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Bleomycin-induced lung injury

Bleomycin-induced lung injury
Literature review current through: Jan 2024.
This topic last updated: Jan 05, 2024.

INTRODUCTION — Bleomycin is an antitumor antibiotic that was isolated from a strain of Streptomyces verticillus in 1966 [1]. It has been used successfully to treat a variety of malignancies, predominantly germ cell tumors and Hodgkin lymphoma. The major limitation of bleomycin therapy is the potential for life-threatening lung injury that occurs in up to 10 percent of patients receiving the drug [2-5]. Injury patterns vary and include diffuse alveolar damage, interstitial fibrosis, nonspecific interstitial pneumonia, organizing pneumonia, and eosinophilic pneumonia [3].

The pathogenesis, risk factors, evaluation, and treatment of bleomycin-induced lung injury will be reviewed here. A general approach to immunocompromised patients with respiratory symptoms and the evaluation of interstitial lung disease in patients receiving chemotherapy are presented elsewhere. Details regarding choice of bleomycin therapy for the treatment of stromal tumors and Hodgkin lymphoma are also discussed separately.

(See "Approach to the immunocompromised patient with fever and pulmonary infiltrates".)

(See "Pulmonary toxicity associated with systemic antineoplastic therapy: Clinical presentation, diagnosis, and treatment".)

(See "Initial risk-stratified treatment for advanced testicular germ cell tumors".)

(See "Initial treatment of advanced (stage III-IV) classic Hodgkin lymphoma".)

CLINICAL PRESENTATION — The range of clinical presentations of bleomycin-induced lung injury includes symptoms or physical examination findings (eg, dyspnea, cough, chest pain, and crackles on physical examination), the presence of opacities on chest radiographs, or an asymptomatic decline in diffusing capacity for carbon monoxide (DLCO) during bleomycin therapy. Uncommonly, bleomycin-induced lung injury may be diagnosed several years after bleomycin exposure as chronic fibrotic lung disease or after an exacerbation of fibrotic lung disease (most commonly in the postoperative setting).

Symptoms of bleomycin-induced lung injury usually develop subacutely (over days to weeks) within one to six months of beginning bleomycin treatment but may rarely occur more than six months following the administration of the drug [6]. Symptoms and physical signs associated with bleomycin-induced lung injury are nonspecific, with the earliest symptom being dyspnea and the earliest sign being auscultatory crackles (table 1) [4].

Less commonly, the symptoms proceed more rapidly or insidiously, which often suggests particular histopathologic patterns:

Bleomycin-induced eosinophilic pneumonia and diffuse alveolar damage typically present with more rapidly progressive symptoms.

An indolent onset of dyspnea on exertion several months after completion of bleomycin therapy is suggestive of the fibrotic form of bleomycin lung toxicity, similar to interstitial pulmonary fibrosis. (See "Clinical manifestations and diagnosis of idiopathic pulmonary fibrosis", section on 'Clinical manifestations'.)

PATHOGENESIS — The mechanism of bleomycin-induced lung injury is not entirely clear but likely includes components of oxidative damage, relative deficiency of the deactivating enzyme bleomycin hydrolase, immunologic responses, elaboration of inflammatory cytokines, and scar formation by myofibroblast activity. Despite these multifactorial mechanisms of toxicity, bleomycin reliably induces dose-dependent pulmonary injury, which has led to its longstanding use as an experimental pulmonary injury and fibrosis model.

Mechanism of action and injury – The antineoplastic effect of bleomycin is unique among anticancer agents and is thought to involve the production of single- and double-strand breaks in deoxyribonucleic acid (DNA; scission) by a complex of bleomycin, ferrous ions, and molecular oxygen [2,7,8]. Bleomycin binds to DNA by intercalation of the bithiazole moiety between base pairs of DNA and by electrostatic interactions of the terminal amines. The reduction of molecular oxygen by ferrous ions chelated by bleomycin leads to hydrogen subtraction from the C3 and C4 carbons of deoxyribose, resulting in cleavage of the C3-C4 bond and liberation of a base with a DNA strand break [7].

Study of acute pulmonary injury in rodent models suggests that the initial insult is also due to the primary antineoplastic effect, namely oxidative DNA strand scission with resulting chromosomal injury [4,9-13].

Lung susceptibility and bleomycin hydrolase activity – Bleomycin hydrolase, an enzyme that degrades bleomycin, is highly active in all tissues with the exception of the skin and the lung, where its lower activity may account for organ-specific toxicity [2,7,14].

Role of the innate and adaptive immune response – The chronic fibrotic response to repeated bleomycin-induced injury has been associated with an acquired further loss of bleomycin hydrolase activity [15] and is mediated by an immunologic mechanism. Nude (athymic) mice are resistant to bleomycin-induced lung injury, suggesting that inflammatory processes are important to the pathogenesis of the disease [16]. The recruitment of both tissue-derived and monocyte-derived macrophages to areas of lung injury has been found to play a role in the development and later resolution of the inflammatory process [17-19]. In contrast, severe combined immunodeficiency (SCID) mice are not resistant, suggesting that T lymphocytes may not play a profibrotic role in the murine model of bleomycin-induced fibrosis [20].

Inflammatory cytokines – In animal models, neutralization of the biologic activity of proinflammatory cytokines with neutralizing antibodies (eg, to anti-tumor necrosis factor alpha [TNFa] and anti-transforming growth factor-beta), soluble receptors (eg, recombinant human TNFa receptors), or receptor antagonists (eg, to interleukin-1) results in the amelioration of bleomycin-induced lung fibrosis [21-24].

Myofibroblast activity – Myofibroblast-like cells, which express both smooth-muscle and fibroblast cell markers, increase in number by more than 10-fold after bleomycin-induced injury [25]. Many of these cells are likely derived from the bone marrow [26] and are responsible for the vast majority of new collagen synthesis after bleomycin-induced injury in animal models [24]. This new collagen deposition is thought to be structurally responsible for scar formation and lung fibrosis.

