Mitomycin pulmonary toxicity

INTRODUCTION — Mitomycin (also known as mitomycin-C), an antineoplastic antibiotic derived from Streptomyces caespitosus, is a cell cycle-specific alkylating agent [1]. Although it is active against a wide variety of tumors, newer agents have largely replaced mitomycin except in anal cancer; outside of the United States, mitomycin is infrequently used for treatment of advanced non-small cell lung cancer (NSCLC), and breast cancer. As with many other chemotherapeutic agents, most of the adverse effects of mitomycin are dose-related, including myelosuppression (which is typically delayed in onset), nausea, vomiting, diarrhea, stomatitis, dementia, and alopecia [1-3]. Pulmonary toxicity associated with mitomycin is unpredictable, but more likely to occur at higher doses.

The pulmonary complications associated with mitomycin therapy will be reviewed here. A general discussion of the clinical presentation, pathogenesis, diagnosis, differential diagnosis, and management of antineoplastic agent-induced pulmonary toxicity is presented separately. (See "Pulmonary toxicity associated with systemic antineoplastic therapy: Clinical presentation, diagnosis, and treatment".)

INCIDENCE AND SCOPE — Pulmonary toxicity associated with mitomycin is unpredictable, but more likely to occur at higher doses (in most literature reviews, >20 mg/m²) [4-7]. The frequency of clinically significant adverse pulmonary reactions from mitomycin is estimated to be between 2 and 12 percent [4,7-9].

The various pulmonary disorders that have been described with mitomycin include:

●Acute bronchospasm

●Acute lung injury (diffuse alveolar damage)

●Interstitial pneumonitis

●Thrombotic microangiopathy with acute lung injury

●Pulmonary hypertension and pulmonary veno-occlusive disease

●Pleural disease

As with other antineoplastic drugs, the concomitant administration of other drugs, prior thoracic irradiation, or supplemental oxygen creates difficulties in determining the exact etiology of pulmonary injury in a given patient. Most of the reports of mitomycin pulmonary toxicity are in patients treated with combined mitomycin plus a vinca alkaloid.

Although most cases have been described after intravenous (IV) use of mitomycin, at least one case report documents rapid onset of pulmonary toxicity (acute interstitial pneumonitis) after two months of weekly intravesical mitomycin for bladder cancer [10]. The patient died of progressive respiratory failure despite empiric antibiotics and IV pulse methylprednisolone. In addition, pulmonary toxicity (interstitial pneumonitis, pleural effusion) has also been reported following the use of intraperitoneal mitomycin [11,12]. (See 'Pleural disease' below.)

BRONCHOSPASM — Acute bronchospasm associated with mitomycin occurs with an estimated frequency of 4 to 6 percent, and is of unknown pathogenesis [13]. Most cases are reported with concomitant use of vinca alkaloids (ie, vincristine, vinblastine, vinorelbine, vindesine) and mitomycin, and the two drugs appear to act synergistically to produce this adverse effect [13-16]. The important role played by vinca alkaloids can be illustrated by the following findings:

●In several cases, bronchospasm was temporally related to administration of the vinca alkaloid, occurring within hours of injection, but several days to weeks after mitomycin administration [13,16]

●Acute bronchoconstriction has been associated with administration of vinorelbine without mitomycin [17]

●In one case, rechallenge with vindesine alone in a patient originally treated with combined mitomycin plus vindesine resulted in a recrudescence of dyspnea [13]

Bronchoconstriction typically resolves within 12 to 24 hours, either spontaneously or following the administration of bronchodilators [13]. In some cases, bronchoconstriction is accompanied by the appearance of parenchymal reticular opacities on plain chest radiographs or noncardiogenic pulmonary edema [13]. The radiographic opacities noted at the time of acute bronchoconstriction may clear or persist; if they persist, patients may develop chronic interstitial lung disease [15]. (See 'Interstitial pneumonitis' below.)

