

recovery of liver function. Recovery should occur within 2 weeks of chemotherapy.

If full recovery does not occur, further therapy (agents, doses, or both) may require

modifications.

Table 94-13

Select Anticancer Agents

a Requiring Dose Modification in Hepatic Dysfunction

Fluorouracil Methotrexate

Daunorubicin Paclitaxel

Docetaxel Vinblastine

Epirubicin Vincristine

Etoposide

aThe agents listed in this table are examples and are not meant to be an exhaustive list of agents that may need

dose adjustments. Additionally, specific dose reductions may depend on multiple factors including treatment goals

(curative versus palliative), performance status, and specific protocols.

Sources: Thatishetty AV et al. Chemotherapy-induced hepatotoxicity. Clin Liver Dis. 2013;17(4):671–686, ix–x.;

Bahirwani R, Reddy KR. Drug-induced liver injury due to cancer chemotherapeutic agents. Semin Liver Dis.

2014;34(2):162–171.

p. 1996

p. 1997

LONG-TERM COMPLICATIONS OF ANTICANCER

THERAPY

Secondary Malignancies After Anticancer Therapy

CASE 94-12

QUESTION 1: T.D., a 55-year-old woman, was diagnosed with an early-stage breast cancer and successfully

treated with radical mastectomy followed by four cycles of adjuvant AC (doxorubicin 60 mg/m

2

IV on day 1,

cyclophosphamide 600 mg/m

2

IV on day 1). Eighteen months after her breast cancer therapy was completed,

T.D. presents to her primary care physician with complaints of fatigue, SOB, easy bruising, and sinusitis. A

peripheral blood smear shows a WBC count of 120,000 cells/μL with a differential of greater than 90%

leukemic blasts and a bone marrow biopsy confirms acute myeloid leukemia (AML). Subsequent cytogenetic

analysis revealed abnormalities involving chromosome 11q23. What factors support the diagnosis of anticancer

therapy-associated acute leukemia in T.D.?

Acute leukemia has been associated with cytotoxic therapies used to treat

hematologic malignancies, solid tumors, and nonmalignant diseases.

265