Author's Accepted Manuscript

Chemotherapy Agents With Known Pulmonary Side

Effects and Their Anesthetic and Critical Care
Implications
Adriana Dana Oprea MD

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PII: S1053-0770(15)00569-8
DOI: http://dx.doi.org/10.1053/j.jvca.2015.06.019
Reference: YJCAN3334

To appear in: Journal of Cardiothoracic and Vascular Anesthesia

Cite this article as: Adriana Dana Oprea MD, Chemotherapy Agents With Known
Pulmonary Side Effects and Their Anesthetic and Critical Care Implications, Journal of
Cardiothoracic and Vascular Anesthesia, http://dx.doi.org/10.1053/j.jvca.2015.06.019

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Chemotherapy agents with known pulmonary side effects and their anesthetic and critical

care implications

Adriana Dana Oprea, MD 1

1
Assistant Professor of Anesthesiology, Yale University School of Medicine, New Haven CT;

Name of Department(s) and Institution(s)

From the Departments of Anesthesiology and Medicine, Yale University, New Haven, CT

Disclaimers

None

Corresponding author

Adriana Dana Oprea, MD

Department of Anesthesiology

Yale University

333 Cedar St, TMP 3

PO Box 208051

New Haven, CT 06520- 8051

Tel: 203 785 2802

Fax 203 785 6664

E-mail: adriana.oprea@yale.edu

Reprints

None applicable

Financial support

None

Conflicts of interest

None
Chemotherapy agents with known pulmonary side effects and their anesthetic and

critical care implications

I. Introduction

II. Diagnosis and clinical presentation

III. Antineoplastic agents

A. Antibiotics

1. Bleomycin

2. Mitomycin C

3. Doxorubicin

4. Epirubicin

5. Mitoxantrone

B. Alkylating agents

1. Busulfan

2. Cyclophosphamide

3. Ifosfamide

4. Chlorambucil

5. Melphalan

C. Antimetabolites

1. Methotrexate
 2. Cytosine arabinoside (cytarabine)

3. Fludarabine

4. Gemcitabine

5. Carmustine (BCNU)

D. Monoclonal antibodies

1. Bevacizumab

2. Trastuzumab

3. Other

E. Microtubule inhibitors

1. Taxanes

2. Camptothecins

F. Tyrosine Kinase Inhibitors

1. Gefitinib

2. Erlotinib

3. Imatinib

G. Other agents

1. All-trans retinoic acid (ATRA)

2. Oxaliplatin

IV. Anesthetic considerations

 V. Conclusions
Chemotherapy agents with known pulmonary side effects and their anesthetic and

critical care implications

I. Introduction

The lungs frequently experience toxicity related to antineoplastic chemotherapy. Ten to

twenty percent of patients treated with chemotherapy develop pulmonary complications.1,

2
While some toxicities can be prevented and/or effectively treated, other presentations

can be severe and rapidly fatal. The clinical presentation and radiographic appearance of

these complications are most often nonspecific, and may, in particular, be difficult to

distinguish from infectious complications to which this population is prone, because of

immunosuppression. The picture may be further confounded by the presence of lung

metastases from the underlying cancer. There are no available universal criteria for the

diagnosis of drug-induced pulmonary toxicity therefore the diagnosis generally depends

upon an appropriate history of drug exposure, histologic evidence of lung injury and,

most importantly, the exclusion of other causes of the lung injury.

Chemotherapy- induced lung disease was first recognized in the early 1960s in

association with busulfan.3 Antineoplastic agents that are known to specifically cause

pulmonary injury include bleomycin and methotrexate.4 Currently, pulmonary toxicity

due to chemotherapy is commonly encountered, due to patients being exposed to a

variety of standard antineoplastic agents, as well as a host of newer agents. (Table)

There is a paucity of literature (especially recent) discussing the perioperative

management of patients treated with chemotherapy agents having potential lung toxicity.

This manuscript summarizes available data on pulmonary toxicity of chemotherapy and

potential implications for the anesthesiologist.

II. Diagnosis and clinical presentation

Pulmonary toxicity related to chemotherapy has a variety of clinical presentations, with

several syndromes being described. While there is no uniform definition, clinical

symptomatology, radiographic signs and pathological findings are often combined under

the term lung toxicity.5

The pathogenesis of antineoplastic agent-induced lung injury is unknown with several

pathophysiologic mechanisms proposed including recruitment of inflammatory cells due

to direct injury to pneumocytes, endothelial dysfunction with subsequent capillary leak

syndrome, and free oxygen radicals causing direct lung tissue injury and impairment of

lung repair.