ACUTE LUNG INJURY — A relatively rapid onset of acute lung injury has been described in some patients who have had only a brief exposure to mitomycin [14,18-22]. As with bronchospasm, in many of these cases, the acute lung injury has occurred in patients treated with combined mitomycin plus a vinca alkaloid, and symptoms were temporally related to the administration of the vinca alkaloid. However, because there are no reports in which treatment with vinca alkaloids alone produced pulmonary parenchymal toxicity, it has been hypothesized that prior treatment with mitomycin predisposed patients to this complication. The mechanism of lung toxicity may involve alveolar epithelial cell senescence based on in vitro evidence that mitomycin leads to activation of the serine-threonine kinase Akt1 and glycogen synthase kinase-3-beta (GSK3b) pathway, which modulates senescence [23].

A case series of 387 patients reported a 6 percent incidence of acute dyspnea with radiographic abnormalities following combination chemotherapy using mitomycin and vindesine or vinblastine for advanced non-small cell lung cancer (NSCLC) [20]. The median number of mitomycin doses was three.

High concentrations of inspired oxygen may contribute to the risk of mitomycin acute lung injury (as it appears to do with bleomycin). As an example, a study of 20 patients who received mitomycin and thoracic irradiation for esophageal cancer found that no patient who received a fraction of inspired oxygen (FiO₂) <0.3 developed pulmonary disease, whereas an FiO₂ >0.5 appeared to be a risk factor for lung injury [24]. In a patient who had received chemotherapy with mitomycin, vinblastine, and cisplatin, acute lung injury, which was presumed secondary to mitomycin, developed immediately following operative resection of a NSCLC, and was presumed secondary to the combination of mitomycin and high inspired concentrations of oxygen [25]. (See "Adverse effects of supplemental oxygen" and "Bleomycin-induced lung injury", section on 'Thoracic surgery and high fractions of inspired oxygen'.)

Clinical manifestations — Patients with mitomycin-associated acute lung injury typically present with the rapid onset of dyspnea without other respiratory symptoms. Among patients treated with combined mitomycin plus a vinca alkaloid, symptoms typically occur on a day when the vinca alkaloid is administered [20]. Physical examination may reveal wheezes or crackles.

In the majority of cases (87 percent in one series of mitomycin-associated acute lung injury [20]), chest radiographs show new focal or diffuse reticular or ground glass opacities. Arterial blood gases demonstrate hypoxemia with an elevated alveolar-arterial oxygen gradient, and pulmonary function tests reveal severely impaired diffusing capacity [20].

Pathology — Although the data are limited, acute lung injury due to mitomycin is characterized by the histopathologic finding of diffuse alveolar damage (DAD) [10,18,25]. Autopsies obtained from two patients who died of progressive respiratory failure within three weeks of receiving their second dose of mitomycin showed DAD progressing to interstitial pulmonary fibrosis (picture 1 and picture 2) [18]. DAD, the underlying lesion of the acute respiratory distress syndrome (ARDS), is characterized by edema of the alveolar septae and by formation of hyaline membranes that line the alveolar spaces (picture 3 and table 1). No eosinophilic or granulomatous lesions to suggest a hypersensitivity reaction were seen in the lung biopsies. (See "Pulmonary toxicity associated with systemic antineoplastic therapy: Clinical presentation, diagnosis, and treatment", section on 'Pathogenesis'.)

Diagnosis — The diagnosis of acute lung injury due to mitomycin is based upon a combination of clinical features (eg, dyspnea without fever, productive cough, or peripheral edema), the presence of a compatible radiographic pattern, and the exclusion of infection or pulmonary involvement from the underlying malignancy. When the patient is able to tolerate the procedure, bronchoscopy with bronchoalveolar lavage is commonly performed to exclude infection and malignancy. (See "Pulmonary toxicity associated with systemic antineoplastic therapy: Clinical presentation, diagnosis, and treatment", section on 'Evaluation' and "Pulmonary toxicity associated with systemic antineoplastic therapy: Clinical presentation, diagnosis, and treatment", section on 'Diagnosis' and "Basic principles and technique of bronchoalveolar lavage".)

Treatment — The treatment of mitomycin-associated acute lung injury has not been well studied. As initial steps, mitomycin and vinca alkaloid therapy is discontinued if the patient is receiving ongoing therapy, and empiric antibiotics are usually initiated. Supportive care is provided with measures such as supplemental oxygen to maintain a pulse oxygen concentration >90 percent with the lowest fraction of inspired oxygen possible, intubation and mechanical ventilation if respiratory failure develops, careful hemodynamic management, prophylaxis against deep vein thrombosis (DVT), and stress ulcer prophylaxis. (See "Acute respiratory distress syndrome: Fluid management, pharmacotherapy, and supportive care in adults" and "Acute respiratory distress syndrome: Ventilator management strategies for adults" and "Stress ulcers in the intensive care unit: Diagnosis, management, and prevention".)