Short telomere syndromes – In animal models, bleomycin induces telomere damage in multiple cell types [27]. Treatment with bleomycin in patients with breast colorectal cancer resulted in more accelerated loss of telomere length in individuals with short baseline telomeres [28]. Short telomere length is a key emerging risk factor for pulmonary toxicity in a variety of interstitial lung diseases, but the effect of bleomycin on human lung disease in individuals with short telomeres has not yet been evaluated.

RISK FACTORS — Several factors influence an individual's risk for the development of bleomycin lung toxicity (table 2) [3,5,29]. At presentation, patient age, renal function, and severity of the underlying malignancy impact the risk for lung injury. Treatment-associated variables include the cumulative dose of bleomycin, concomitant use of other chemotherapeutic agents, neoadjuvant or simultaneous radiation therapy, or post-treatment thoracic surgery. The risks associated with surgery may be higher with exposures to high levels of oxygen.

Age — In most series, the risk of bleomycin-induced lung toxicity appears higher in older patients:

The United Kingdom Royal Marsden NHS Trust reported that among 835 patients treated with bleomycin-containing regimens for germ cell tumors, the rate of pulmonary complications was more than twice as high among those over 40 years of age (hazard ratio = 2.3) [5].

In a study of 141 patients with Hodgkin lymphoma who received regimens including bleomycin, the mean age of those with and without bleomycin toxicity was 49 versus 29 years [29].

A Scottish study of 194 patients treated with bleomycin for germ cell tumors reported that the median age of the five patients who died of pulmonary toxicity was 55 years compared with a median age of 33 years among those who did not develop fatal pulmonary toxicity [30].

The incidence of bleomycin toxicity in 739 United States veterans treated with bleomycin for Hodgkin lymphoma was 9.3 percent overall, with odds ratios of 1.7 (50 to 59 years), 3.2 (60 to 69 years), and 6.0 (≥70 years) compared with those aged ≤49 years [31].

Cumulative exposure — The incidence of bleomycin-induced pulmonary fibrosis is largely dependent on cumulative drug dose [2,32-36]. In patients exposed to a total of 270 international units or less (one international unit = 1 mg), high-grade lung toxicity is seen in 0 to 2 percent, while rates among patients receiving doses of 360 international units or more range from 6 to 18 percent [2,32-35]. Cumulative doses >400 international units are associated with higher rates of pulmonary toxicity and are generally avoided [37]. Although high-grade lung injury is rare with cumulative doses under 400 international units, injury can occur at doses less than 50 international units. Rapid intravenous infusion may also increase the risk of toxicity [38,39]. In large part due to this toxicity, most standard bleomycin-containing treatment regimens lead to a cumulative dose of approximately 200 to 300 international units, with more intensive regimens calling for 300 to a maximum of 400 international units. (See "Initial treatment of advanced (stage III-IV) classic Hodgkin lymphoma" and "Initial risk-stratified treatment for advanced testicular germ cell tumors", section on 'Treatment options'.)

Kidney dysfunction — Bleomycin is primarily eliminated by the kidney in normal individuals (>80 percent) [40], so impaired kidney function increases the cumulative exposure to the drug and is a risk factor for bleomycin toxicity [5,41]. In one cohort of 835 patients treated with bleomycin-containing regimens for germ cell tumors, the rate of pulmonary complications was over three times higher among those with a glomerular filtration rate <80 mL/minute [5].

Other chemotherapy and radiation therapy — In the treatment of germ cell and ovarian sex-cord-stromal tumors, bleomycin is administered in conjunction with other chemotherapy agents, including cisplatin. At least some data suggest that high cumulative doses of cisplatin also contribute to late impairment of pulmonary function and restrictive lung disease in long-term testicular cancer survivors [42], although others have not found such an association [43]. (See "Treatment-related toxicity in testicular germ cell tumors", section on 'Late chemotherapy toxicity'.)

Concomitant administration of gemcitabine with bleomycin may also increase the risk of pulmonary toxicity [44].

In many (but not all [36,45]) reports, thoracic irradiation increases the risk of bleomycin lung toxicity whether it is administered prior to or simultaneously with bleomycin [46-49]. It is uncertain to what extent a longer interval between radiation therapy (RT) and administration of bleomycin eliminates the increased risk of lung injury.

Thoracic surgery and high fractions of inspired oxygen — Several case reports have described the development of acute respiratory distress syndrome in patients treated with bleomycin who underwent thoracic procedures within several months of bleomycin administration [50-53]. The relative contributions of high concentrations of oxygen, volutrauma/barotrauma, and volume-associated pulmonary edema to the development of acute respiratory distress syndrome (ARDS) in these patients are highly uncertain. Current practice is to minimize both excess supplemental oxygen and fluid administration and practice lung-protective ventilation in patients requiring general anesthesia after bleomycin administration. (See "Mechanical ventilation during anesthesia in adults", section on 'Lung protective ventilation during anesthesia' and "Adverse effects of supplemental oxygen", section on 'Lung parenchymal injury'.)

Thoracic surgery has been associated with the development of acute exacerbations of idiopathic pulmonary fibrosis as well as the development of ARDS in the general population. Potential mechanisms include oxidative injury from high oxygen levels as well as volu- or barotrauma from intraoperative mechanical ventilation. Several trials and meta-analyses have found decreased risk of ARDS and lung injury using "lung-protective ventilation" during surgery [54,55]. (See "Acute exacerbations of idiopathic pulmonary fibrosis", section on 'Pathophysiology and risk factors' and "Acute respiratory distress syndrome: Epidemiology, pathophysiology, pathology, and etiology in adults", section on 'Other risk factors' and "Mechanical ventilation during anesthesia in adults", section on 'Lung protective ventilation during anesthesia'.)

Data are conflicting about whether exposure to high concentrations of inspired oxygen specifically increases the likelihood of lung toxicity after bleomycin chemotherapy. Evidence of potential risk has been derived from animal models, in which coexposure to bleomycin and excess oxygen predispose to increased lung damage, likely via increased oxidative injury [56-58]. (See 'Pathogenesis' above.)