Clinically patients typically present with nonspecific complaints – nonproductive cough,

dyspnea, low-grade fever or weight loss. The clinical course may be insidious or rapidly

progressive, resulting in respiratory failure. Clinically, the signs of toxicity typically

present within weeks or a few months after therapy initiation. Notable exceptions to this

include bleomycin and nitrosurea compounds, where drug-induced lung fibrosis can

become apparent years after therapy has been discontinued.4

Physical examination, likewise, can be highly variable. Auscultation may demonstrate

clear lungs, bibasilar crackles indicative of interstitial pathology, or wheezing suggesting

bronchospasm. The presence of a rash, especially in the setting of wheezing, may be

indicative of a hypersensitivity reaction.

Common nonspecific findings include elevated white blood cell count in peripheral

blood, erythrocyte sedimentation rate, and C-reactive protein levels. Chest imaging (chest

X-ray and computed tomography) may show diffuse or patchy, unilateral or bilateral,

reticular markings, ground-glass opacities, or consolidations.6 High resolution computed

tomography is more sensitive in detecting ground glass or interstitial opacities, however

their characterization and location are of limited value in the diagnosis of chemotherapy

induced lung toxicity.7

Pulmonary function tests (PFT’s) typically demonstrate changes consistent with

restrictive lung physiology, including reduced lung volumes and diffusion capacity.5, 8

Bronchoscopy can be very useful in the diagnosis of lung toxicity. While bronchoalveolar

lavage (BAL) fluid cell counts (neutrophilia, lymphocytosis, eosinophilia) are typically

nonspecific, BAL is helpful in excluding other processes (infection, hemorrhage,

lymphangitic spread of the cancer) that might produce similar clinical or radiographic

findings.9

Transbronchial or open-lung biopsies are not routinely used in confirming the diagnosis

since the findings are usually nonspecific (interstitial pneumonitis, organizing

pneumonia, eosinophilic pneumonia, pulmonary fibrosis, and diffuse alveolar damage).

However, as with BAL, biopsy can be helpful in excluding alternative diagnoses, such as

infection or metastatic disease.10

After exclusion of other etiologies, the diagnosis of chemotherapy-induced pulmonary

toxicity can generally be made when there is a temporal relationship between the

pulmonary signs or symptoms to the initiation of treatment (hours to weeks) and there is

resolution after withdrawal of the drug in question. This temporal relationship can
become tenuous when the pulmonary dysfunction appears years after the chemotherapy

agents were discontinued, as discussed below.

Therapeutic measures are mostly empiric and based on case reports. They include

discontinuation of the chemotherapy agents, administration of steroids and supportive

measures. The efficacy of such treatments remains unclear.

III. Antineoplastic agents

A. Antibiotics

1. Bleomycin

Bleomycin-induced lung injury is classically described as lung fibrosis, fibrosing

alveolitis (10% of cases), or rarely as bronchiolitis obliterans organizing pneumonia

(BOOP) or a hypersensistivity pneumonitis. Signs of bleomycin toxicity are usually

insidious with nonspecific, subacute symptoms characteristic of interstitial lung disease

(cough, dyspnea, low grade fever, tachypnea). Symptoms typically appear 1- 6 months

after completion of therapy and progressing towards lung fibrosis. A more acute, rapid

presentation starting within a month of treatment initiation points toward an early onset

form of lung toxicity due mostly to a hypersensitivity reaction.11

While not completely understood, the pathophysiology of bleomycin toxicity appears to

be mostly due to oxidative damage. Genetic susceptibility, deficiency of bleomycin

hydrolase and inflammatory cytokines seem to play additional roles.12

Risk factors for bleomycin-induced lung toxicity include age (patients over 40 years of

age have a 2.3 fold higher incidence of pulmonary complications), renal dysfunction,

preexisting lung disease, cumulative dose > 400 U (patients with cumulative doses > 550
U have a 10% death rate), and rapid drug infusion (bolus administration). Several other

factors that synergistically predispose patients to lung injury are concurrent or prior

radiation therapy, concurrent cyclophosphamide treatment, tobacco smoking, and

concomitant treatment with granulocyte colony stimulating factor, and exposure to high

concentrations of oxygen.5, 11 Significant attention has been given to the effects of a high

fraction of inspired oxygen (FiO2), particularly within 6 months of bleomycin therapy,

and perhaps for prolonged periods of time after exposure to bleomycin. This is

particularly important in the perioperative setting. The lowest clinically feasible oxygen

concentration has been recommended during anesthesia in these patients, with a

saturation (SaO2) goal of 90-92% considered acceptable. Newer evidence is emerging

that exposure to higher concentrations of oxygen (up to FiO2 of 1) may be safe.4, 13-15

2. Mitomycin C

Pulmonary complications due to mytomycin C vary in incidence from 2-12% and seem to

be more common at cumulative doses > 20 mg/m2. Several syndromes have been

described with the use of mitomycin C including bronchospasm, acute lung injury,

interstitial pneumonitis, a thrombotic microangiopathy associated with respiratory failure,

pulmonary hypertension, and pleural effusions. Severe bronchospasm is reported when

mitomycin C is used in conjunction with vinca alkaloids. This toxicity usually remits

within 24 hours of therapy, is responsive to bronchodilators and is accompanied by

pulmonary parenchymal reticular opacities.

