key: cord-0040025-e8j0ao1v authors: Cutillas, Jorge Roig; Rodríguez, Elvira Gea; Viñals, Nuria Barral title: Chemotherapy-induced pulmonary toxicity in lung cancer management date: 2001-07-01 journal: nan DOI: 10.1007/bf02712689 sha: 8944dcb651446350b80df07ea49910813fe751af doc_id: 40025 cord_uid: e8j0ao1v Chemotherapy is the cornerstone of therapy in many stages of lung cancer. Many diagnostic options have to be taken into account when a patient suffering from lung cancer presents with nonspecific, respiratory, clinical manifestations. A multidisciplinary diagnostic approach is then warranted. The top priority is to rule out those life-threatening causes, such as lung infection, that could be properly treated if a right diagnosis is early. To reach a definite diagnosis frequently requires that one or more diagnostic, pneumologic techniques are performed. Regarding to drug-induced pulmonary disease, prevention is mandatory. In this review we have tried to highlight the risk and characteristics of cytostatic-induced pulmonary toxicity caused by those agents that have been commonly employed to treat lung cancer for the last decades. When treating lung cancer patients, a high clinical suspicion of chemotherapy-induced lung toxicity should be kept in mind since an early withdrawal of the offending drug is the most efficacious therapy. . Because of their own prognostic and therapeuthic implications the following etiologies have to be firstly considered in the initial diagnostic approach: lung infection, either by conventional pathogens or atypical microorganisms, malignancy-related thromboembolic pulmonary disease, local tumor progression, iatrogenic intra-alveolar hemorrhage, radiotherapy-induced adverse effects, Chemotherapy is the cornerstone of therapy in many stages of lung cancer. Many diagnostic options have to be taken into account when a patient suffering from lung cancer presents with nonspecific, respiratory, clinical manifestations. A multidisciplinary diagnostic approach is then warranted. The top priority is to rule out those life-threatening causes, such as lung infection, that could be properly treated if a right diagnosis is early. To reach a definite diagnosis frequently requires that one or more diagnostic, pneumologic techniques are performed. Regarding to drug-induced pulmonary disease, prevention is mandatory. In this review we have tried to highlight the risk and characteristics of cytostatic-induced pulmonary toxicity caused by those agents that have been commonly employed to treat lung cancer for the last decades. When treating lung cancer patients, a high clinical suspicion of chemotherapy-induced lung toxicity should be kept in mind since an early withdrawal of the offending drug is the most efficacious therapy. Key words: Lung cancer, chemotherapy, lung toxicity. Rev Oncología 2001; 4: 183-195. Toxicidad pulmonar inducida por citostáticos en el tratamiento del cáncer de pulmón La quimioterapia es la opción terapéutica más eficaz en diversos estadios del cáncer de pulmón. El clínico se enfrenta ante un amplio abanico de posibilidades diagnósticas cuando un paciente afecto de cáncer de pulmón presenta manifestaciones clínicas respiratorias inespecíficas. En tal circunstancia es obligada una aproximación diagnóstica multidisciplinaria. La prioridad fundamental es la exclusión de aquellas etiologías susceptibles de un tratamiento eficaz y que representen una amenaza vital para el paciente como es el caso de la infección pulmonar. La confirmación de un diagnóstico etiológico definido va a requeir frecuentemente la adopción de uno o varios procedimientos diagnósticos mediante la práctica de determinadas técnicas neumológicas específicas que deben ser individualizadas en cada caso. En relación a la toxicidad pulmonar inducida por medicamentos, es prioritaria una actitud preventiva. En esta revisión se subrayan los aspectos fundamentales de la toxicidad pulmonar causada por aquellos citostáticos que se han venido utilizando durante las últimas décadas en el tratamiento del cáncer de pulmón. Dado que la retirada precoz del agente causante es la medida terapéutica más eficaz, el oncólogo debe mantener siempre un alto índice de sospecha para la detección de una posible toxi- Oncologists have often to face a broad differential diagnosis when lung cancer patients under cytos-in those patients that have undergone thoracic surgery, oxygen toxicity, and eventually druginduced pulmonary toxicity. In that last case, most patients are also receiving