The role of systemic glucocorticoid therapy is unclear, as a portion of the patients improve spontaneously following drug discontinuation and outcomes data regarding glucocorticoids are limited [18]. On the other hand, a number of series have reported dramatic improvement after the administration of glucocorticoids, although improvement after such treatment is not universal [10,18,20,25]. (See "Pulmonary toxicity associated with systemic antineoplastic therapy: Clinical presentation, diagnosis, and treatment", section on 'Glucocorticoids'.)

For patients with more severe initial symptoms or progressive respiratory failure, we suggest initiation of methylprednisolone 250 mg intravenously every six hours for two to three days, followed by oral prednisone at a dose of 0.5 mg/kg daily for four to six weeks [18,26]. After the initial high-dose phase, prednisone is subsequently slowly tapered to zero over four to six weeks, as tolerated. For patients with less severe disease, oral prednisone may be used for initial therapy.

Rechallenge with mitomycin is not recommended and vinca alkaloids should be administered with caution in patients with prior mitomycin lung toxicity. In one report, both patients who recovered from acute lung injury and were rechallenged with mitomycin experienced recurrent acute pulmonary toxicity [20]. In a separate report, a patient who recovered from an episode of acute respiratory failure after mitomycin-vinblastine combination developed recurrent respiratory failure after rechallenge with vinblastine [6]. The predominant findings on postmortem examination were alveolar and septal edema.

Prognosis — Depending upon the severity of the lung injury, patients may improve spontaneously over 24 to 48 hours, progress to acute respiratory distress syndrome (ARDS), or develop progressive interstitial fibrosis [7,20]. (See 'Interstitial pneumonitis' below.)

A few patients with acute lung injury have a fulminant and occasionally fatal course [5,6,20,27]. In a series of 25 patients with acute lung injury while receiving mitomycin, four required mechanical ventilation for 1 to 10 days and one died [20]. Other reports have detailed fatalities in patients with acute lung injury occurring within hours of mitomycin administration (cumulative doses of 30 to 133 mg/m²) or after administration of a vinca alkaloid in a patient who had previously received mitomycin [5,6].

INTERSTITIAL PNEUMONITIS — Interstitial pneumonitis has been described in patients treated with mitomycin, some of whom had experienced acute toxicity with bronchospasm or acute lung injury attributed to mitomycin [11,28]. In these cases, mitomycin has often been used with other chemotherapeutic drugs, making it difficult to determine the exact contribution of the individual agents [7,28-30]. Several cases of interstitial pneumonitis and fibrosis have been reported after instillation of mitomycin into the urinary tract to treat bladder cancer [10,31].

The frequency of interstitial pneumonitis due to mitomycin is not known, but it appears to be less than 5 percent [7,32-35]. In a prospective study to determine the incidence of interstitial pneumonitis, in which serial chest radiographs, computed tomography (CT) scans, and pulmonary function tests were monitored in 37 patients receiving mitomycin, none developed clinical signs of pulmonary toxicity, and only one patient developed CT evidence of asymptomatic interstitial changes [4].

Similar to the interstitial fibrosis caused by bleomycin, mitomycin-associated interstitial fibrosis appears to be dose-related. In one report of 14 patients who developed mitomycin lung toxicity, the median cumulative dose was 29 mg/m² (range 20 to 39 mg/m²) at the time lung toxicity became apparent [7].

Mitomycin is also associated with an increased risk of radiation pneumonitis in patients who receive thoracic irradiation [36] and may also increase the risk of erlotinib-induced pneumonitis [37]. (See "Radiation-induced lung injury" and "Pulmonary toxicity associated with antineoplastic therapy: Molecularly targeted agents", section on 'Erlotinib'.)

