Chemotherapy Clinical Manifestations

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As increasing numbers of patients are cured with chemotherapy, reports of agents responsible for acute, and possibly chronic, pulmonary toxicity are expanding. Drug-related lung injury is most commonly an acute phenomenon, occurring during or shortly after the chemotherapeutic agent(s) are administered [25]. Three typical patterns of pulmonary toxicity have been described: pneumonitis or fibro-sis, acute hypersensitivity (or inflammatory interstitial pneumonitis) and noncardiogenic pulmonary edema. Hypersensitivity reactions are rare but can be induced by such agents as methotrexate, procar-bazine, bleomycin, BCNU and paclitaxel. Cough, dyspnea, low-grade fevers, eosinophilia, "crackles" on exam and interstitial or alveolar infiltrates are noted. These reactions occur during therapy and usually resolve with discontinuation of the offending drug and, potentially, corticosteroid use. Noncardiogenic pulmonary edema, characterized by endothelial inflammation and vascular leak, may arise upon initiation of treatment with methotrexate, cytosine arabi-noside, ifosfamide, cyclophosphamide and inter-leukin-2 [25,70,132]. All-trans retinoic acid (ATRA) syndrome occurs in 23-28% of patients receiving

ATRA. Pulmonary edema has also been described in patients treated with bleomycin who are exposed to supplemental oxygen. These acute reactions generally have a good prognosis. Hypersensitivity reactions and non-cardiogenic pulmonary edema are unlikely to result in late-onset pulmonary toxicity.

Drug-induced pneumonitis or fibrosis has a similar clinical presentation to that described after RT. Bleomycin, the nitrosoureas and cyclophosphamide are most commonly the etiologic agents, although methotrexate and vinca alkaloids have also been implicated [25]. This syndrome is particularly worrisome because symptoms may not be detectable until months after a critical cumulative dose has been reached or exceeded. In addition, persistent subclinical findings may indicate a potential for late decompensation.

Bleomycin. The incidence of bleomycin pulmonary toxicity is 6-10%, with a mortality of 1-2%. One study in children with rhabdomyosarcoma exposed to bleomycin demonstrated an incidence of toxicity of 70% based on decreased DLCO [62]. A risk factor for bleomycin-induced pulmonary toxicity is the cumulative dose with a 10% risk at doses of 400-500IU/m2 [13, 120] although injury may occur at doses as low as 20 IU/m2. The elderly [13] and children or adolescents [39] may be more sensitive, especially when bleomycin is administered in conjunction with RT. Of children treated for Hodgkin's disease with 70-120 IU/m2 of bleomycin [39], 9% had grade 3 or 4 pulmonary toxicity, according to DLCO. Three patients (5%) had clinical symptomatology, and one patient died. Only one patient had received RT. Although pediatric trials now use a significantly lower maximal dose than many adult studies, 80 % of the drug is excreted by the kidney,which can result in an increased risk of toxicity due to renal insufficiency [100,130].0ther chemotherapeutic agents,such as cisplatin, cyclophosphamide, doxorubicin, metho-trexate and vincristine [8,108] may also increase risk. Exposure to high levels of oxygen or to pulmonary infection, especially within a year of treatment, is associated with a risk for immediate progressive respiratory failure [42]. Risks associated with surgery after treatment with bleomycin may be due to fluid overload [31]. These risks may persist for longer periods of time. There may be a potential increase in pulmonary toxicity with the use of granulocyte colony stimulating factor (G-CSF), which mediates via the increased numbers of neutrophils [7,26].

Patients with acute bleomycin toxicity most commonly present with dyspnea and a dry cough. Fine bibasilar rates may progress to coarse rales involving the entire lung. Radiographs reveal an interstitial pneumonitis with a bibasilar reticular pattern or fine nodular infiltrates. In advanced cases, widespread infiltrates are seen, occasionally with lobar consolidation [120]. The consolidation may involve only the upper lobes, however. Large nodules may mimic metastatic cancer [81]. Loss of lung volume may occur. Pulmonary function testing reveals a restrictive ventilatory defect with hypoxia, hypocapnia and chronic respiratory alkalosis due to impaired diffusion and hyperventilation [140]. The DLCO is thought by some to be the most sensitive screening tool for bleomycin toxicity [140]. In patients who develop mild toxicity, discontinuation of bleomycin may lead to a reversal of the abnormalities [28], but some patients will have persistent radiographic or pulmonary-function abnormalities [9,95,151].