Patients may present with acute lung injury and rapid onset of acute dyspnea in addition

to radiographic abnormalities (presence of focal, diffuse reticular or ground glass

opacities). As with bronchospasm, this more commonly follows a combined treatment

with mitomycin C and vinca alkaloid. Similar to bleomycin, higher inspired oxygen

fraction (FiO2 >0.5) in patients previously treated with mitomycin C may be a risk factor

for development of lung toxicity. In addition to therapy discontinuation and supportive

measures, with a target SaO2 of 90%, steroids can be beneficial in patients with
16
mitomycin C-induced lung toxicity.

Interstitial pneumonitis appears to be dose related and is responsive to steroids in 40% of

12
cases.

Thrombotic microangiopathy associated with acute respiratory failure is a syndrome

distinctly associated with mitomycin C. It resembles thrombotic thrombocytopenic

purpura/hemolytic uremic syndrome (TTP/HUS) in that it presents with hemolytic

anemia, thrombocytopenia, hypertension, renal failure and neurological symptoms.17 The

2
incidence is higher after a single dose higher than 60 mg, a cumulative dose > 20 mg/m ,

a duration of chemotherapy longer than 5-11 months, treatment with tamoxifen or 5

fluorouracil (5-FU) and blood transfusions, as the latter fuels coagulopathy.

While the optimal treatment is not known, as with any patient with HUS/TTP, plasma

exchange should be considered as first line treatment, in addition to discontinuation of

chemotherapy and administration of steroids.18, 19

Pulmonary hypertension and pleural disease (effusions, fibrosis) have also been reported

as side effects of mitomycin C.1, 4

While lung toxicity is associated mostly with systemic administration, newer reports

comment on interstitial fibrosis as a side effect on mitomycin C when administered

intraperitoneally or intrapleurally (in conjunction with doxorubicin).20, 21

 3. Doxorubicin

Cardiac toxicity is the most common side effect of doxorubicin administration although

cases of lung toxicity have been rarely described. Patients receiving pegylated liposomal

preparations can develop transient dyspnea in 8% of cases 1-5 minutes after starting the

infusion. BOOP has also been reported after doxorubicin use.5

4. Epirubicin

Up to 9% of patients treated with epirubicin develop interstitial pneumonitis, as described

22
in a case series.

5. Mitoxantrone

Toxicity to mitoxantrone manifested as interstitial pneumonitis responsive to steroid

23
administration has been reported.

B. Alkylating agents

1. Busulfan

Busulfan pulmonary toxicity is described as occurring in 6% of treated adults and

children. The clinical course is insidious, with appearance of symptoms and signs such

as dyspnea, fever, cough, and rales usually several years after the treatment. The onset of

symptoms has been reported as late as 10 years after therapy. Patients with busulfan

induced lung injury usually have a poor prognosis, with the majority developing

progressive fibrosis and respiratory decline. In addition to supportive treatment, steroids

can be tried although it is unclear if they are beneficial.4

2. Cyclophosphamide

Cyclophosphamide induced lung toxicity is rare (<1%), and appears to be more prevalent
in patients with concurrent risk factors for lung injury (radiation to the chest, other toxic

chemotherapy, high FiO2). Two clinical entities have been described in the literature. An

early onset pneumonitis (within 6 months) usually has a good prognosis, being

responsive to cyclophosphamide discontinuation and steroid administration. In contrast,

late onset pneumonitis (more than 6 months after treatment) typically has a progressive

course leading to pulmonary fibrosis, and is usually unresponsive to glucocorticoids.12, 24, 25

3. Ifosfamide

Ifosfamide pulmonary toxicity is described in case reports. It has been described as

causing interstitial pneumonia when used as a single agent, though toxicity has been

noted in combination with other antineoplastic therapies. In these cases, the role of

ifosfamide is unclear. The differential diagnosis of acute pulmonary symptoms while on

ifofamide should include methemoglobinemia, which has been described in case reports.26

Its metabolite, 4-thioifosfamide, is known to react with glutathione and can deplete the

red blood cell antioxidant reserve, resulting in methemoglobinemia.26, 27

4. Chlorambucil

Lung toxicity due to chlorambucil is a rare complication, and may occur during or after

discontinuation of treatment. The most common presentation is a chronic interstitial

pneumonitis, though acute interstitial pneumonitis and BOOP have also been reported. In

patients with chronic interstitial pneumonitis, symptoms usually develop six months to

three years or longer after initiation of therapy. Patients present with an insidious clinical

picture including cough and dyspnea in addition to weight loss, fever, and hemoptysis.