many drugs, other than cytostatics, that sometimes may cause lung toxicity 4 . For most clinicians the diagnosis and treatment of pneumonia in an non-immunocompetent patient is often the top priority from a practical point of view. However, it is worthwhile to be aware of other entities that may overlap the clinical presentation of pulmonary infection, as it has been recently emphasized 5 (table 1 ) . Usually, a multidisciplinary approach is warranted to try to elucidate the cause of new clinical pulmonary findings in lung cancer patients that are treated with chemotherapy, especially when a multimodality therapeutic program is going on. An algorithmic approach to evaluation of pulmonary infiltrates and nonspecific respiratory symptoms and signs in lung cancer patients on chemotherapy is schematically shown in figure 1. The increasing use of combined chemotherapy and concurrent or alternanting radiotherapy makes it even more dif-ficult for clinicians a right diagnostic approach in these circumstances. The progressive trend of lung cancer to be diagnosed in people aged > 70 years has raised the subject of an alledged i ncrease of drug toxicity in that population 6 . Probably, the multiple underlying diseases which are often present in many elderly patients may afford a better explanation for this finding that age per se. Sometimes physicians have to confront with the dilemma of slowly resolving pulmonary infiltrates in lung cancer patients receiving antibiotics for a confirmed diagnosis of pneumonia. Clinicians have to kept in mind that a slower than usual radiologic resolution of pneumonia may be found in the elderly, in those cases of severe pneumonia with extensive pulmonary shadowing, and with some etiologies such as Legionella 5, 7 . The aim of this article is to review the subject of chemotherapy-induced lung toxicity with a more specific emphasis in those cytostatics that have recently been more commonly used in the therapeutic approach of lung cancer (table 2) . Since a variety of mechanisms have been postulated in chemotherapy-induced-pulmonary toxicity but the actual pathogenesis remains speculative 8 , we have focused only in clinically relevant data of the subject. The role of biological response modifiers, hormonal agents, and other non-cytostatic agents in causing adverse respiratory effects is then beyond the scope of this review. Related topics as the radiation sensitizer action of different cytostatics, the interactions of radiotherapy with antineoplastic agents in producing lung damage, and the perioperative considerations of thoracic surgery following chemotherapy have been adressed in other in-depth reviews [9] [10] [11] . Although a certain clinical or radiographic presentation may occasionally be suggestive of pulmonary toxicity caused by a determined cytostatic, it can be in general stated that clinical and radiologic findings are usually not distinctive for any particular chemotherapeutic agent [1] [2] [3] [4] 8 . Since clinical and radiographic manifestations are protean, it must be emphasized that a high index of clinical suspicion is needed to establish a right diagnosis and institute an appropiate therapy. Affected patients may present with dyspnea, cough, malaise, and sometimes fever. The onset of clinical symptoms is often progressive but a subacute or even abrupt clinical presentation is also possible. In those cases of insidious, progressive pulmonary injury, a relationship between dose and duration of chemotherapy and the onset of lung last entity requires other additional criteria to be established. The microscopic diagnosis of diffuse alveolar damage usually corresponds to the early histopathological expression of any ARDS, whatever its cause is. Many different types of radiographic abnormalities have been reported 12 . In general, the chest radiograph findings lag behind the onset of clinical symptoms. Chest CT scan may help to define the extent and characteristics of the opacities 13 . High-resolution CT scan may occasionally detect subtle parenchymal abnormalities when the chest radiograph is still normal. On the basis of the differences found in magnetic resonance characteristics, a possible role for magnetic resonance spectrometry could be suggested but further studies are clearly warranted to support this concept 14 . The clinical utility of nuclear scintigraphy to both improve sensitivity and to try to correlate the extent o disease with the inflamamatory activity is well established 15 . However, gallium scans, as