Nitrosoureas. The risk of nitrosourea pulmonary toxicity is age and dose-dependent with patients who have received higher doses of nitrosoureas (e.g. greater than 1500 mg/m2 in adults and 750 mg/m2 in children) more likely to present with an interstitial pneumonitis identical to that seen after bleomycin therapy [1]. Fibrosis may be early onset or late onset. Radiation therapy also increases risk, as does underlying pulmonary abnormality, such as chronic obstructive pulmonary disease, although this is rarely a factor in children. Bone marrow transplant patients may develop pulmonary fibrosis with BCNU as one of the contributing etiologies [92]. As part of a preparative regimen including etoposide and melpha-lan, BCNU at 600 mg/m2 was associated with unacceptable pulmonary toxicity, but doses of 450 mg/m2 were tolerated in the acute period [2]. Chemotherapy prior to bone marrow transplant may induce inflammatory changes that render the lung more susceptible to further, potentially irreversible, injury with

Table 11.2. Pulmonary toxicity of commonly used chemotherapy agents

Agent

Toxicity

Risk factors

Bleomycin

Interstitial pneumonitis Fibrosis

Non-cardiogenic pulmonary edema

Age,cumulative dose, renal impairment, radiation therapy, oxygen therapy,fluid overload, combination chemotherapy

Nitrosoureas

Interstitial pneumonitis Fibrosis

Age,cumulative dose, combination chemotherapy

Cyclophosphamide

Fibrosis

Non-cardiogenic pulmonary edema

Radiation therapy, oxygen therapy, combination therapy

Methotrexate

Interstitial pneumonitis Non-cardiogenic pulmonary edema Fibrosis Bronchospasm

No clearly identified risk factors No clearly identified risk factors No clearly identified risk factors No clearly identified risk factors

Busulfan

Fibrosis

Potentially dose, combination chemotherapy, radiation therapy

Cytosine arabinoside

Non-cardiogenic pulmonary edema

No clearly identified risk factors

high dose therapy [11]. Although pulmonary fibrosis has been most commonly associated with BCNU, it has been described after other nitrosoureas as well [12,29]. Bibasilar rales with a bibasilar reticular pattern may be seen on chest radiograph, and restrictive ventilatory defects are seen. Abnormalities may be restricted to the upper lobes. A decreased diffusion capacity may precede all other signs [124]. Discontinuation of therapy may alter the course of BCNU-induced pulmonary disease. However, once pulmonary infiltrates are noted, the disease may be irreversible [150]. In a documented study, 47% of survivors of childhood brain tumors treated with BCNU and radiation died of lung fibrosis, 12% within 3 years of treatment and the remainder 6-17 years post treatment. Additional patients were known to have pulmonary fibrosis and remained at risk for late decompensation. In this study, age was a risk factor. The median age of the patients who died was 2.5 years, and the median age of survivors 10 years. All patients treated under the age of 5 years had died [93].

Cyclophosphamide. Fibrosis after treatment with cyclophosphamide is rare, with a reported incidence less than 1 %. However, Makipemaa and colleagues

[79] found that four of 15 children treated with highdose cyclophosphamide without mediastinal RT had significantly decreased forced vital capacities; two of these children also had a decreased FEVr In addition, one of the children had pulmonary fibrosis and a chest deformity. Two children who received more than 50 g/m2 of cyclophosphamide had delayed (greater than 7 years) fatal pulmonary fibrosis, with severe restrictive lung disease. Severely decreased anteroposterior chest dimensions in these patients were attributed to inability of the lung to grow in accordance with body growth. Fibrosis may also develop late after prolonged treatment with relatively low doses of cyclophosphamide. Although there may be recovery if symptoms occur during therapy and the drug is discontinued and treatment instituted with corticosteroids, the course may be one of progressive fibrosis.

Other Agents. Acute pulmonary effects have occurred with cytosine arabinoside (noncardiogenic pulmonary edema) [3,52] and vinca alkaloids in association with mitomycin (bronchospasm or interstitial pneumonitis) [24, 48], but delayed pulmonary toxicity has not been described. Hypersensitivity reactions to the antimetabolites (methotrexate, mercaptopurine and azathioprine) may cause either a desquamative interstitial pneumonitis or an eosinophilic pneumonitis [70,141,145]. Recovery usually occurs within 10-45 days after methotrexate-induced pulmonary toxicity [131].

However, long-term follow-up of 26 childhood-leukemia survivors revealed that 17 (65%) patients had one or more abnormalities of vital capacity, total lung capacity, reserve volume or diffusion capacity [125]. All children with these deficiencies were diagnosed and treated before age eight. The findings have also been attributed to an impairment of lung growth, which normally proceeds exponentially by cell division during the first eight years of life. Other studies have also demonstrated long-term changes in pulmonary function in survivors of ALL treated without spinal radiation or bone marrow transplant [91].

Busulfan can result in late pulmonary fibrosis, with no consistently identified risk factors. Unlike many other agents, the risk does not appear to be dose-related. The clinical and pathologic picture is like that of bleomycin-induced fibrosis. The mortality from busulfan fibrosis is high [1]. Although reports of pulmonary toxicity with other agents are rare, pneumonitis and fibrosis should be considered in the differential of patients presenting with respiratory symptoms. New agents may also present a risk for late pulmonary toxicity. See Table 11.2. [1,82].

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