As with busulfan, the prognosis is usually poor unless patients present with BOOP, in
which case they may improve in response to stopping chemotherapy and initiation of

steroid therapy.28, 29

5. Melphalan

There are few cases of pulmonary toxicity described in association with melphalan, with

the clinical course of pulmonary injury varying from acute to subacute. An acute

pneumonitis and acute bronchospasm have been attributed to melphalan. Treatment

typically includes discontinuation of the drug, with initiation of steroids and beta-

adrenergic agonists to treat bronchoconstriction.4, 12

C. Antimetabolites

1. Methotrexate

Two to eight percent of patients receiving methotrexate develop evidence of lung

toxicity.30, 31 The toxicity is usually evident shortly after intravenous or intrathecal use but

may not appear until months of oral use. In most cases, symptoms occur within a year of

methotrexate initiation. The most common presentation is hypersensitivity pneumonitis

manifested as widespread interstitial and alveolar opacities, peripheral or lung

eosinophilia in conjunction with fever, nonproductive cough, severe dyspnea, and

hypoxemia. Chest radiographs may also demonstrate atypical findings such as pleural

effusions, hilar adenopathy, or superior mediastinal adenopathy. Other pulmonary injury

associated with methotrexate use includes BOOP, acute lung injury with noncardiogenic

pulmonary edema, pulmonary fibrosis, pleural effusion or pleuritis.31

Risk factors include diabetes mellitus, age more than 60 years, hypoalbuminemia as well

as underlying lung disease due to rheumatoid arthritis. Treatment includes stopping

methotrexate, supportive treatment and glucocorticoids, which may speed recovery but

may not prevent progression of disease.32-34

2. Cytosine arabinoside (cytarabine)

Lung toxicity due to cytarabine is described as noncardiogenic pulmonary edema, and

occurs in up to 14% of treated patients. It is usually apparent 1-2 weeks after therapy

initiation in patients receiving high doses (1-3 g every 4-6 hours). The clinical

presentation includes a subacute picture of low-grade fever, mild dyspnea, tachypnea,

cough, moderate to severe hypoxemia, and presence of rales on physical examination,

with chest radiographic evidence of alveolar consolidation with or without pleural

effusions. Treatment includes discontinuation of the drug and supportive measures.35, 36

3. Fludarabine

Approximately 10% of patients on fludarabine exhibit pulmonary toxicity.37 Affected

individuals experience dyspnea as early as 3 days after the first cycle of chemotherapy,

although later onset of pulmonary symptoms has been described. Radiographic studies

typically show mixed alveolar and interstitial opacities, but nodular opacities that may be

concerning for malignancy or fungal infection have also been reported. Most patients

respond to discontinuation of this drug and receive symptomatic and objective benefits

from corticosteroid therapy.37 Fludarabine can be intensely immunosuppressing for long

periods of time, so pulmonary infection should be considered in treated patients, even

weeks to months after completion of therapy.

 4. Gemcitabine

Gemcitabine induced lung injury is present in 1-2% of cases, but is more prevalent when

other potentially pulmonary toxic chemotherapy drugs are used concurrently (e.g.

bleomycin, taxanes). A range of pulmonary toxicities has been described, including

interstitial pneumonitis, diffuse alveolar damage, capillary leak syndrome with

noncardiogenic pulmonary edema, alveolar hemorrhage, pleural effusions, and acute

eosinophilic pneumonia. The most common clinical presentation is a combination of

dyspnea, cough, and fever associated with new radiographic opacities occurring within

48 days after institution of chemotherapy. The clinical spectrum varies from self-limited

dyspnea to respiratory failure. The typical radiographic findings include bilateral ground

glass or reticular opacities. Treatment is generally supportive and includes

discontinuation of the drug. For severe cases, a short oral course of glucocorticoids

frequently leads to a rapid improvement in clinical and radiographic parameters (within

days), as described in several case reports.38, 39

5. Carmustine (BCNU)

The incidence of pulmonary toxicity associated with the administration of BCNU varies

from 1 to 20% in different studies. While the onset of pulmonary symptoms is typically

within 6 months of therapy initiation, late toxicity has been described, with symptoms

appearing up to 17 years after treatment with carmustine. Carmustine induced lung

toxicity is dose related. A 50% incidence of lung disease is reported in patients who

received a total dose of more than 1500 mg/m2.40 Other chemotherapy drugs (e.g.

cyclophosphamide) and radiation may have a synergistic toxic effect. Carmustine induces

two types of lung toxicity: an acute onset pulmonary injury (dry cough, dyspnea,
histologic evidence of interstitial fibrosis) and delayed-onset pulmonary fibrosis, with a

predilection for the upper lobes. The latter presentation is reported as fatal in as many as

50% of cases.41 Therapy usually consists of withholding the offending agent and

instituting corticosteroids, which has variable and often only transient, beneficial
42
effects.