any imaging technique, have inherent limitations in specificity. We think that, when considering a diagnosis of pulmonary drug toxicity, the most important role of any radiologic tecnique is to detect a new abnormality, whatever it is, either in clinically symptomatic patients or as a radiologic finding in a subclinical phase. An early diagnosis of lung toxicity, even before radiographic shadowing appears, may also be suggested if pulmonary function testing shows an unexplained decrease in carbon monoxide diffusing capacity (DL-CO) in patients that complain about dyspnea of unknown cause 16 . In contrast to the decreased DLCO usually found in the more common pattern of interstitial lung involvement, an increased DLCO may be sometimes noticed in those rare cases of diffuse alveolar hemorrhage 1 7 . In severe cases, hypoxemia and an increased alveolar-arterial (A-a) gradient are usually observed. Pulmonary function testing also may help to evaluate the degree of restrictive ventilatory alteration that is often found and to monitorize the functional outcome in a non-invasive way. Fiberoptic bronchoscopy with bronchoalveolar lavage may be helpful in ruling out an infectious etiology and in supporting the diagnosis of chemotherapy-induced pneumonitis 18 . A nonspecific Iymphocytic predominance with imbalance of the CD4/CD8 ratio is often observed in certain drug-induced pneumonitis but it should be kept in mind that the clinical usefulness of this finding in diagnosing drug toxicity is clearly limited. In certain cytostatic-induced pulmonar toxicities, such as cyclophosphamide or busulfan, characteristic bizarre pneumocytes in sputum or lavage fluid can be identified. The clinical relevance of a few preliminary studies that suggested the uselfulness of determining serum markers for cytostatic-induced lung toxicity has not been confirmed so far 19, 20 . Pathology Some attempts have been made to try to correla- te radiographic findings with the underlying histopathologic process 1 2 . In those cases of chemotherapy-induced lung toxicity in which a biopsy procedure has been performed, many pathologic patterns, most of them showing a variable degree of an inflammatory component, have been reported 2 1 . A variety of interstitial pneumonias, usually chronic or nonspecific interstitial neumonia, and many other histologic patterns have been observed (table 8) . In cases with a protracted course, different degrees of non-reversible interstitial or alveolar duct fibrosis are found after acute abnormalities have evolved to a late proliferative phase. In summary, the diagnosis of lung toxicity caused by cytostatics in lung cancer patients should be based on clinical history, especially from a chronologic point of view, nonspecific clinic findings, and the reasonable exclusion of infection and other less common causes of infiltrative lung disease, either patchy or diffusse. As stated before, a multidisciplinary diagnostic approach is mandatory, and the possible need of invasive techniques, such as bronchoalveolar lavage, transbronchial, thoracoscopic or open pulmonary biopsy, has to be considered in some cases in an individualized way. TREATMENT More benign, early detected cases may resolve after cessation of the incriminated cytostatic agent [1] [2] [3] [4] . Therefore, the most appropiate treatment for many cases of cytostatic-induced lung toxicity is withdrawal of the offending drug. In the usually more severe case a short course of corticosteroid therapy is warranted. However, the outcome is variable depending on the offending agent and the degree of established lung damage. After an improvement of symptoms is observed, tapering of the dosage has to be instituted on an individualized basis. Lung transplantation has exceptionally been considered in very selected cases for patients cured of a malignancy who had developped chemotherapy-induced fibrosis 22, 23 . ALKYLATING AGENTS Table 9 shows a summary of pulmonarv toxicity caused by alkylating agents. Two patterns of cyclophosphamide-induced pulmonary toxicity have been clearly identified 24 . Early-onset acute pneumonitis is reversible and responds to discontinuation of the drug or, in more severe cases, to corticosteroid therapy. Clinical features of late-onset pneumonitis are those of progressive pulmonary fibrosis with associated pleural thickening on chest radiograph. These patients do not respond neither to cessation of cyclophosphamide nor to institution of corticosteroid therapy. The incidence of pulmonary