Clinical manifestations — Symptoms and signs of interstitial pneumonitis associated with mitomycin may develop in patients who are recovering from mitomycin-associated acute lung injury or may appear in patients without prior lung toxicity [20,28]. The patients with new onset lung disease typically have the insidious onset of dyspnea and nonproductive cough and on physical examination have tachypnea and crackles [28,38]. In one series of six patients who developed interstitial pneumonitis while receiving a mitomycin-containing chemotherapy regimen for lung cancer, symptoms developed 80 to 118 days after the start of treatment [38].

The chest radiograph may show bilateral diffuse ground glass or reticular opacities with occasional fine nodularity. Similar findings are noted on high resolution CT (HRCT) [39]. (See "High resolution computed tomography of the lungs".)

Pulmonary function testing typically reveals a restrictive pattern and a decrease in diffusing capacity (DLCO) [7,8,28,40]. However, pulmonary function testing is not a useful tool for the early detection of this syndrome. In a prospective study, a decline in the DLCO occurred in approximately one-fourth of patients receiving three cycles of mitomycin-containing chemotherapy, but was not associated with a worse prognosis and did not predict the development of overt pulmonary toxicity [8]. (See "Overview of pulmonary function testing in adults", section on 'Restrictive ventilatory defect'.)

Pathology — Among patients who have had a lung biopsy, histopathological changes resemble those of bleomycin-induced pulmonary injury and fibrosis, with intraalveolar mononuclear cell inflammation, type 2 alveolar cell hyperplasia, and a thickened interstitium with collagen deposition [2,28]. In addition, nuclear atypia of both type I and type II cells has been described, a finding that is also seen in pneumonitis related to cyclophosphamide, busulfan, and methotrexate. One report of mitomycin-associated pulmonary toxicity noted alveolar septal fibrosis and an organizing pneumonia (previously known as bronchiolitis obliterans organizing pneumonia) with intraalveolar masses of fibrous tissue (Masson bodies) [40]. (See "Bleomycin-induced lung injury", section on 'Lung biopsy' and "Busulfan-induced pulmonary injury", section on 'Pathogenesis and pathology' and "Cyclophosphamide pulmonary toxicity", section on 'Pathology' and "Cryptogenic organizing pneumonia", section on 'Histopathologic diagnosis of organizing pneumonia'.)

Diagnosis — The diagnosis of interstitial pneumonitis due to mitomycin is usually based on the history of mitomycin therapy, the presence of chronic or gradually developing dyspnea and cough, a compatible radiographic appearance, and exclusion of other possible diagnoses. Bronchoscopy with bronchoalveolar lavage is commonly performed to exclude infection and malignancy. Lung biopsy is generally not necessary unless the diagnosis is unclear. (See "Pulmonary toxicity associated with systemic antineoplastic therapy: Clinical presentation, diagnosis, and treatment", section on 'Diagnosis'.)

Treatment — The treatment of mitomycin-associated interstitial pneumonitis has not been well studied. Mitomycin therapy has usually been completed by the time pulmonary toxicity develops, but should be discontinued if therapy is ongoing.

In a number of cases, treatment with glucocorticoids resulted in rapid improvement of dyspnea and radiographic opacities [2,7,26,28]. For patients with moderate-to-severe or progressive respiratory impairment, we suggest administration of oral glucocorticoids. A typical glucocorticoid regimen consists of prednisone 60 mg per day for at least two to three weeks, followed by a gradual taper over a four week period, and an increase in dose with any clinical deterioration [28]. Approximately 40 percent of patients experience progressive pulmonary insufficiency despite an initial response to glucocorticoids and despite increases in the glucocorticoid dose [7]. Abrupt cessation or early withdrawal of glucocorticoids can result in a relapse of dyspnea and pulmonary opacities [28].

THROMBOTIC MICROANGIOPATHY AND ACUTE RESPIRATORY FAILURE — Chemotherapy-related thrombotic microangiopathy (TMA) is a distinct syndrome associated with mitomycin that may resemble thrombotic thrombocytopenic purpura (TTP) or hemolytic uremic syndrome (HUS). In contrast to other causes of chemotherapy-related TMA, approximately 50 percent of cases of mitomycin-TMA are associated with acute respiratory failure due to acute lung injury [41,42]. (See "Pathophysiology of TTP and other primary thrombotic microangiopathies (TMAs)" and "Diagnosis of immune TTP".)