D. Monoclonal antibodies

1. Bevacizumab

There are several reported pulmonary toxicities associated with bevacizumab therapy

including pulmonary hemorrhage, pulmonary embolism and tracheoesophageal fistula

formation. Pulmonary hemorrhage is more common in patients with squamous cell

5
carcinoma of the lung (31%) versus non small cell cancers (2.6%). In this population,

pulmonary hemorrhage may lead to respiratory failure, and fatalities have been reported

in 1.6% of patients treated with bevacizumab.5

2. Trastuzumab

The incidence of trastuzumab-induced pneumonitis ranges from 0.4 to 0.6%.5

Trastuzumab-induced pneumonitis may present with rapidly progressive respiratory

failure after receiving one dose of trastuzumab but has been described months after 6

cycles of chemotherapy regimens containing the drug. In addition to pulmonary

infiltrates, BOOP and an acute neutrophilic alveolitis after trastuzumab treatment also

have been reported. 15% of patients may experience infusion-related symptoms

(hypotension, angioedema, bronchospasm, dyspnea, fever, chills, and urticarial) but

severe episodes of hypotension, bronchospasm, and hypoxemia leading to death are rare.5

3. Other

12
Rituximab and cetuximab have also been associated with interstitial pneumonitis.

E. Microtubule inhibitors

1. Taxanes

The taxanes can cause a variety of pulmonary symptoms. Mild to moderate infusion

anaphylactoid reactions resulting in bronchospasm usually develop within the first 10 to

15 minutes of the first or second drug infusion and can usually be overcome by stopping

the infusion for 30 minutes, and then restarting at a lower rate. Severe reactions require

more aggressive treatment, such as intravenous fluids or vasopressor medications.

Diffuse interstitial pneumonitis may appear in patients receiving taxanes within days to

weeks of starting either paclitaxel or docetaxel, or can also occur later in the course of

therapy. The incidence with paclitaxel varies between 10 to 68%, with severity appearing

to be related to the dose, treatment schedule, use of concurrent chemotherapy agents, and

use of concurrent or sequential radiation therapy. Docetaxel has been associated with

fluid retention that is attributed to capillary leak syndrome. The usual initial signs are

peripheral edema and weight gain, followed by pleural effusions and pulmonary edema,

particularly if the initial peripheral edema is untreated.4, 12

 2. Camptothecins

Lung toxicity (pneumonitis) is a dose-limiting side effect of irinotecan occurring in up to

20% of patients treated using standard doses. The incidence of severe lung toxicity with

irinotecan ranges from 1 to 2%. Pulmonary toxicity is characterized by the nonspecific

onset of cough, shortness of breath, and fever. Radiographic studies demonstrate

reticulonodular infiltrates and, occasionally, pleural effusions. Discontinuation of

treatment is warranted with the development of any of these findings. Glucocorticoids

have been reported in case studies as having a good response.43 However, deaths have

been reported in spite of the institution of empiric glucocorticoid therapy, even after a

single dose of irinotecan. Toxicity to topotecan is much less common.4

F. Tyrosine Kinase Inhibitors

1. Gefitinib

Gefitinib is associated with pulmonary toxicity manifesting as interstitial lung disease.

The presentation may be mild and insidious, but may also appear as acute and severe with

diffuse alveolar damage and rapidly progressive pulmonary fibrosis. Pulmonary toxicity

is usually evident within 90 days of therapy initiation and has an incidence of 0.3-2%.

Gefitinib-induced pneumonitis is fatal in one third of cases. The incidence of pneumonitis

is increased in patients with previous lung damage from smoking, chemotherapy,

irradiation, infection, or underlying interstitial lung disease.5, 44, 45

 2. Erlotinib

The incidence of pneumonitis due to erlotinib is less striking than gefitinib, varying from

0.8% to 1%, with few cases of erlotinib-induced pneumonitis resulting in respiratory

failure. Patients typically present with an acute picture of fever, cough, and hypoxemia

within 4 to 6 days after the initiation of erlotinib. Chest imaging may reveal ground-glass

opacities and the BAL may show high neutrophil counts.46, 47 Although the severity of

erlotinib-associated interstitial lung disease appears to be less than with gefitinib, all the

tyrosine kinase inhibitors should be considered as having the potential to cause

pulmonary toxicity.

3. Imatinib

Although most cases of imatinib-induced pulmonary adverse events have been reported

in patients with chronic myelogenous leukemia (0.2 to 1.3%), there have been rare cases

of pneumonitis described in patients with gastrointestinal stromal tumors treated with

imatinib. Dyspnea during imatinib therapy is most often related to fluid retention and

pulmonary edema. Imatinib induced pneumonitis may develop within weeks to months of

treatment, with median onset at 49 days after treatment. Patients typically present with

dry cough, dyspnea, hypoxemia, fever and eosinophilia. The chest computer tomography

shows diffuse or patchy ground-glass opacities, consolidation, or fine nodular opacities.