injury associated with this cytotoxic agent is not exactly determined but it is thought to be lower than 1%. A syndrome of water retention with marked hypervolemia and hyponatremia may be induced by h i g h dose intravenous cyclophosphamide therapy 2 5 . Secondary pleuropulmonary findings may then rarely be observed, especially in older patients that receive a fluid overload to prevent hemorrhagic cystitis. In an experimental study cyclophosphamide-induced lung toxicity was shown to be potentiated by hyperoxia 2 6 . Radiation therapy and cyclophosphamide seem to be a particularly toxic combination for the lung. Bischloroethylnitrosurea (BCNU) and cyclohexylcloroethylnitrosourea (CCNU) have been infrequently used in a few combination chemotherapy regimens for small-cell lung cancer. Pulmonary toxicity, resulting in alveolitis and fibrosis, has been reported after BCNU and CC-NU therapy, usually in cumulative doses greater than 1,000 mg/m 2 27-29 . Interestingly, preexisting lung disease and abnormal pulmonary function tests, two relatively common findings in lung cancer, have been identified as risk factors for the development of BCNU-induced lung toxicity in a malignant glioma series 2 8 . In that subset of population a 20%-30% incidence of lung toxicity has been reported [27] [28] [29] . Although toxicity is usually dose-related, an acute form of pneumonitis cag occur at either end of the dose schedule 3 0 . However, most cases present with the clinical features of an insidious chronic pulmonary fibrosis. Enhanced oxygen toxicity has been reported after BCNU therapy 31 . Hypersensitivity reactions, that may imply respiratory manifestations, are possible when ifosfamide is administered, as usual, in conjunction with mesna. The risk of CNS depression following ifosfamide therapy (about 12%) 3 2 has to be taken in consideration in those patients that suffer from advanced chronic obstructive lung disease, a common association in lung cancer, since somnolence may worsen hypercapnia and enhance encephalopathy. A word of caution is also needed in the case of underlying central or obstructive sleep apnea syndrome, since the prevalence of the last one in general population is relatively high. Direct pulmonary toxicity is very rare but possible 3 3 . This nonclassic alkylating agent, sometimes used in small-cell lung carcinoma, may cause rarely an hypersensitivity reaction including lung infiltrates that may force discontinuation of the drug [34] [35] [36] . Pleural effusion has been occasionally reported 3 7 . Since procarbazine is used primarily in combination therapy, most reported cases of hypersensitivity have occurred in patients receiving other cytotoxic drugs. Procarbazine is one of the drugs that occasionally may cause neuropathies that could impair respiratory muscle function 3 8 . Platin-based regimens have been the goldstandard of combined chemotherapy for the last decade. The lack of any direct pulmonary toxicity is a characteristic of both cisplatin and carboplatin therapies. Two cases of noncardiogenic pulmonary edema associated with hemolytic uremic syndrome had been allegedlly atributted to cisplatin in a 1991 report 39 . In our opinion, the absence of new references so far and the fact that Usually recovery Acute encephalopathy respiratory depresion* Rarely AP * Special concern in advanced COPD and SAS; AP: acute pneumonitis; CPF: chronic pulmonary fibrosis; HR: hypersensitiviy reaction; COPD: chronic obstructive pulmonary disease; SAS: sleep apnea syndrome; CNS: central nervous system. both patients suffered from acute cisplatin nephropaty and that the noncardiogenic edema seemed to be triggered by a red blood cell transfusion make this association very doubtful. Adverse lung effects have not been reported so far with the new orally available platinum-containing anticancer drugs. ANTIMETABOLITES Table 10 shows a summary of pulmonary toxicity caused by antimetabolites. The role of this folate antagonist as a therapeutic agent seems to be nowadays more in the field of autoimmune disease than in that of lung cancer 4 0 . Al-though a subacute clinical presentation is most common, acute and chronic forms also occur. Pulmonary toxicity may be diagnosed as early as a few days and as late as many years of treatment 4 1 . The incidence of pulmonary toxicity has been a matter of controversy but present studies estimate a rate of 2% to 8%. Difficulties found in comparing the incidence and characteristics of methotrexate-induced lung toxicity among series