When faced with the cancer patient who has new pulmonary signs, symptoms, or radiographic abnormalities, there is a broad spectrum of pathogens that must be considered. These include infectious agents, neoplastic disorders, and a wide variety of other injuries including pulmonary hemorrhage, cardiogenic and noncardiogenic pulmonary edema, graft-vs-host reactions, and radiation- and chemotherapy-induced lung injury (toxic lung injury). Perhaps the most challenging of these to diagnose is toxic lung injury because it can mimic both infectious and neoplastic lung disorders. Furthermore, if the toxicity goes unrecognized, continuing the offending agent may result in death. This section will review the mechanisms of lung injury (when known) and histopathologic findings associated with chemotherapeutic agents as well as the “risk factors,” clinical features, radiographic and physiologic findings, diagnosis, and treatment of the pulmonary abnormalities associated with these drugs. Although any drug has the potential to cause lung injury, the more common chemotherapeutic agents associated with pulmonary toxicity are listed in Table 2.

Clinicopathologic Syndromes

While much of the pathophysiology of toxic lung injury from specific agents is unknown, three common clinicopathologic syndromes have been associated with chemotherapyinduced lung injury: interstitial pneumonitis/fibrosis (IP/F), hypersensitivity pneumonitis (HP), and an acute pneumonitis with or without noncardiogenic pulmonary edema (NCPE). One could think of toxic lung injury as an imbalance that occurs in the lung among factors that keep it healthy. For example, an upset in the balance between oxidants and antioxidants can result in damage. Certain cytotoxic drugs can trigger the formation of reactive oxygen metabolites such as superoxide anions, hydrogen peroxide, and hydroxyl radicals. These substances, in turn, can result in direct injury or they can initiate a metabolic cascade that produces immunoreactive substances, like prostaglandins and other cytokines, leading to inflammation and lung damage.

Cytotoxic drugs can also alter the balance between collagen formation and collagenolysis as well as the balance between effector and suppressor cells. The former may result in fibrosis through modulation of fibroblast proliferation and/or excessive collagen deposition, while the latter may result in a hypersensitivity reaction. NCPE is a lessrecognized toxic lung injury syndrome of anticancer therapy compared with IP/F or HP. Its pathophysiology remains unclear, but there are studies suggesting that both a direct cytotoxic insult to the lung epithelial cells and induction of a cytokine-triggered inflammatory response may be involved. Drug-induced interstitial pneumonitis can lead to permanent damage with fibrosis, whereas HP and NCPE are usually reversible. Commonly recognized clinicopathologic syndromes are discussed below and are all listed in Table 3 with their associated chemotherapeutic agents. Some drugs can cause more than one type of toxicity.

Interstitial pneumonitis/fibrosis

Bleomycin, the most well-recognized agent in this category, is an antitumor antibiotic used to treat a variety of neoplasms, including carcinoma of the head and neck, cervix, and esophagus, germ cell tumors, and Hodgkin’s and non- Hodgkin’s lymphoma. Its major limitation is its potential for causing life-threatening pneumonitis that can progress to fibrosis in up to 10% of patients receiving the drug. In one study of 180 patients treated for germ cell tumors between 1991 and 1995, the fatality rate from bleomycin-induced lung injury was 2.8%. Risk factors in this group of patients were age > 40 years and abnormal renal function.

The lack of an inactivating enzyme, bleomycin hydrolase, in the lung, may account for the specific lung toxicity of this agent. The central event in the development of bleomycininduced pneumonitis is endothelial damage with extravasation of fluid into the interstitial and alveolar spaces. There is destruction of type I pneumocytes along with proliferation of type II pneumocytes, which look bizarre and resemble hobnails. The latter finding is suggestive but not pathognomonic of chemotherapy-induced lung injury. The chronic fibrotic response to bleomycin is thought to be mediated by an immunologic mechanism in which tumor necrosis factor (TNF), derived from the alveolar macrophage, plays a key role. Evidence supporting the role of TNF in the pathogenesis of bleomycin pneumonitis is the fact that animals whose TNF receptors have been deleted are protected from the development of injury and fibrosis. Other forms of lung injury, such as HP, pulmonary nodules, and BOOP, have been reported with bleomycin but less commonly.