The resolution of pneumonitis may happen spontaneously after imatinib discontinuation

or after corticosteroid therapy.5, 48, 49

 G. Other agents

1. All-trans retinoic acid (ATRA)

All-trans retinoic acid is associated with several pulmonary toxicities, including edema

and fluid retention with pleuropericardial effusions that may evolve due to a generalized

capillary leak syndrome. Pulmonary parenchymal toxicity induced by ATRA occurs

between day 2 and day 21 of treatment and includes nodular pulmonary infiltrates,

noncardiogenic pulmonary edema and adult respiratory distress syndrome. These

manifestations are part of the differentiation syndrome (previously know as retinoic acid

syndrome), which also includes fever, muscle pain, renal and liver dysfunction.

Differentiation syndrome has an incidence of up to 25% and was described when ATRA

is used for induction therapy in patients with acute promyelocytic leukemia.50

Differentiation syndrome is thought to be due to cytokines released by maturing

myelocytes in the presence of ATRA.51 As with other chemotherapy, treatment includes

stopping the offending agent and intravenous corticosteroid therapy.4 Prompt recognition

of the syndrome and initiation of steroids is effective in most cases leading to resolution

of symptoms, although differentiation syndrome still carries a mortality of 2-5%.52

2. Oxaliplatin

Oxaliplatin, used mainly in the treatment of colorectal cancer combined with fluorouracil,

can be associated with interstitial pneumonia, cryptogenic organizing pneumonia,

eosinophilic pneumonia, and diffuse alveolar damage.5 Interstitial pneumonitis with

fibrosis has been reported after 3 to 6 months of therapy; patients present with slowly

progressive cough and dyspnea. Oxaliplatin infusion-related reactions and severe

anaphylactic reactions occur within 5 to 50 minutes after starting the infusion. These

reactions are rare (1.3% incidence) and transient.5

IV. Anesthetic considerations

As with any patient, the preanesthetic evaluation of a cancer patient must include a
53
pertinent, comprehensive history and physical examination. Awareness of the side

effects of the various chemotherapeutic agents is necessary to determine whether further

testing and therapy should be initiated preoperatively. In many cases, patients receive

their chemotherapy regimens outside the institution where the surgical procedure

occurs, so communication with the patient’s oncologist and obtaining medical records

with pertinent cancer treatment information (drug, dosage, route and timing of

administration) is an equally important part of the preoperative preparation of the

oncologic patient.

During the preoperative evaluation of patients receiving or having received

chemotherapy agents known to cause pulmonary toxicity, signs and symptoms of

pulmonary compromise (dyspnea, cough, rales on examination) must be thoroughly

53
assessed.

Preoperative blood tests and EKG should be ordered as dictated by the complexity of the

patient’s medical condition and the planned procedure. Performing routine pulmonary

testing (chest radiograph, spirometry, arterial blood gases) is not recommended. These

tests should be reserved for patients with concerning findings on the physical

examination or new complaints pertaining to the respiratory system. Diagnostic tests are
particularly useful when additional treatment can be offered preoperatively, minimizing

the postoperative consequences of the underlying pulmonary pathology.54

The role of PFT’s in the preoperative pulmonary evaluation is controversial, but they can
55
be helpful when patients have clinically unexplained dyspnea. Preoperative optimization

can be guided by PFT results in patients with known pulmonary compromise due to

fibrosis who have received radiation to the chest and/or bleomycin therapy or have poor
53
functional status.

In order to optimize pulmonary function preoperatively, patients with chronic obstructive

pulmonary disease may benefit from steroids, inhalers and pulmonary rehabilitation

before elective surgery. In addition, a preoperative therapeutic thoracentesis for a benign

or malignant pleural effusion may increase a patient's pulmonary reserve during

anesthesia.53

As mentioned above, anesthesiologists should be aware that certain chemotherapeutic

agents can cause interstitial pneumonia or pulmonary fibrosis in up to 25% of patients.

The most well studied chemotherapeutic agent causing lung injury is bleomycin.

Bleomycin toxicity manifests as progressive pulmonary fibrosis leading to severe

restrictive lung disease. Current literature suggests that the perioperative management

may affect pulmonary function in patients that previously received bleomycin, in contrast

with many chemotherapy agents for which there is a lack of data.16

The majority of reports from human and animal data over several decades have suggested

that high concentrations of inspired oxygen during or after recent bleomycin treatment

might promote pulmonary toxicity and lead to postoperative respiratory distress. Even
patients with apparently normal pulmonary preoperative examination and function, who

were treated with bleomycin previously, are at risk at developing post-operative

respiratory insufficiency necessitating prolonged post-operative intubation and

mechanical ventilation.56-59 Evidence supporting oxygen exacerbation of bleomycin-

induced lung toxicity dates from more than 20 years ago and is largely based on reports

or series.