Case series have largely examined fraction of inspired oxygen (FiO2) in the context of surgery, and as such, patient outcomes are subject to several confounding factors. Even in this context, evidence that oxygen exposure increases the risk of pulmonary toxicity is largely anecdotal and conflicting:

Acute respiratory failure from ARDS has been reported following general anesthesia in patients previously treated with bleomycin [50-53]. Following the death of five bleomycin-treated patients from postoperative pulmonary complications at a single institution, a new intraoperative protocol was developed in which oxygen exposure was minimized and intravenous fluid replacement was judiciously administered [50]. With adoption of this protocol, none of the subsequent 12 patients who underwent post-bleomycin surgery for metastatic germ cell tumors developed pneumonitis or died from postoperative pulmonary complications.

Other data from large case series do not demonstrate a consistent deleterious effect of inspired oxygen on bleomycin lung injury. In a review of 316 patients who had previous bleomycin chemotherapy and underwent a surgical procedure lasting at least one hour, ARDS developed in seven [59]. No difference was noted in the mean or peak FiO2 between those who developed ARDS and those who did not. Similarly, a review of 77 patients undergoing major surgery following bleomycin-containing chemotherapy failed to demonstrate a correlation between perioperative oxygen restriction and either postoperative pulmonary morbidity or mortality [60].

Cigarette smoking — Cigarette smoking is reported to be a risk factor for bleomycin pulmonary toxicity in some [4,43,61,62] but not all studies [31,41,45,63-66]. The discrepancy may be due to other confounding factors such as bleomycin dose, renal function, patient age, use of other chemotherapeutic agents, and thoracic irradiation. In one study of patients previously treated with bleomycin, current or former cigarette smoking was associated with higher risk for development of ARDS following major surgery [59]. (See 'Thoracic surgery and high fractions of inspired oxygen' above.)

Colony stimulating factors — Concomitant treatment with granulocyte colony-stimulating factor (G-CSF; filgrastim) during bleomycin-containing chemotherapy was identified as a possible risk factor for the development of bleomycin-induced lung injury in animal studies. However, data in humans are conflicting [14,29,45,67-72]. One reason for the disparate results may be the confounding influence of age. (See 'Incidence' below.)

Regardless, many clinicians avoid routinely using G-CSF during treatment with regimens containing bleomycin, particularly ABVD (doxorubicin, bleomycin, vinblastine, and dacarbazine). (See "Initial treatment of advanced (stage III-IV) classic Hodgkin lymphoma".)

In germ cell tumors, G-CSF is typically used only in patients who have had prior febrile neutropenia; when necessary, G-CSF administration is scheduled on a different day than the bleomycin infusion [73]. (See "Initial risk-stratified treatment for advanced testicular germ cell tumors", section on 'Treatment options'.)

INCIDENCE — The potential for bleomycin-related pulmonary toxicity has been appreciated for many decades, but the scope of the problem is not well documented. The available data on incidence come predominantly from patients treated with a bleomycin-containing regimen for a testicular or ovarian germ cell tumor or ovarian sex cord-stromal tumor, or Hodgkin lymphoma.

Germ cell and ovarian sex cord-stromal tumors — In trials of regimens used for germ cell and ovarian sex cord-stromal tumors (typically using 90 international units per cycle for three or four cycles) (table 3), rates of any grade of pulmonary toxicity range from 5 to 16 percent, and rates of fatal pulmonary toxicity have been in the range of 0 to 1 (for three cycles) and 0 to 3 percent (for four cycles), respectively [32-35,73-81]. With few exceptions [33,34,75], most of these reports defined bleomycin pulmonary toxicity according to symptoms and clinical findings of pneumonitis and respiratory failure and not by systematic assessment for asymptomatic pulmonary toxicity using pulmonary function tests (PFTs). With careful monitoring of pulmonary function and avoidance of a full-dose fourth cycle, the incidence of pulmonary toxicity from BEP (bleomycin, etoposide, and cisplatin) is on the lower end of this range [43]. (See 'Surveillance of asymptomatic patients for lung toxicity' below.)

Patients with primary mediastinal nonseminomatous germ cell tumors (PMNSGCTs) who require postchemotherapy thoracic surgery to remove residual disease may be more susceptible to postoperative respiratory complications related to bleomycin; however, the data are inconsistent [82-84]:

In one report, among 221 patients with PMNSGCT who underwent postchemotherapy mediastinal or lung surgery at a single institution, acute respiratory failure or pneumonia developed in 22 of the 166 patients who had received BEP (13 percent) and in none of the 55 who had received etoposide, ifosfamide, and cisplatin (VIP) [82].

On the other hand, in a smaller single-center report, there was no significant difference in pulmonary complications among patients with PMNSGCT treated with or without bleomycin. In addition, no fatal pulmonary complications were observed [84].

We remain comfortable treating PMNSGCTs with BEP (with serial monitoring of PFTs) in patients without other risk factors for bleomycin pulmonary toxicity. Appropriate intraoperative management of patients previously treated with BEP, including avoidance of excessive oxygen supplementation and appropriate lung-protective ventilation, is recommended. (See 'Thoracic surgery and high fractions of inspired oxygen' above and 'Supplemental oxygen and future perioperative management' below and "Extragonadal germ cell tumors involving the mediastinum and retroperitoneum", section on 'Mediastinal nonseminomatous GCTs'.)

Hodgkin lymphoma — Depending on the definition used and the cumulative bleomycin dose, rates of bleomycin-induced pulmonary toxicity in adults receiving ABVD (doxorubicin, bleomycin [20 international units/m2 per course], vinblastine, dacarbazine) (table 4) for Hodgkin lymphoma range from 10 to 53 percent, and rates of fatal pulmonary toxicity are 4 to 5 percent [29,31,63,72,85,86].

