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CHAPTER 95: Toxicities of Chemotherapy 895

lung examination. The onset of respiratory failure is reported anywhere peribronchial cuffing, GGOs, consolidation, nodules, air bronchograms,
from 2 to 21 days following treatment and in most cases, efforts to rule and pleural effusions. 22-25
out alternate etiologies were carried out by sampling of respiratory Bleomycin is best known for causing a late onset, dose-dependent
secretions and cardiac evaluations. Histological findings reported are pulmonary fibrosis 1 to 6 months after administration in up to 10%
those showing massive alveolar edema with a highly proteinaceous, of patients. Bleomycin exerts its cytotoxic effect in the lungs via
26
noninflammatory infiltrate suggesting increased vascular permeability generation of reactive oxygen species and resultant oxidative injury to
as the mechanism of disease. Radiographic findings ranged from a dif- pneumocytes. The generation of ROS may be exacerbated by admin-
fuse interstitial pattern, mixed interstitial and alveolar patterns, alveolar istration of supplemental oxygen and is felt to have contributed to the
pattern and normal. These findings were more often diffuse and bilateral development of postoperative respiratory failure in patients previously
than localized. Mortality due to cytarabine-induced NCPE from case treated with bleomycin in case reports. A recent case report described
27
reports range from 13% to 69%, though the number of total cases is the use of nitric oxide in a case of postop ARDS as an oxygen-sparing
limited. Corticosteroids at doses ranging 0.75 to 4 mg/kg per day have strategy to minimize hyperoxia-induced bleomycin toxicity. The study
been used with good results, though there are no clinical studies to better confirmed earlier findings by Dellinger et al of an increase in Pa O 2 with
define their efficacy or optimal dosing. 19 the addition of nitric oxide to lowest possible concentration of oxygen.
Gemcitabine has also been associated with NCPE though much more The mechanism of this benefit is likely due to improved V/Q matching;
rarely at approximately 0.1%. This entity is distinct from a transient, however, the effects on mortality are less clear. 28,29
self-limited dyspnea that is associated with gemcitabine administration Pulmonary venoocclusive disease due to deposition of fibrinous
5% to 8% of the time. The pulmonary toxicity of gemcitabine is thought material in the pulmonary veins and venules has been reported after
to escalate with each successive dose; however, cases of NCPE have treatment with bleomycin as well as mitomycin and BCNU. Typical of
been reported on first administration. There are less than a dozen case any occlusive process with in the pulmonary circulatory bed, clinical
20
reports, all demonstrating significant mortality unless identified early findings include pulmonary hypertension with resultant dyspnea and
and systemic steroids administered and gemcitabine discontinued. 34 hypoxia. Onset is rarely acute and treatment involves discontinuation of
Administration of IL-2 has a 3% to 20% dose-related incidence of NCPE the implicated drug and supportive therapy with mechanical ventilation.
in the context of a generalized vascular leak syndrome. Radiographic find- Treatment of pulmonary hypertension with prostacyclin is currently not
ings include bilateral infiltrates and pleural effusions. With knowledge of recommended due to adverse effects in case reports. 30,31
the mechanism of IL-2–induced pulmonary toxicity, careful attention to Alveolar hemorrhage can been seen in instances of germ cell tumors
volume resuscitation can limit these effects. Clinical and radiographic with pulmonary involvement undergoing initial chemotherapeutic
findings typically resolve with discontinuation of the IL-2. 16,21 Other che- treatment, though this is as a result of tumor response to chemotherapy
motherapeutic agents rarely associated with NCPE and respiratory failure rather than the chemotherapeutic agent itself. Bevacizumab has been
includes intrathecal methotrexate, vinblastine, and mitomycin C. associated with pulmonary hemorrhage and hemoptysis in 2.3% of
Retinoic acid syndrome, or ATRA syndrome, is characterized by a patients treated for NSCLC. 16
collection of clinical findings including fever, weight gain, elevated WBC Finally, innumerable chemotherapeutic agents as well as radiation
count, respiratory distress, interstitial infiltrates, pleural and pericardial therapy have been demonstrated to cause pneumonitis and interstitial
effusions, episodic hypotension, and acute renal failure after initiation of lung disease. This topic will not be discussed as it lies outside of the
therapy for APML. Respiratory distress and fever are represented most focus of this text. For a review of the pulmonary manifestations likely to
commonly (>80%). Initially it was associated with an incidence of 26% be encountered in the acute, ICU setting, please see Table 95-3.
in patients treated with all-trans-retinoic acid (ATRA) and is highly In general, as stated earlier, the diagnosis of pulmonary-related drug
responsive to high-dose steroids and temporary cessation of ATRA, toxicity is a diagnosis of exclusion. Treatment typically involves dis-
though more recent reports indicate this may be decreasing (2%-11%). continuing the offending agent, supportive care with bronchodilators
Its onset occurs at a median of 5 days based on published controlled and mechanical ventilation, taking care to avoid high inspired oxygen
trials and case reports with a mortality of 2%. Radiographic findings concentrations in cases of bleomycin and mitomycin C toxicity, and
suggest pulmonary edema and can include pulmonary vascularity, systemic steroids ranging 0.5 to 1.0 mg/kg/day depending on severity.

TABLE 95-3 Pulmonary Toxicities
Clinical Manifestation Agents Implicated Treatment Comments
ARDS Anthracyclines, cytarabine Supportive • High mortality associated
Noncardiogenic pulmonary Cytarabine, all-trans-retinoic acid, Supportive; possible steroids but lacking • Onset 2-21 days following treatment
edema (capillary-leak syndrome) mitomycin, gemcitabine, IL-2 clinical studies to support their routine use. • Incidence ranges 11%-28% except for gemcitabine (5%-8%)
Pulmonary Fibrosis Bleomycin Avoidance of exposure to high fractional • Dose dependent (especially at dose >400 units)
inspiration of oxygen; discontinue drug; • Onset 1-6 months after treatment
inhaled nitric oxide shown to be effective • Incidence ∼10%; risk increased with concomitant radiation
in case reports treatment
in improving Pa O 2
Venoocclusive disease Bleomycin, mitomycin, BCNU Supportive therapy • Resultant pulmonary hypertension should not be treated
with prostacyclin
Alveolar hemorrhage Bevacizumab Supportive management of hypoxemia • Incidence ∼2.3% in patients treated for nonsmall cell
and hemoptysis lung cancer
Pneumonitis Bleomycin, busulfan, BCNU, cyclophos- Supportive; may be steroid responsive • Incidence, prognosis and chest x-ray findings can be variable
phamide, mitomycin, methotrexate
Retinoic acid syndrome All-trans-retinoic acid Supportive; corticosteroids • Chest x-ray findings consistent with pulmonary edema
including pulmonary vascularity and pleural effusions

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