Patients with prior exposure to bleomycin, but with no other pulmonary risk factors,

appear to be at minimum risk from exposure to hyperoxic conditions (FiO2 > 0.3).

Patients exposed to higher concentractions of oxygen 1-2 months after treatment with

bleomycin appear to be at higher risk of respiratory failure as compared to those exposed

after a longer delay, although cases of respiratory failure have been described years after

treatment.56 However, those individuals with one or more major risk factors (smoking,

previous radiation to the chest, age >70, concurrent chemotherapy, a bleomycin total dose

> 500 U) may be at a higher risk for the development of bleomycin-induced pulmonary
60
injury in the operating room. To date, there are no randomized studies addressing this

issue, therefore the perioperative recommendations are formulated based on these data.

Newer literature challenges the concept of oxygen exacerbating lung toxicity after

treatment with bleomycin and restricting oxygen in patients previously exposed to

bleomycin has become a controversial matter.61 Donat et al. described a series of 77

patients undergoing surgery 6 months after a chemotherapeutic regimen containing

bleomycin. Although 25% of the 77 patients experienced desaturation postoperatively, it

was not evident that this was related to prior bleomycin therapy or simply the

consequence of a prolonged surgery (average 10 hours) with major blood loss requiring
multiple transfusions. The patients received on average a very high FiO2 (0.87) for 56

minutes during induction and emergence and a mean of 0.4 FiO2 during the remainder of

the procedure. None of the patients developed adult respiratory distress syndrome, all

responded to aggressive diuresis and pulmonary therapy (and antibiotics for pneumonia),

and there were no deaths recorded. The authors did not find exposure to elevated oxygen

concentrations to be a risk factor.62

A case series of 47 young patients undergoing surgery shortly after completing a

bleomycin chemotherapy regimen concluded that preoxygenation with 100% oxygen for
13
3 minutes prior to induction followed by maintenance with FiO2 less than 0.3 was safe.

Another series on 15 patients treated with hyperbaric oxygen after a median of 34 months

after bleomycin therapy is challenging further the concept of synergy between the two

lung toxicities.14

Despite the current controversy surrounding oxygen exacerbating lung toxicity in patients

previously treated with bleomycin, these patients are recommended to be maintained with

the minimum FiO2 that can be used safely in order to achieve an SaO2 of at least 90-92 %

by pulse oximetry. Positive end expiratory pressure can be used to allow a decrease in the

FiO2 requirement.60 For those surgical procedures in which higher FiO2 concentrations are

normally utilized, more invasive monitoring, such as continuous mixed venous oximetry

may allow the anesthesiologist to minimize FiO2 concentrations safely.56

In addition to limiting the FiO2, pretreatment with corticosteroids has been advocated in

patients with risk factors undergoing surgery in which greater than 0.3 FiO2 may be

used.63
Due to concerns of higher concentration of O2 present in nitrous oxide/oxygen mixtures

used for sedation in dental procedures, this sedation technique is not recommended in the

dental literature.64

Other factors that can contribute to post-operative respiratory insufficiency include

excessive fluid intake, perioperative transfusion and duration of surgery. Goldiner et al.

recommended favoring colloid administration in an effort to limit the total volume

administration, despite lack of evidence of superiority versus crystalloid administration.65

Sub-clinical bleomycin-induced pulmonary damage can compromise the ability of the

lungs to handle large volumes of fluid. Thus, judicious administration of intravenous

fluid (crystalloid or colloid), restricting it to the minimum necessary to maintain

hemodynamic stability and to prevent postoperative pulmonary edema, is an important

measure. There is no literature addressing the efficacy lung protective strategies (low

tidal volumes, use of positive end expiratory pressure, or recruitment maneuvers) and

their role in perioperative management of patients previously treated with bleomycin.

Despite a lack of definitive data and the controversies discussed above, it appears

reasonable to recommend cautious use of intra- and postoperative fluid administration in

addition to adjustment of intra-operative inspired oxygen concentrations to the lowest

possible level during and after bleomycin therapy.16, 56, 65

V. Conclusions

In summary, the anesthesiologist must assess the presence of symptomatic pulmonary

dysfunction as well as consider the possibility of occult respiratory compromise in the

oncology patient. An understanding of the potential for pulmonary complications related

to cancer treatments, as well as pre- and intra-operative clinical assessments with those

complications in mind should result in improved clinical care. While clinical data for

anticancer agents other than bleomycin is scarce, it may be reasonable to consider

limiting the FiO2 during procedures on patients exhibiting lung toxicity due to

chemotherapy, due to their potentially negative synergistic effects.