Higher rates of severe toxicity have been noted among elderly patients [45,87,88] (see 'Age' above). As examples:

In one report, researchers analyzed patients 60 years of age or older who were enrolled in trials comparing two courses of ABVD or AVD (Adriamycin [doxorubicin], vinblastine, and dacarbazine), each followed by involved field radiation therapy (RT), versus four cycles of ABVD followed by involved field RT [87]. Bleomycin lung toxicity was uncommon in those whose treatment was limited to two cycles of ABVD (two cases per 137 patients), but it developed in 7 of 68 patients (10 percent) who received four courses of ABVD and was fatal in three (4.4 percent).

Similar findings were noted in a series of 147 individuals with Hodgkin lymphoma age 60 years and over who were treated with at least one to eight (median six) courses of ABVD in three French centers [45]. Bleomycin was stopped in 38 percent of patients and dose-reduced in an additional four percent due to toxicity. Grade 3 or 4 pulmonary toxicity (table 5) occurred in 21 percent of patients and did not correlate with underlying lung disease, tobacco history, age, use of granulocyte colony-stimulating factor (G-CSF), or RT. Of the 15 deaths from acute toxicity, seven were related to pulmonary toxicity (4.8 percent).

eBEACOPP (bleomycin, etoposide, doxorubicin, cyclophosphamide, vincristine, prednisone, and procarbazine in escalated doses) is an alternative bleomycin-containing chemotherapeutic regimen used in younger patients with high-risk Hodgkin lymphoma. Likely because the cumulative bleomycin dose is generally lower and this regimen is reserved for younger patients, it does not seem to be associated with frequent pulmonary toxicity. (See "Initial treatment of advanced (stage III-IV) classic Hodgkin lymphoma", section on 'BEACOPP chemotherapy'.)

SURVEILLANCE OF ASYMPTOMATIC PATIENTS FOR LUNG TOXICITY — Practices vary in terms of surveillance for lung toxicity during bleomycin therapy. For patients without risk factors for bleomycin toxicity (table 2), surveillance may be limited to assessment of symptoms and having a low threshold for stopping bleomycin if dyspnea or nonproductive cough develop. Pulmonary function testing and 18-fluorodeoxyglucose-positron emission tomography (18F-FDG-PET) can identify early toxicity in certain settings, although supportive data are limited. We use pulmonary function testing but do not routinely perform surveillance imaging for bleomycin toxicity in asymptomatic individuals.

Pulmonary function tests (PFTs) — Any use of pulmonary function testing for decision making requires careful assessment of the adequacy of the testing according to American Thoracic Society criteria. Serial PFTs should be obtained in the same laboratory. We assess baseline PFTs, typically spirometry and diffusing capacity for carbon monoxide (DLCO), prior to treatment for all patients with planned bleomycin-containing regimens. In addition, we suggest serial testing at intervals during therapy for the following at risk groups [89] (see 'Risk factors' above):

Patients with germ cell tumors receiving three or four cycles of BEP (bleomycin, etoposide, and cisplatin)

Patients with Hodgkin lymphoma 50 or older receiving ABVD (doxorubicin, bleomycin, vinblastine, dacarbazine)

Patients with regimens involving concomitant use of colony stimulating factors

Patients with planned concomitant thoracic radiation or surgery

Suspected short telomere syndrome in the patient or family members

Patients with imaging findings suggestive of parenchymal lung disease

Patients with impaired DLCO (DLCO ≤75 percent predicted or z-score <-1.645) on baseline pulmonary function testing

Patients with renal insufficiency (estimated glomerular filtration rate [eGFR] <60 mL/min)

Patients with ongoing tobacco exposure

Appropriate interpretation of the DLCO (including adjustments for anemia and reduced inspiratory capacity) are discussed further below. (See 'Pulmonary function testing' below.)

Baseline testing – Pretreatment PFTs serve as a baseline for future comparisons. In patients who can complete a DLCO maneuver (approximately 10-second full inspiration to total lung capacity), a moderate to severe reduction in DLCO (<40 to 60 percent predicted) may indicate increased risk for higher grade toxicity from bleomycin. Some clinical trials have excluded these patients (exact criteria depending on the study) under the rationale that patients with poor baseline DLCO may be more likely to develop symptomatic or life-threatening pulmonary toxicity with even a small degree of bleomycin injury. Prospective data demonstrating the validity of this approach are lacking.

Interpretation of baseline testing can be complicated by inability to perform the maneuver due to airway compression or pain from mediastinal masses. While attempted maneuvers under these circumstances should normally be excluded during interpretation, they occasionally are resulted. In the absence of parenchymal lung disease, reported low DLCO under these circumstances should not exclude patients from receiving bleomycin therapy. High-resolution computed tomography (HRCT) may be helpful to further characterize baseline risk in patients with uninterpretable DLCO.

Timing and frequency of follow-up PFTs, and threshold for bleomycin discontinuation – The optimal frequency of testing during bleomycin therapy is not well established, and various guideline recommendations take different approaches [89,90]. For patients with germ cell tumors, we monitor PFTs prior to each new treatment cycle. For older adults (age ≥60 years) with Hodgkin lymphoma receiving a bleomycin-containing regimen such as ABVD, we monitor closely for symptoms of lung toxicity and repeat PFTs every two to four cycles of therapy or at the onset of symptoms. (See "Initial treatment of advanced (stage III-IV) classic Hodgkin lymphoma", section on 'Older adults'.)

Routine DLCO surveillance is somewhat controversial, in part due to the concern that DLCO surveillance for pulmonary toxicity results in many false positive results and subsequent premature and unnecessary discontinuation of bleomycin. Intertest variability for DLCO ranges from 4 to 8 mL/min, making assessment of test quality vital. (See "Diffusing capacity for carbon monoxide", section on 'Quality control'.)

Evidence is also mixed on the ability to separate DLCO changes leading to toxicity from those that remain clinically insignificant. On the other hand, data reported from the Danish Testicular Cancer database suggest that a systematic approach to assessing spirometry and DLCO before and after therapy results in discontinuation of bleomycin in approximately 10 percent of patients, very low rates of both acute and chronic lung disease, and no detectable impact on oncologic outcomes [43].

