Chest
Volume 133, Issue 2, February 2008, Pages 528-538
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Special Feature
Pulmonary Complications of Novel Antineoplastic Agents for Solid Tumors

https://doi.org/10.1378/chest.07-0851Get rights and content

Antineoplastic agent-induced pulmonary toxicity is an important cause of respiratory failure. Although the incidence of antineoplastic agent-induced pulmonary toxicity seems to be low, more cases can be expected, with increasing numbers of patients receiving the new generations of antineoplastic agents. Antineoplastic agents have previously been associated with bronchospasm, hypersensitivity reactions, venous thromboembolism, and pulmonary hemorrhage. Physicians should be aware of the clinical and radiographic presentations of the pulmonary toxicities associated with the newer antineoplastic agents. The approach to diagnosis, risk factors, and possible mechanisms of antineoplastic agent-induced pulmonary toxicity are discussed in this article.

Section snippets

Clinical Manifestations and Diagnosis

Several clinical syndromes have been described in patients with presumed antineoplastic agent-induced lung toxicity (Table 1). The definition of these clinical syndromes may be confusing due to the different criteria used in the literature. Most clinical trials do not report the details of pulmonary toxicity. Authors describe the pulmonary toxicities based either on clinical criteria (eg, acute lung injury, ARDS, noncardiogenic pulmonary edema, or pneumonitis) or pathologic findings (eg,

Pathogenesis and Risk Factors

The pathogenesis of antineoplastic agent-induced lung injury is poorly understood. Several mechanisms have been suggested. Direct injury to pneumocytes (chemical alveolitis) or the alveolar capillary endothelium and the subsequent release of cytokines and recruitment of inflammatory cells may be responsible, along with some of the cytotoxic medications. The systemic release of cytokines by chemotherapeutic agents (eg, gemcitabine) may also result in capillary leak and pulmonary edema. Positive

Antineoplastic Agents

Table 2 summarizes the pulmonary complications associated with the newer antineoplastic agents used in the treatment of solid tumors.27282930313233343536373839404142434445464748495051525354555657585960616263646566676869707172737475767778798081828384858687888990919293949596979899100101102103104105106107108109110111112 Each agent is discussed separately below.

Chlorozotocin

Chlorozotocin is an alkylating agent with activity against advanced islet-cell carcinoma. Two reported cases2829 of mild subacute interstitial pneumonitis have been reported with this agent. Mild dyspnea, dry cough, and pulmonary infiltrates developed in one patient after the third dose of chlorozotocin. Pulmonary function test results showed reduced diffusion capacity and lung volumes. Acute pneumonitis developed in the second patient after receiving chlorozotocin and mitomycin-C. Pneumonitis

Doxorubicin

Doxorubicin is a cytotoxic antibiotic that inhibits topoisomerase II. It has activity against a variety of solid tumors (ie, cancers of the bladder, breast, stomach, lung, ovaries, and thyroid, soft-tissue sarcoma, and others). Lung toxicity is rare. Infusion reaction may be seen in 8% of patients during pegylated liposomal doxorubicin infusion. Dyspnea may develop in patients within 1 to 5 min after infusion, and the symptoms resolve within 5 to 15 min after stopping the infusion. In vitro

Piritrexim

Piritrexim is an orally bioavailable, second-generation antifolate with activity against transitional cell carcinoma. In a phase II trial,46 piritrexim was administered orally in a dose of 25 mg daily for 5 consecutive days per week for 3 consecutive weeks. In this study,46 pulmonary toxicity (only 1 of 28 patients had grade 3 pulmonary toxicity) developed in 14% of patients (4 of 28 patients).46 de Wit et al47 described a case of diffuse interstitial pneumonitis and respiratory failure after

Bevacizumab

Bevacizumab, a monoclonal antibody against endothelial growth factor, has been used to treat patients with a variety of cancers. There are several reported pulmonary toxicities associated with bevacizumab therapy. Pulmonary hemorrhage and hemoptysis has been reported484950 in 2.3% of patients with nonsquamous NSCLC. In these patients, pulmonary hemorrhage may lead to respiratory failure, and fatalities have been reported in 1.6% of patients treated with bevacizumab. Severe hemoptysis and