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Table

Class Subclass Mechanism of action Agents Therapeutic use

Alkylating agents Alkyl sulfonates The agent and nucleophilic cellular components including Busulfan Bone marrow
DNA form covalent linkages, by alkylation, leading to (Myleran, Busulfex) transplantation, especially
cytotoxicity in chronic myelogenous
4 leukemia
Nitrogen mustards Melphalan Multiple myeloma
(Alkeran) Ovarian cancer
Melanoma
Chlorambucil Chronic lymphocytic
(Leukeran) leukemia
Cyclophosphamide Lymphomas
(Cytoxan, Endoxan) Leukemias
Solid tumors
Ifosfamide Testicular cancer
(Ifex) Breast cancer
Non-Hodgkin's lymphoma
Osteogenic sarcoma
Lung cancer
Cervical cancer
Ovarian cancer
Nitrosoureas Carmustine Glioma
(BCNU, Gliadel) Glioblastoma multiforme
Medulloblastoma and
astrocytoma Multiple
myeloma
Lymphomas

Platinum agents Induce cellular apoptosis by covalently binding purine DNA Oxaliplatin Colorectal cancer
bases and disrupting its function (Eloxatin)
Antimetabolites Antifolates Inhibit dihydrofolate reductase, leading to decreased levels of Methotrexate Non-Hodgkin's lymphoma
tetrahydrofolate necessary for purine and aminoacid (Rasuvo, Otrexup, Trexall, Rheumatrex) Primary CNS lymphoma
formation Acute lymphoblastic
leukemia
Breast cancer
Bladder cancer
Osteogenic sarcoma
Gestational trophoblastic
cancer

Pyrimidine analogues Interfere with DNA/ RNA synthesis and inhibit thymidylate 5 Fluorouracil Breast cancer
syntherase (Adrucil) Colorectal cancer
Anal cancer
Gastroesophageal cancer
Hepatocellular cancer
Pancreatic cancer
Head and neck cancer
Cytarabine Hodgkin's lymphoma
(Cytosar- U) Non-Hodgkin's lymphoma
Acute myelogenous
leukemia
Acute lymphoblastic
leukemia
Capecitabine Breast cancer
(Xeloda) Colorectal cancer
Gastroesophageal cancer
Hepatocellular cancer
Pancreatic cancer
Gemcitabine Pancreatic cancer
(Gemzar) Non–small cell lung cancer
Breast cancer
Bladder cancer
Hodgkin's lymphoma
Ovarian cancer
Soft tissue sarcoma
Purine analogues Fludarabine Hematologic malignancies
(Fludara)
Topoisomerase I Campotechins Bind topoisomerase I, leading to inability to repair the DNA Irinotecan Colorectal cancer
inhibitors and ultimately cell death (Camptosar)
Topotecan Ovarian cancer
(Hycamtin) Cervical cancer
Small cell lung cancer
Topoisomerase II Anthracyclines Bind topoisomerase II, leading to inability to repair the Doxorubicin Breast cancer
inhibitors DNA and ultimately cell death (Adriamycin) Solid tumors
Epirubicin Breast cancer
 (Ellence)
Anthracenediones Mitoxantrone Acute myelogenous
(Novantrone) leukemia
Prostate cancer
Epipodophyllotoxins Etoposide Small-cell lung cancer
(VePesid, Testicular cancer
Toposarm,
Etopophos)
Antimicrotubule Taxanes Disrupt microtubule dynamics by reducing the critical Docetaxel Breast cancer
agents tubulin concentration required for microtubule assembly and (Taxotere) Gastric cancer
produce similar disruptive effects on the mitotic spindle Head and neck cancer
apparatus and the mitotic process, induce a mitosis block at Prostate cancer
the metaphase/anaphase transition Non–small cell lung cancer
Ovarian cancer

Antitumor Inhibit DNA /RNA synthesis Bleomycin Testicular cancer

antibiotics (Blenoxane) Head and neck cancer
Lymphomas
Mitomycin C
(Mutamycin)
Molecular Tyrosine kinase Interfere with products of oncogenes and tumor-suppressor Imatinib Chronic myelogenic
targeted agents inhibitors genes, regulators of cell death pathways or other substrates (Gleevec) leukemia
responsible for tumor growth Gefitinib Nonsmall cell lung cancer
(Iressa) Renal cell carcinoma
Elotinib Gastrointestinal stromal
(Tarceva) tumors

Proteasome Bortezomib Multiple myeloma

inhibitors (Velcade) Non Hodgkins lymphoma
 Differentiating ATRA Leukemia
agents (Vesanoid, Tretinoin)
Arsenic trioxide Promyelocitic leukemia
(Trisenox)
Antibodies Trastuzumab Metastatic breast cancer
(Herceptin) Colorectal cancer
Cetuximab Head and neck cancer
(Erbitux) Colorectal cancer
Bevacizumab Nonsmall cell lung cancer
(Avastin)

Table. Chemotherapy agents with known pulmonary side effects, mechanism of action and their uses

DNA, deoxyribonucleic acid; RNA, ribonucleic acid