In early clinical trials, decreases in lung volumes and DLCO appeared to precede the development of severe bleomycin lung damage, and a decline in DLCO appeared to be the earliest and most sensitive indicator of subclinical lung injury [91,92]. Subsequent studies suggested that PFTs, including DLCO, are neither sensitive nor specific for bleomycin lung toxicity, and many questioned the clinical significance of these changes [4,46,93-95]. At least one randomized trial concluded that changes in PFTs during bleomycin therapy were only weakly correlated with increased toxicity, and only at the end of treatment [96].

Is there a role for imaging? — Monitoring of uptake on 18F-FDG-PET scans has been studied as a potential surveillance method for early detection of bleomycin-induced pulmonary injury, but the data are limited and this is not yet a standard approach [86,97-99]. Despite sensitivity for detecting disease [100], HRCT is not used as a surveillance method due to radiation exposure and concern for overdetection of clinically insignificant changes.

For patients with Hodgkin lymphoma who are receiving a bleomycin-containing combination such as ABVD, interim 18F-FDG-PET computed tomography (PET-CT) is often obtained to restage disease activity for the purpose of tailoring subsequent treatment. The 18F-FDG-PET appearance in bleomycin toxicity is typically low-level, diffuse, bilateral, often subtle uptake in the lower lobes, which can predate abnormalities on HRCT [101]. While the 18F-FDG-PET pattern is not sufficiently specific to make a diagnosis, any 18F-FDG uptake in the lungs is abnormal and requires further evaluation. (See 'Imaging' below.)

EVALUATION OF PATIENTS WITH SUSPECTED PULMONARY TOXICITY

When to suspect bleomycin toxicity — For patients who develop pulmonary symptoms (eg, dyspnea, cough, or chest pain), new hypoxemia, or crackles on pulmonary examination during or within several months of bleomycin treatment, there should be a high level of concern for bleomycin toxicity. (See 'Clinical presentation' above.)

For asymptomatic patients, a substantial decrease in diffusing capacity for carbon monoxide (DLCO; ie, ≥15 percent decrease from baseline), new parenchymal opacities on chest imaging, or diffuse low-level bilateral uptake in the lungs on surveillance 18-fluorodeoxyglucose-positron emission tomography (18F-FDG-PET) raise suspicion for developing toxicity and should prompt further evaluation or close interval follow-up. A decrease in DLCO of more than 25 percent from baseline suggests clinically significant bleomycin toxicity and requires evaluation for alternative causes. (See 'Diagnosis and differential diagnosis' below.)

Laboratory — For patients with germ cell tumors and suspected bleomycin toxicity, we obtain tumor markers to rule out tumor progression, although pulmonary progression by germ cell tumors during therapy is rare. We also obtain a complete blood count (CBC) because, rarely, eosinophilia may be present with bleomycin toxicity due to an acute hypersensitivity reaction resulting in eosinophilic pneumonia. If the patient has been on an anthracycline, we obtain a brain natriuretic peptide (BNP) or pro-BNP level to rule out heart failure. (See 'Diagnosis and differential diagnosis' below and "Serum tumor markers in testicular germ cell tumors" and "Diagnosis and treatment of relapsed and refractory testicular germ cell tumors", section on 'Diagnosis' and "Ovarian germ cell tumors: Pathology, epidemiology, clinical manifestations, and diagnosis".)

Imaging — In patients with suspected bleomycin toxicity, we typically obtain a chest radiograph. If no obvious alternate explanation is identified, we proceed with noncontrast high-resolution computed tomography (HRCT). There is no established role for other imaging modalities.

Chest radiograph – We generally obtain a chest radiograph to initially evaluate symptoms or signs of bleomycin toxicity and to rule out alternative causes. The appearance of bleomycin-induced lung injury on chest radiographs is variable (table 6). The classic pattern of bleomycin-induced pulmonary fibrosis includes bibasilar subpleural reticular opacification with volume loss and blunting of the costophrenic angles; however, fine nodular densities may also be present. These early findings may evolve to progressive consolidation and honeycombing. For most patients, findings suggestive of bleomycin toxicity should be further evaluated with cross-sectional imaging. (See "Evaluation of diffuse lung disease by conventional chest radiography".)

Pneumothorax and/or pneumomediastinum are rare complications of bleomycin-induced pulmonary fibrosis [102].

High-resolution computed tomography (HRCT) – Chest HRCT is used to identify suspected occult lung injury, to further characterize the pattern, location, and extent of abnormalities noted on a chest radiograph, or to evaluate gas transfer abnormalities noted on pulmonary function tests (PFTs). It should usually be performed without intravenous contrast.

Multiple different patterns of disease may be seen in bleomycin-induced lung injury. HRCT patterns associated with toxicity usually reflect the underlying histopathology [103]. (See "Idiopathic interstitial pneumonias: Classification and pathology" and "High resolution computed tomography of the lungs".)

Airspace consolidation or ground-glass opacities in dependent locations suggest acute infection or diffuse alveolar damage (image 1).

Diffuse or upper-lobe predominant bilateral ground-glass opacities and/or centrilobular nodules may suggest eosinophilic pneumonia [103] (image 2).

Ground-glass opacities, increased reticular markings in a subpleural location, and bronchiolectasis may suggest nonspecific interstitial pneumonitis.

Ground-glass opacities or consolidations in an asymmetric bilateral, subpleural, or peribronchial pattern can suggest secondary organizing pneumonia (image 3). Rare presentations of organizing pneumonia may show one or more nodular densities, which may mimic tumor metastases [100,104].

Extensive reticular markings at the lung periphery, traction bronchiectasis, and honeycombing suggest usual interstitial pneumonia (image 4).

It is important not to confuse the new development of bleomycin-induced inflammatory nodules with progressive cancer. In difficult cases, biopsy may be needed. (See 'Diagnosis and differential diagnosis' below.)