Gemcitabine

Gemcitabine is a nucleoside analog with activity against a variety of solid tumors, especially NSCLC and pancreatic cancer. A variety of forms of pulmonary toxicity have been described with the use of gemcitabine. Dyspnea developing within hours of infusion has been reported to occur in about 10% of patients. Most patients improve with therapy with diuretics and corticosteroids. Bronchospasm develops in about 0.6% of patients. These infusion-related reactions are usually mild and rarely have

Etoposide

Etoposide is a topoisomerase II inhibitor. This agent is used primarily in the treatment of small cell lung cancer. The most common pulmonary toxicity is a hypersensitivity reaction that can present with symptoms of anaphylaxis, angioedema, chest discomfort, bronchospasm, and hypotension.64 Etoposide-induced acute pneumonitis or acute lung injury, although uncommon, may occur. The pathology of etoposide-induced lung injury is diffuse alveolar damage, fibrin membrane formation, and alveolar wall

Temsirolimus

Temsirolimus is a rapamycin analog that is active against renal cell carcinoma, endometrial carcinoma, breast cancer, glioblastoma multiforme, and GI neuroendocrine tumors. Temsirolimus binds with immunophilin FK-506 binding protein-12 and forms a complex that inhibits the protein activity of mammalian target of rapamycin (mTOR). mTOR is a serine-threonine kinase that regulates cell growth, proliferation, and apoptosis. Interstitial pneumonitis is a non–dose-dependent complication of

Taxanes

Taxanes are mainly used in the treatment of breast, ovarian, and lung cancers. Paclitaxel and docetaxel are known to cause pneumonitis with estimated frequencies of 0.73 to 12% and 7 to 26%, respectively. Dyspnea, cough, hypoxemia, and pulmonary infiltrates usually develop 1 week to 3 months after treatment. Possible risk factors for pulmonary toxicity are weekly or biweekly therapy compared to triweekly therapy and concurrent treatment with gemcitabine and irinotecan. Severe pneumonitis and

Irinotecan

Irinotecan is a topoisomerase I inhibitor that is used mainly in the treatment of colon cancer, particularly in combination with other chemotherapy agents. Pneumonitis is a dose-dependent side effect of irinotecan. Moderate-to-severe pneumonitis has been reported in 2 to 16% of patients treated with irinotecan. Severe hypoxemia and respiratory failure requiring mechanical ventilation may develop in about 9% of the patients. Fatalities due to severe pneumonitis have been reported in 1 to 3.5% of

Thalidomide

Thalidomide was approved in 2006 for the treatment of multiple myeloma. Thalidomide is also being investigated for treatment of several other cancers. Dyspnea in association with thalidomide therapy has been reported9091 in 4 to 54% of patients. Opportunistic infections including Pneumocystis carinii pneumonia, disseminated herpes zoster, and herpes simplex infections have been described in leukopenic patients receiving thalidomide.9293 Several studies9495 have found increased incidence of DVT

Gefitinib

Gefitinib is an oral EGFR tyrosine kinase inhibitor that is active against NSCLC, and ovarian, colon, head and neck, and breast cancers. Gefitinib- induced lung toxicity usually occurs within the first 90 days of treatment with gefitinib. Interstitial pneumonitis, diffuse alveolar damage, alveolar hemorrhage, and pulmonary fibrosis have been described.9899100101102103 The reported incidence of gefitinib-induced lung toxicity in Japan is between 1% and 2%, which is higher than the incidence of

Treatment

The mainstay of therapy for drug-induced pneumonitis is the cessation of the presumed culprit agent and systemic corticosteroids. Although corticosteroids are used widely to treat drug-induced pneumonitis, this treatment has not been evaluated in controlled clinical trials. It is important to exclude an infectious etiology prior to initiating corticosteroid therapy. We recommend therapy with methylprednisolone, 1 g/d for 3 days, in patients with respiratory failure. Lower doses of

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    The authors have reported to the ACCP that no significant conflicts of interest exist with any companies/organizations whose products or services may be discussed in this article.

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