promoted the scoring system published by Searles et al in 1987 4 2 . In a large study on methotrexate induced lung injury following treatment for rheumatoid arthritis a few risk factors were identified: age greater than 60 years, hypoalbuminemia, diabetes mellitus, and rheumatoid pleuropulmonary involvement 4 3 . The most frequent pulmonary manifestation is hypersensitivity pneumonitis, with peripheral blood eosinophilia that may be observed in up to 40%-50% of patients. Lymphocitic predominance with an increase in CD4+ T cells and CD4/CD8 ratio in bronchoalveolar lavage fluid, and a characteristic pathologic pattern of poorly defined granulomatous infil-tration with interstitial mononuclear infiltrates have also been consistently reported 4 4 . A fulminant presentation of respiratory failure has been well described, even after intrathecal administration in nonpulmonary malignancies. The unusual radiographic finding of hilar adenopathy has been very occasionally reported. Acute chest pain caused by pleuritis without parenchymal involvement may rarely occur 45 . While the drug has been used to control severe corticosteroid-dependent bronchial asthma, methotrexate-induced bronchial hyperreactivity has been paradoxically reported. A reversible pulmonary non-Hodgkin's B-cell Iymphoma may appear in patients under methotrexate therapy. Characteristically, it may regress after cessation of the drug. An interesting association with Epstein-Barr virus infection has been reported 46 . Acute encephalopathy that may present with confusion and even coma has been reported with high-dose therapy. Respiratory implications in severe COPD, in a manner similar to ifosfamide, must be remembered by clinicians. Piritrexim, a methrotrexate analog that has been ocasionally used in upper respiratory tract tumors, which are commonly associated with lung cancer, may also cause pulmonary toxicity 4 7 . The use of fluorinated pyrimidines in lung cancer has been mostly restricted to Japanese studies. To the best of our knowledge, significant pulmonary toxicity has not been reported so far. Fluoruracil administration could enhance the risk of mitomycin-induced thrombotic microangiopathy with acute respiratory distress syndrome 8 . This pyrimidine analog shows a good activity against a wide range of solid tumors, including lung cancer. Consequently, it has become one of the most widely used cytostatics in the therapeutic approach of lung tumors. One benign respiratory side effect of gemcitabine is dyspnea, which may start within a few hours of administration of the drug and is thought to be related to bronchospasm [48] [49] [50] [51] [52] . A potentially more serious event is the appearance of parenchymal infiltrates that sometimes may be associated with acute respiratory distress syndrome [53] [54] [55] [56] . A few fatalities atributted to diffuse alveolar damage and ARDS have been reported. Since that drug shows an structure and metabolism quite similar to cytosine arabinoside (ara-C) a capillary leak phenomena has also been allegedlly incriminated in gemcitabine-induced pulmonary toxicity. Rare instances of pulmonary veno-occlusive disease and hemolytic uremic syndrome have been reported 57, 58 . A recent German study reported a worrying 7.1% percentage of unexplained non-cardiogenic pulmonary distress «most likely related to gemcitabine» in a series of 56 patients 56 . A more extensive retrospective study based on 4,448 trial patients shows a 0.45% incidence of serious pulmonary toxicity 50 . Although high dose steroid pretreatment has allowed succesful rechallenge with gemcitabine after initial severe pulmonary toxicity in a few instances, this approach does not seem to be prudent since a potential risk of repeated toxicity with reexposure can not be definitely avoided. Although many pulmonary toxicities caused by gemcitabine are mild, oncologists must be aware of possible life-threatening cases in order to administer corticosteroid therapy in a timely fashion 59 . Concern about an increased risk of severe pulmonary toxicity in patients treated with a combination of gemcitabine and docetaxel has been reported 60, 61 . Table 11 shows a summary of pulmonary toxicity caused by antibiotics. Although mitomycin-induced pulmonary toxicity is unpredictable the reported global range of significant pulmonary reactions from mitomycin is 3%-12% and more likely to occur at higher dosages [62] [63] [64] [65] [66] [67] [68] . Mitomycin lung toxicity can not be prevented with corticosteroid