No role for 18-fluorodeoxyglucose-positron emission tomography (18F-FDG-PET) – As a diagnostic tool in patients with suspected toxicity, 18F-FDG-PET scans are nonspecific and do not differentiate between bleomycin toxicity and infection. 18F-FDG-PET scanning has been evaluated as a surveillance method for bleomycin pulmonary toxicity. Incidental findings consistent with lung toxicity on 18F-FDG-PET should prompt additional work-up [101]. (See 'Is there a role for imaging?' above.)

Pulmonary function testing — We suggest obtaining spirometry, lung volumes, and DLCO in all patients who develop dyspnea, cough, crackles on chest examination, or an abnormal chest radiograph while receiving bleomycin. In patients with bleomycin-induced lung toxicity, pulmonary function testing typically demonstrates a restrictive lung disease pattern, with decreases in forced vital capacity (FVC), total lung capacity (TLC), functional residual capacity (FRC), and DLCO. Testing may also be helpful in identifying other common causes of cough and dyspnea such as exacerbations of asthma and chronic obstructive pulmonary disease (COPD).

Most patients treated with bleomycin will have a decrease in their DLCO during treatment, and those with significant pulmonary toxicity will also demonstrate a decrease in lung volumes (eg, FVC and TLC). As an example, two randomized trials comparing a cisplatin, etoposide, plus bleomycin regimen versus cisplatin plus etoposide alone without bleomycin reported a median decline in DLCO of 14 to 20 percent in the bleomycin arms compared with 0 to 2 percent without bleomycin [34,75]. However, only a small percentage of patients exposed to bleomycin develop clinical signs or symptoms of lung toxicity.

Reductions in DLCO need to be interpreted with caution. When monitoring DLCO, a corrected "predicted value" for DLCO needs to be calculated for patients with anemia as a decrease in hemoglobin leads to a reduction in carbon monoxide uptake (calculator 1 and calculator 2). The correction for anemia is discussed separately. (See "Diffusing capacity for carbon monoxide", section on 'Anemia'.)

Additionally, the DLCO can be affected by airflow limitation due to mediastinal masses, so the DLCO should only be considered valid if the inspiratory volume in the DLCO test is at least 85 percent of the vital capacity, as measured on spirometry. (See "Diffusing capacity for carbon monoxide", section on 'Quality of testing'.)

Invasive testing, in select patients

Bronchoalveolar lavage — The main role for bronchoalveolar lavage (BAL) in assessing possible bleomycin lung toxicity is to exclude infection or malignancy as causes of radiographic abnormalities. Only some clinical presentations and CT patterns may be suspicious for infectious and malignant etiologies, so not all patients will require this invasive test. Data regarding typical BAL findings in bleomycin lung toxicity are limited. In one report, neutrophilia was most common, although eosinophilia may be seen in BAL samples from patients with hypersensitivity reactions to bleomycin resulting in eosinophilic pneumonia [3,105,106]. Cytologic atypia with hyperchromatic, multinucleated cells, and prominent macronucleoli may also be seen [106]. (See "Approach to the immunocompromised patient with fever and pulmonary infiltrates", section on 'Lung sampling'.)

Lung biopsy — Lung biopsy is rarely needed, as discontinuation of bleomycin usually leads to respiratory improvement. If the diagnosis is challenging enough that biopsy is contemplated, we recommend discission of options for obtaining tissue, in the context of the relevant differential diagnosis, in a multidisciplinary discussion that includes clinicians, radiologists and pathologists, prior to invasive procedures. When needed, typically because the etiology of symptoms, signs, and/or radiographic abnormalities remains unclear, tissue has usually been obtained via video-assisted thoracoscopic surgery (VATS) or thoracotomy. Because the histologic patterns of bleomycin lung injury are nonspecific, smaller sample sizes, such as those obtained by forceps biopsies or transbronchial lung cryobiopsy (TBLC), may be inadequate for confident diagnosis. There are currently no data on the usefulness of TBLC in the evaluation of suspected bleomycin toxicity. (See "Role of lung biopsy in the diagnosis of interstitial lung disease", section on 'Overview'.)

Pathology — Gross lung specimens from subjects with bleomycin-induced lung injury typically demonstrate a subpleural distribution of lung injury and fibrosis [2]. Histopathology is nonspecific, although squamous metaplasia is a characteristic finding [4]. Various patterns of interstitial lung disease have been described, including usual interstitial pneumonia, nonspecific interstitial pneumonia, diffuse alveolar damage, organizing pneumonia, and eosinophilic pneumonia [103]. More than one of these patterns may be present at the same time [6].

For patients with a pattern of diffuse alveolar damage, histopathologic findings include endothelial and type I epithelial cell necrosis, type II epithelial cell hyperplasia, and hyaline membranes. In some patients, the diffuse alveolar damage will resolve, in others, it will progress to fibroproliferative lesions and excess collagen deposition.

Bleomycin-induced pulmonary nodules usually have histopathology similar to diffuse alveolar damage, although patterns of granulomatous infiltration, organizing pneumonia, and eosinophilic pneumonia may also occur [3,103,107]. (See "Idiopathic interstitial pneumonias: Classification and pathology" and "Cryptogenic organizing pneumonia".)

Hypersensitivity reactions can demonstrate eosinophilic pneumonia with focal consolidation [106,108,109]. Focal areas of organizing pneumonia and dysplastic type II epithelial cells can also be seen.

DIAGNOSIS AND DIFFERENTIAL DIAGNOSIS — The diagnosis of bleomycin-induced pulmonary toxicity is usually made based on compatible clinical findings (symptoms, signs, pulmonary function test [PFT] abnormalities, and imaging findings) during treatment with bleomycin and the exclusion of infection and pulmonary involvement from the underlying malignancy. After exclusion of other etiologies, we use either pulmonary symptoms with imaging abnormalities or a diffusing capacity for carbon monoxide (DLCO) decrease of at least 25 percent as an indication for treatment, although we recognize that other expert bodies use different cutoffs. (See 'Treatment' below.)