Factors associated with an increased risk of bleomycin interstitial pneumonitis include advanced age, higher doses, abnormal renal function, and concurrent or subsequent use of oxygen, radiation therapy, and other chemotherapeutic agents (see Table 4). Although administration of higher doses clearly increases the risk of lung toxicity, injury can occur at doses < 50 mg/m². Concentrations of inspired oxygen increase the risk of developing bleomycin toxicity. Whether there is a threshold fraction of inspired oxygen, duration of therapy, or interval following bleomycin treatment after which higher oxygen concentrations will not increase the risk of lung injury is unknown. Previous or simultaneous thoracic irradiation increases the risk of toxicity; however, as is the case with oxygen therapy, it is not known whether a long interval between irradiation and administration of bleomycin eliminates the risk. Although earlier reports identified concomitant treatments with granulocyte colony-stimulating factor as a possible risk factor, recent studies have shown no increase in pulmonary toxicity when granulocyte colony-stimulating factor is co-administered.

The clinical presentation of bleomycin toxicity usually begins between 1 and 6 months after bleomycin treatment. Symptoms, physical signs, and pulmonary function abnormalities are nonspecific and include the following: insidious onset of dyspnea, dry cough, fever, tachypnea, “Velcro” rales, a decrease in diffusing capacity out of proportion to the lung volumes (which may be normal or restricted), and hypoxemia, particularly with exercise. An acute chest pain syndrome affecting approximately 1% of patients during the infusion of bleomycin has been described but does not predict the development of pulmonary fibrosis. The classic chest radiograph shows reticular densities at the bases and peripherally; these findings can progress to consolidation with honeycombing. The major advantage of chest CT is that it better defines the subpleural location of the infiltrates. Rounded masses on chest radiograph or CT scan may mimic metastatic disease and often present a diagnostic dilemma.

Most important in the treatment of bleomycin toxicity is recognition of the syndrome and discontinuation of the drug. Avoidance of oxygen and/or subsequent thoracic irradiation is important in the treatment. Although there are no specific studies addressing the efficacy, effective dose, or optimal duration of corticosteroid therapy, short-term improvement occurs in 50 to 70% of treated patients. It is our practice to initiate treatment with 1 mg/kg of prednisone and taper the dose over a period of at least 3 to 6 months. In most cases, Pneumocystis carinii prophylaxis should be given because of the prolonged period of steroid use. Because symptoms may relapse when therapy is tapered and then become more difficult to control, the patient should be closely monitored during prednisone tapering. It is unclear whether screening pulmonary function tests are useful in the assessment of patients during bleomycin therapy because both false-positive and false-negative results have been reported. However, during the tapering of prednisone, it is our practice to follow both the diffusing capacity and the rest and exercise oximetry. If either deteriorates during the taper, prednisone is increased, usually to the previous dose, and continued until stabilization occurs.

Other drugs known to cause IP/F lung injury are listed in Table 3. Although mitomycin C can cause a histopathologic picture similar to that caused by bleomycin, it has been associated with several other pulmonary disorders that will be discussed later. The mechanism of injury from these drugs is unknown, but in most cases it is thought to occur from direct injury to the epithelial lining cells through production of toxic oxygen species. The interval between initiation of therapy and onset of pulmonary symptoms with busulfan, cyclophosphamide, chlorambucil, and the nitrosoureas can be very long, sometimes > 10 years after exposure to the drug. Symptomatic pulmonary injury is estimated to occur in < 5% of patients receiving these drugs with the exception of carmustine (BCNU). One study of 94 Hodgkin’s lymphoma patients receiving carmustine reported early-onset interstitial pneumonitis in up to 47% of the patients whose doses were > 535 mg/m2 and 26% of these patients died, whereas 15% developed toxicity at doses < 475 mg/m2. Statistical analysis revealed that the only independent variables associated with lung disease were total dose of carmustine and female sex. Late-onset carmustine lung fibrosis has been reported in survivors of childhood brain tumors; after 16 to 20 years of follow-up, 8 of 17 patients died of pulmonary fibrosis. As with idiopathic fibrosis, no treatment is effective for late-onset carmustine lung injury. Lung transplant offers the best hope of long-term survival.

Factors associated with an increased risk of toxicity from these drugs are listed in Table 4. Because cytologic and pathologic findings associated with these chemotherapeutic agents are nonspecific, as with bleomycin, the diagnosis of toxicity is usually established clinically and is one of exclusion. As with all drug-induced pulmonary toxicity, withdrawal of the drug is the mainstay of treatment. Although there are no controlled studies evaluating the usefulness of corticosteroids, patients are usually given prednisone at a dose of 1 mg/kg of body weight. If there is a response, the corticosteroids are tapered slowly over a 3- to 6-month period.