pre-medication. An acute or subacute pneumonitis, sometimes with bronchospasm and acute respiratory failure, and also a more chronic, progressive form, have both been described. Chronic pneumonitis seems to be related to the total dose of the drug administered and it is very uncommon when the cumulative dose is less than 30 mg/m 2 . Most cases of mitomycin-induced lung damage occur when a vinca alkaloid is administered concomitantly 8 . In that population lifethreatening reactions, such as severe noncardiogenic edema and adult respiratory distress syndrome with diffuse alveolar damage, have been reported 63, 64, 66 . When mitomycin is administered as part of a combination neoadjuvant chemotherapy, lung toxicity may be enhanced by high concentrations of oxygen during surgery 69, 70 . It has been suggested that the administered oxygen concentration should not exceed a FiO 2 of 0.5. Pleural involvement is an uncommon radiographic finding. Type I and type II cells atypia is also possible, a cytological finding similar to those that may be observed after busulfan or cyclophosphamide therapy. Once pulmonary toxicity has been diagnosed withdrawal of the drug and the institution of corticosteroid therapy may not avoid a progressive respiratory failure in up to 40% of cases. Pulmonary toxicity has also been reported with the new mitomycin analogs, such as KW-2149 7 1 . The most severe form of pulmonary reaction from mitomycin is a thrombotic microangiopathy with renal failure, hemolytic anemia, and noncardiogenic pulmonary edema 72 . This entity overlaps the «hemolytic uremic syndrome» and causes an adult respiratory distress syndrome in approximately 50% of cases. Blood transfusions and 5-fluoruracil have been allegedly incriminated in the appearance of this distinctive syndrome 8 . The syndrome is unusual, especially if a low cumulative dose is administered, but the prognosis is poor since the overall case-fatality rate is about 70% 8 . Abnormal pulmonary findings in patients receiving anthracycline antibiotics are usually secondary to primary cardiac toxicity [1] [2] [3] [4] , which has been reported in up to 10% of patients and seems to be related to cumulative dose. The risk of congestive heart failure seems to remain low until a total dose of 450 to 550 mg/m 2 has been reached. However, severe congestive myocardiopathy is possible even after a single dose and it has been suggested that the risk of congestive heart failure begins to increase at total doses of doxorubicin above 350 mg/m 2 or 700 mg/m 2 of daunorubicin 73 . Doxorubicin may rarely produce pleural disease. Table 12 shows a summary of pulmonary toxicity caused by antimicrotubule agents, including vinca alkaloids and taxanes. When used alone, the vinca alkaloids are very rare causes of direct lung toxicity 74, 75 . Most reported cases are associated with combined mitomycin chemotherapy or radiotherapy 63, 64, 66 . Acute pulmonary edema after intravenous vinblastine infusion has been noted 7 6 . Dyspnea of unclear etiology has been observed following administration of vindesine used in combination with mitomycin-C 7 7 . Vincristine is one of the drugs that can impair respiratory muscle function 3 8 . Although sensory neuropathies are usually the most common manifestation, motor or sensorimotor neuropathies may also occur. Involvement of respiratory muscles is rare but possible. Vinorelbine is now probably the most widely used vinca alkaloid in the treatment of lung cancer 74 . Dyspnea has been reported to occur in up 5% of patients. An acute bronchospasm, similar to an hypersensitivity reaction, or an subacute clinical presentation with dyspnea and cough have both been observed. The last one usually occurs within one hour after treatment and the chest radiograph occasionally may show a patchy interstitial shadowing 7 5 . Paclitaxel has emerged as one of the most efficacious cytostatics in the therapeutic approach of lung cancer. Before premedication with corticosteroids up to 30% of patients in early trails suffered from dyspnea caused by bronchospasm and other symptoms, such as rash and hypotension, secondary to anaphylaxis [78] [79] [80] . The mechanism seems to be a direct injury to basophils that causes an immediate histamine release. The routine administration of antihistaminics, corticosteroids, and H2 blockers, before paclitaxel intravenous inphusion, has decreased the incidence of that hypersensitiv i t y to about 1%. Interestingly, parenteral desensitization to paclitaxel has been reported