The differential diagnosis of bleomycin-induced lung injury includes lung infection, cardiogenic pulmonary edema, radiation-induced pulmonary fibrosis, metastatic disease, and an adverse reaction to other medications. (See "Pulmonary toxicity associated with systemic antineoplastic therapy: Clinical presentation, diagnosis, and treatment", section on 'Differential diagnosis'.)

TREATMENT

Permanent discontinuation of bleomycin — The key step in the management of bleomycin-induced pulmonary toxicity is immediate and permanent discontinuation of bleomycin. Bleomycin should be discontinued in all patients with documented or strongly suspected bleomycin-induced lung injury, including a significant asymptomatic decline in diffusing capacity for carbon monoxide (DLCO). There is no widespread consensus as to the threshold of decline in DLCO that should prompt discontinuation of bleomycin, but we use a 25 percent decrease in DLCO (adjusted for hemoglobin) from the pretreatment value.

Many experts disagree about the appropriate threshold for discontinuation of bleomycin therapy, with the majority suggesting that a threshold drop in DLCO of 15 to 35 percent warrants treatment discontinuation [43,63,79,110-113]. One reason for this disagreement is the concern that routine DLCO surveillance for pulmonary toxicity results in many false positive results, which may lead to the premature and unnecessary discontinuation of bleomycin. However, the reassuring results from the Danish Testicular Cancer database suggest that the 25 percent threshold provides noninferior cancer control accompanied by good long-term pulmonary outcomes [43]:

In this case series, 565 consecutive patients treated with BEP (bleomycin, etoposide, and cisplatin) for a germ cell tumor underwent systematic and close monitoring of pulmonary function tests (PFTs) before, during, and for five years after treatment. The maximum cumulative dose of bleomycin was limited for most patients to 150 international units/m2 (300 international units) by using one-third of the standard dose in the fourth cycle. This is admittedly not currently standard practice for patients with intermediate- and poor-risk germ cell tumors. (See "Initial risk-stratified treatment for advanced testicular germ cell tumors", section on 'Intermediate- and poor-risk advanced disease'.)

During treatment, 9 percent of patients discontinued bleomycin due to a decrease in DLCO but subsequently experienced improvement in DLCO into the range of other participants. The mean dose of bleomycin was 142 international units/m2 among those completing therapy and 100 international units/m2 among those in whom bleomycin was stopped early. Persistently reduced lung volumes and DLCO were noted in 4 percent of patients after five years of follow-up. Bleomycin-induced lung toxicity requiring glucocorticoids was noted in two patients, and late (15 years after therapy) appearance of pulmonary fibrosis was reported in three patients.

Reinitiation of bleomycin is generally not recommended in patients with bleomycin-induced pulmonary toxicity and is contraindicated in patients with pulmonary fibrosis. Successful reinitiation of bleomycin in patients with eosinophilic pneumonia related to bleomycin has been described in case reports [108,114]. However, we suggest not resuming bleomycin in patients who are thought to have eosinophilic pneumonia (as established by high-resolution computed tomography [HRCT] and eosinophilia on bronchoalveolar lavage [BAL] or histopathology) unless there is no effective alternative antineoplastic agent for the patient's disease.

Glucocorticoids, for symptomatic patients with most patterns of injury — Although data are limited, we suggest the use of systemic glucocorticoids for most patients with symptomatic respiratory impairment due to suspected bleomycin toxicity after negative work-up for infectious and malignant causes. Exceptions include asymptomatic patients without hypoxemia (for whom discontinuation of bleomycin alone is often sufficient) and those with slow-onset interstitial fibrosis (for whom glucocorticoids are unlikely to be effective and may be harmful). (See 'Avoidance of glucocorticoids, in patients with late-onset interstitial fibrosis' below.)

Because spontaneous resolution is common in patients who have more mild asymptomatic changes in DLCO [34,75,100], we use cessation of bleomycin alone and watch for worsening of symptoms and/or DLCO (adjusted for hemoglobin) before initiating glucocorticoids in asymptomatic patients without hypoxemia.

The optimal dosing and duration of glucocorticoid therapy for symptomatic bleomycin-induced lung injury are not known. Based on clinical experience and data from case series, we typically initiate treatment with prednisone at 0.75 to 1 mg/kg (using ideal body weight [IBW]) per day up to 100 mg per day [115]. After initial therapeutic response, prednisone is generally maintained at 0.5 to 1 mg/kg IBW (approximately 30 to 60 mg per day) for four to six weeks before tapering over three to six months. Prophylaxis for pneumocystis pneumonia should be used when prednisone dose is ≥20 mg. (See "Treatment and prevention of Pneumocystis pneumonia in patients without HIV", section on 'Prophylaxis'.)

The response to treatment and subsequent taper of glucocorticoids varies somewhat based on the pattern of pulmonary damage. Although the specific histologic type of lung toxicity (eg, nonspecific interstitial pneumonia, diffuse alveolar damage, organizing pneumonia) is rarely definitively established, decisions regarding glucocorticoids are made based on pace of disease, radiographic appearance, and bronchoscopic findings:

Interstitial pneumonitis and diffuse alveolar damage – Patients with this pattern of lung injury often respond to glucocorticoids, but the response is variable and not always durable. We typically taper glucocorticoids over three to four months in this group depending on their symptomatic and radiographic response to initial therapy and the clinical impact of glucocorticoid side effects.

Case reports and case series have described substantial recovery in patients with subacute or acute bleomycin-induced interstitial pneumonitis when a significant inflammatory pneumonitis was present (eg, nonspecific interstitial pneumonia or acute interstitial pneumonia [aka, diffuse alveolar damage]) [2,6,115,116]. In a series of 10 patients with bleomycin-induced lung toxicity, the seven patients who were treated with systemic glucocorticoids experienced significant clinical and radiographic improvements, while the three patients who were not treated with glucocorticoids died [115].

