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ADVERSE EFFECTS

Most adverse events of inhaled chemotherapy are due to direct local effects of the chemotherapeutic agents on the upper and lower respiratory tract. After IV administration, chemotherapeutic agents have the potential to produce a variety of pulmonary toxic effects, including some that are severe and life threatening. After inhaled chemotherapy, nonpulmonary side effects are infrequently reported. Metallic taste, cough, weight loss, neurotoxicity, and cardiotoxicity have been observed (Table 5.3).

Among a variety of agents given by inhalation, dose-limiting pulmonary toxicity was only observed with doxorubicin. Several symptoms such as cough, wheezing, shortness of breath, bronchospasm, and chest pain occur with varying frequency after inhalation of chemotherapy. An alveolar interstitial pattern is often seen radiologically and this is associated with histological findings of moderate fibrosis (Selting et al. 2008, 2011). Bilateral ground glass opacities and hypoxemia have been occasionally reported. Severe pulmonary toxicity has been observed with inhaled doxorubicin (Otterson et al. 2007), GEM (Lemarie et al. 2011), and liposomal cisplatin (Chou et al. 2013). Bronchoconstriction and a drop in pulmonary function observed after inhaled chemotherapy could be mitigated by prior administration of inhaled bronchodilators and corticosteroids (Otterson et al. 2007, 2010; Lemarie et al. 2011; Chou et al. 2013).

TABLE 5.3

Adverse Effects with Inhaled Chemotherapy

Type of Adverse Effect

Symptoms

Severity

Remarks

Respiratory

Cough, hoarseness, bronchoconstriction, dyspnea, fall in pulmonary function, acute lung injury

Dose-limiting lung toxicity can occur but is uncommon.

Pre-treatment with bronchodilators and corticosteroids is recommended.

Gastrointestinal (GI)

Glossitis, pharyngitis, nausea, vomiting

Glossitis and pharyngitis could be dose limiting.

GI side effects are common.

Hematological

Anemia, cytopenias

Hematological effects are uncommon.

Neutropenia may occur with repeated dosing.

Biochemical

No significant changes

Biochemical changes are rare.

Inhalation of chemotherapy is associated with very few biochemical derangements.

Miscellaneous

Metallic taste, fever, fatigue

These are usually not dose-limiting.

These side effects are more frequent. Other systemic side effects, e.g., ototoxicity, occur infrequently.

Adverse effects due to inhaled nonchemotherapeutic agents include reduction in forced vital capacity, bilateral infiltrates, pleural effusion, and bronchospasm with inhaled GM-CSF in patients with metastatic disease (Anderson et al. 1999; Markovic et al. 2008). In contrast, other investigators have reported only minor toxicity in patients who received inhaled GM-CSF. Inhalation of IL-2 is limited by the development of pulmonary vascular leakage, which is dose, route, and formulation dependent (Huland et al. 2003). Adenoviral vectors tend to create neutralizing antibodies and can be associated with significant local and systemic inflammation involving neutralizing antibodies and cytotoxic lymphocytes. In contrast, adenoassociated virus has not been associated with any significant toxicity. Nonviral vectors and polymers exhibit cytotoxicity, which is mainly due to their strong electrostatic charge. The molecular weight of the polymers plays an important role, with higher-molecular- weight polymers producing higher incidence of adverse respiratory effects.

 
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