The evaluation and management of a patient with suspected mitomycin-induced TMA are discussed in detail separately. (See "Drug-induced thrombotic microangiopathy (DITMA)".)

The distinction between mitomycin-induced TMA and other causes of microangiopathic hemolytic anemia and thrombocytopenia is also presented separately. (See "Diagnostic approach to suspected TTP, HUS, or other thrombotic microangiopathy (TMA)".)

PULMONARY HYPERTENSION AND VENO-OCCLUSIVE DISEASE — Pulmonary hypertension associated with mitomycin has been reported in isolated case reports, some of which were in the context of a thrombotic microangiopathy [43]. (See 'Thrombotic microangiopathy and acute respiratory failure' above.)

Pulmonary veno-occlusive disease (PVOD), a rare cause of pulmonary hypertension that is characterized by obstruction of small pulmonary veins, has been reported in patients treated with mitomycin for squamous anal cancer or non-small cell lung cancer [44-48]. The overall incidence is unknown, but it is thought to be uncommon. In a registry-based French series, seven cases of suspected mitomycin-induced PVOD were identified over a three-year period among an estimated 1800 cases of anal cancer (estimated incidence among patients with anal cancer 3.9 per 1000); however, this might represent an underestimation given that not all patients with anal cancer received mitomycin [47]. These seven patients had received two to four cycles of mitomycin and developed PVOD approximately four months (range 2 to 12 months) after completion of chemotherapy. Four of the seven patients died, two from right heart failure. (See "Epidemiology, pathogenesis, clinical evaluation, and diagnosis of pulmonary veno-occlusive disease/pulmonary capillary hemangiomatosis in adults".)

PLEURAL DISEASE — Pleural disease has been reported in several patients receiving mitomycin therapy, often in the setting of noncardiogenic pulmonary edema [2,8,49]. It is characterized by exudative effusions, fibrinous exudates, and fibrosis over the pleural surfaces with occasional aggregates of lymphocytes and eosinophils. Pleural effusion is often associated with parenchymal lung disease. (See 'Acute lung injury' above.)

Pleural effusions are reported in 64 percent of patients undergoing heated intraperitoneal chemotherapy with mitomycin following radical cytoreductive surgery for bulky intraperitoneal disseminated malignancies [12]. No correlation was found between the prevalence of pleural effusion and the dose of mitomycin, and most cases did not require treatment.

LOCAL EFFECTS OF LARYNGOTRACHEAL MITOMYCIN — In a literature review including 538 patients, topical application of mitomycin to wounds in the circular structures of the upper aerodigestive tract to prevent scar formation was generally safe when followed by consecutive irrigations with saline [50]. However, local complications developed in 19 patients over a mean follow-up of 14.5 months [50]. Complications included accumulation of fibrinous debris at the site, synechiae, glottic web formation, stenosis, and partial airway obstruction [50,51]. A single patient developed squamous cell carcinoma after multiple procedures for vocal fold keratosis, which itself is a risk factor for squamous cell carcinoma [52].

Application of mitomycin generally follows laser dilation, so it is difficult to know the contribution of each of the therapies to the subsequent complication. It is also unclear whether the dose or the duration of application of mitomycin are factors in the development of complications [50]. Saline irrigation after mitomycin application may reduce the number of complications [50].

PREVENTION — Several interventions are thought to reduce the incidence of pulmonary toxicity in patients treated with mitomycin, although supportive data are limited. Pretreatment with glucocorticoids may lower but not eliminate the incidence of lung toxicity [7,53,54]. However, there is concern that glucocorticoids might interfere with antitumor efficacy [54].

Other potentially beneficial interventions include limiting the cumulative mitomycin dose to no more than 30 mg/m² of body surface area, extending mitomycin dosing intervals to greater than four weeks, avoiding concomitant administration of a vinca alkaloid, and limiting unnecessarily high FiO₂ concentrations [54].

●Using lower doses of mitomycin appears to result in a lower incidence of pulmonary toxicity, although in some reports, the avoidance of concomitant administration of a vinca alkaloid may also have contributed. As examples:

•Among 186 patients who received mitomycin (6 to 8 mg/m² every 21 days for a maximum of four cycles with one of the treatment arms that also included vinblastine) for advanced NSCLC, in which glucocorticoid pretreatment was not given, there were no instances of pneumonitis or microangiopathy [55]. However, one patient developed pulmonary edema.