with succesful A different type of pulmonary damage is that derived from direct pulmonary toxicity, which seems to be dose-related [81] [82] [83] [84] [85] [86] . With doses less than 350 mg/m 2 lung toxicity seems to be extremely rare. Transient pulmonary infiltrates have been occasionally reported. More serious pulmonary toxicities have been observed with high dose paclitaxel therapy, particularly when combined with other cytostatics in the setting of patients that undergo bone marrow transplantation. The use of concurrent lung irradiation and paclitaxel therapy deserves a few comments [87] [88] [89] [90] [91] [92] [93] . Compared to other radiosensitizer cytostatics, a higher than usual enhancement of radiation-induced lung damage has been reported. At least in one study, this combination modality therapy was associated, to some extent, with an increased risk of postoperative complications in stage lll lung cancer patients 9 4 . However, differences in drug combinations and radiation doses among studies suggest that larger, prospective studies are warranted before any definite conclusion is reached. A recall pneumonitis may be very uncommonly observed in patients previously treated with radiotherapy. A very unusual acute difusse interstitial pneumopathy has been described 9 5 . As stated before, a few cases of lung toxicity caused by combined therapy wih docetaxel and gemcitabine have been reported 60, 61 . Hypersensitivity mechanisms are thought to be incriminated since recovery is rapid after steroid therapy. The appearance of a pleural effusion, often moderate, in patients that are being treated with docetaxel, should not be misdiagnosed as a pleuropulmonary side-effect of the drug. A fluid retention syndrome, sometimes causing weight gain as well as pleural effusion and ascitis, is a characteristic and unexplained toxicity of that drug. The incidence and severity of this fluid-retention syndrome increases at cumulative doses of 400 mg/m 2 or greater. The topoisomerase I inhibitors, topotecan and irinotecan, have been used in the treatment of refractory or relapsed small-cell lung cancer. A very low rate of reversible pulmonary toxicity, basically mild to moderate dyspnea, has be-en observed with topotecan. In a phase II study of topotecan in malignant mesothelioma, one out of 22 patients had a grade 2 pulmonary toxicity 9 6 . Transitory dyspnea in up to 22% of patients, coughing, and rhinitis are possible respiratory adverse effects when irinotecan (CPT-11) is administered. More serious events such as dyspnea with radiographic infiltrates and fever show an incidence range of 1% to 3% 97, 98 . However in a large phase II Japanese trial with a dose of 100 mg/m 2 weekly up to 8% of patients had pulmonary toxicity. In another Japanese trial of 16 patients that received the irinotecan as a second-line therapy with the same weekly schedule, 2 patients had extensive pulmonary shadowing (13%) 100 . In concurrent chemoradiotherapy for lung cancer, CPT-11 has been identified in multivariate analysis as a significant risk factor associated with eventual development of pneumonitis 101 . These topoisomerase II inhibitors keep a significant role in the treatment of small-cell lung cancer. Although etoposide (VP-16) shows a distinctive low risk profile of general toxicity a very few cases of biopsy-proven pulmonary toxicity have been reported [102] [103] [104] [105] . A fatality after following oral therapy has also been observed 103 . A very rare hypersensitivity reaction including loss of consciousness, non-specific chest pain, and bronchospasm is also possible after etoposide infusion 104 . Teniposide (VM-26) was reported to have produced an acute lung injury in one case but the significance of that report is unclear since the patient had previously received BCNU 1 . IPOMEANOL Ipomeanol (IPO) has been administered to nonsmall cell lung cancer patients in a phase I trial with a reported preliminary rate of serious (grade 4) pulmonary toxicity of about 2% 106 . Chemotherapy-induced lung toxicity may have a substantial impact on the prognosis of lung cancer partients that follow cytostatic therapy. Although the incidence is in general low, oncologists must we aware of this entity since if it remains unrecognized the likelihood of a fatal outcome is clearly increased. Several lines of evidence support the notion that an early diagnosis of any drug-induced pulmonary toxicity is mandatory to improve survival. 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