•Similarly, in another series, 216 patients with NSCLC who received an mitomycin-containing regimen (6 mg/m² intravenously every three weeks for four cycles), no instances of pulmonary toxicity were reported. Glucocorticoid pretreatment was not used [56].

•Pulmonary toxicity is generally not reported in patients receiving mitomycin-containing chemoradiotherapy for anal cancer [57]. In this setting, the dose of mitomycin is limited to 10 mg/m² IV on days 1 and 29 of radiation therapy, and the dose is reduced or eliminated if the leukocyte count is low on day 29. (See "Treatment of anal cancer", section on 'Role of mitomycin'.)

●A safe fraction of inspired oxygen (FiO₂) to administer to patients who have received mitomycin has not been defined, but one study of 20 patients who received mitomycin and thoracic irradiation for esophageal cancer found that no patients who received an FiO₂ <0.3 developed pulmonary disease, whereas an FiO₂ >0.5 appeared to be a risk factor [24].

SUMMARY AND RECOMMENDATIONS

●Mitomycin is an antineoplastic antibiotic that is used in chemotherapy regimens for anal cancer, and uncommonly for non-small cell lung cancer (NSCLC) and breast cancer. Pulmonary toxicity occurs in 3 to 12 percent of patients treated with mitomycin. Factors such as the dose of mitomycin, concomitant administration of other drugs (especially vinca alkaloids), supplemental oxygen, and prior thoracic irradiation appear to contribute to the development of pulmonary toxicity. Several types of pulmonary toxicity have been described, including acute bronchoconstriction, acute lung injury, interstitial pneumonitis, thrombotic microangiopathy, pulmonary hypertension, pulmonary veno-occlusive disease, and exudative pleural effusions. (See 'Incidence and scope' above.)

●Acute bronchospasm appears to occur primarily in patients who have received a vinca alkaloid in addition to mitomycin. Bronchospasm generally resolves spontaneously or with bronchodilator within 24 hours. For symptomatic patients with acute bronchoconstriction associated with mitomycin-vinca alkaloid administration, inhaled short-acting beta-agonist is the treatment of choice. (See 'Bronchospasm' above.)

●Acute lung injury due to mitomycin is characterized by the development of the clinical picture of noncardiogenic pulmonary edema, which is associated with the histopathologic finding of diffuse alveolar damage (DAD).

For patients with acute lung injury associated with mitomycin, diffuse involvement of the lungs radiographically, or progressive respiratory insufficiency, we suggest initiation of systemic glucocorticoid therapy (Grade 2C). For patients with respiratory failure, the usual dose is methylprednisolone 250 mg intravenously every six hours for two to three days, followed by oral prednisone at a dose of 0.5 mg/kg daily for four to six weeks. For patients with less severe disease, the prednisone dose is used for initial therapy. After this initial high dose phase, prednisone is tapered over four to six weeks and discontinued. (See 'Acute lung injury' above.)

●Chronic interstitial pneumonitis due to mitomycin may follow an episode of acute bronchospasm or acute lung injury or may develop insidiously without prior respiratory complaints.

The diagnosis is usually based on the history of mitomycin therapy, the gradual onset of dyspnea and cough, diffuse parenchymal lung disease on imaging, and exclusion of other possible diagnoses.

For patients with moderate-to-severe or progressive respiratory impairment, we suggest administration of oral glucocorticoids (Grade 2C). The usual dose is the equivalent of prednisone 60 mg per day for at least two to three weeks, followed by a gradual taper over a four week period. Some patients require more long-term prednisone therapy. (See 'Interstitial pneumonitis' above.)

●Thrombotic microangiopathy is a severe and frequently fatal side effect of mitomycin that may be associated with acute respiratory failure in about 50 percent of patients. (See "Drug-induced thrombotic microangiopathy (DITMA)".)

●For all types of pulmonary toxicity due to mitomycin, we recommend AGAINST rechallenge with mitomycin (Grade 1B). In addition, for patients with acute lung injury while receiving the combination of mitomycin and a vinca alkaloid, we avoid rechallenge with a vinca alkaloid. (See 'Acute lung injury' above.)