Short-term improvement occurs in 50 to 70 percent of glucocorticoid-treated patients, but symptoms may relapse when therapy is tapered [115]. Some patients who respond to glucocorticoid therapy initially may subsequently develop progressive interstitial pulmonary fibrosis that is unresponsive to glucocorticoid therapy. Pulmonary function abnormalities may or may not improve with therapy and may recur after a period of one to five years, even in patients with an initially positive response to glucocorticoids.

Organizing pneumonia – Secondary organizing pneumonia is generally responsive to systemic glucocorticoid therapy, although it can occasionally remit spontaneously. Relapses may occur, most frequently after tapering to relatively low doses of prednisone. We treat organizing pneumonia in the setting of bleomycin toxicity like cryptogenic organizing pneumonia, which is discussed separately (algorithm 1 and algorithm 2). (See "Cryptogenic organizing pneumonia", section on 'Treatment'.)

Hypersensitivity reactions (eosinophilic pneumonia) – For patients who are diagnosed with drug-induced hypersensitivity based on an acute onset of symptoms, a consistent radiographic appearance, and either BAL eosinophilia or histopathologic confirmation of eosinophilic pneumonia, the response to glucocorticoid therapy is usually excellent as long as bleomycin is discontinued. In comparison with other forms of bleomycin-induced lung toxicity, there is usually a more rapid response to glucocorticoid treatment, although this is based on anecdotal reports. Tapering of prednisone is usually accomplished over several weeks [108].

Avoidance of glucocorticoids, in patients with late-onset interstitial fibrosis — Some patients who have a later, more indolent onset of interstitial lung disease after bleomycin therapy may have a clinical presentation similar to that of idiopathic pulmonary fibrosis. The radiographic pattern on HRCT is consistent with usual interstitial pneumonia (eg, increased reticular markings and evidence of honeycombing, but minimal or absent ground-glass opacities). These patients generally do not have glucocorticoid-responsive disease. The decision to initiate systemic glucocorticoids should be made understanding the low likelihood of benefit and the substantial adverse effects of glucocorticoids. In patients for whom systemic glucocorticoids are initiated, lack of response within two to four weeks should prompt discontinuation of therapy to avoid further adverse side effects. Patients with clinically significant fibrotic disease may benefit from antifibrotic therapy, although this has not been well studied in the setting of bleomycin toxicity. (See 'Imaging' above and "Idiopathic interstitial pneumonias: Classification and pathology", section on 'Usual interstitial pneumonia' and "Treatment of idiopathic pulmonary fibrosis", section on 'Medical therapies'.)

Supplemental oxygen and future perioperative management — Although the evidence is largely anecdotal and inconsistent, exposure to high inspired oxygen concentrations in the setting of surgery may increase the risk for pulmonary toxicity even several years out from bleomycin administration. This may be due to exacerbations of otherwise undiagnosed fibrotic interstitial lung disease. (See 'Thoracic surgery and high fractions of inspired oxygen' above.)

For patients with prior bleomycin exposure who have hypoxemia, supplemental oxygen should be titrated to an oxygen saturation of 89 to 94 percent. The priority is to maintain adequate oxygen saturation, even if that requires a high fraction of inspired oxygen (FiO2). For bleomycin-exposed patients who are undergoing surgery, lung-protective intraoperative strategies are appropriate [50,83,117]. (See "Mechanical ventilation during anesthesia in adults", section on 'Lung protective ventilation during anesthesia'.)

PROGNOSIS — Even with effective treatment, acute pulmonary toxicity can be fatal in a minority of patients. Long-term respiratory impairment due to bleomycin pulmonary toxicity is less well-reported, but severe pulmonary dysfunction is uncommon.

In those with germ cell tumors treated with BEP (bleomycin, etoposide, and cisplatin), rates of lethal pulmonary toxicity have been in the range of 0 to 1 (for three courses) and 0 to 3 percent (for four courses), respectively [32-35,73-81]. Patients with Hodgkin lymphoma receiving ABVD (doxorubicin, bleomycin, vinblastine, dacarbazine) reportedly die from pulmonary toxicity at a rate of 4 to 5 percent [29,63,72,85,86].

At five years of follow-up of the Danish Testicular Cancer database, only a minority of BEP-treated patients suffered long-term restrictive disease (4.1 percent) or obstructive lung disease (2.7 percent) [43]. After a median follow-up of 16.1 years, the 15-year cumulative risk for pulmonary disease in treated patients was low and comparable to that of patients with stage I germ cell tumors who received no chemotherapy (table 7). There were no differences in long-term outcomes among patients who received all of the doses of bleomycin (median 142 international units/m2) versus those whose doses were attenuated because of changes in the diffusing capacity for carbon monoxide (DLCO; median dose 100 international units/m2).

In another case series, long-term pulmonary toxicity (unspecified) persisted in 8 percent of patients with germ cell tumors treated with three courses of BEP [33].

Long-term functional respiratory impairment is reported in approximately 10 to 20 percent of patients after bleomycin for Hodgkin lymphoma, but this is based on several different measures [36,63,118]. In one case series of 60 patients receiving ABVD, 18 percent had mild pulmonary symptoms at least two years after treatment with ABVD alone, and 30 percent had mild symptoms after ABVD and radiation therapy [63]. In decades-long follow-up of patients receiving primarily bleomycin-containing regimens for Hodgkin lymphoma (with or without chest irradiation), 12 percent of patients showed restrictive spirometry and 21 percent had fibrotic findings on chest radiography [36]. In a final case series with a median follow-up of 57 months, 9 of 67 patients (13 percent) who received bleomycin-containing chemotherapy for Hodgkin lymphoma showed a decrement in DLCO, with only one-third of these also reporting dyspnea [118].

SUMMARY AND RECOMMENDATIONS

Clinical manifestations – Most patients with bleomycin toxicity are identified based on clinical manifestations, which usually develop between one and six months after treatment initiation. Symptoms and signs include nonproductive cough, dyspnea, pleuritic or substernal chest pain, fever, tachypnea, crackles, and hypoxemia. (See 'Clinical presentation' above.)

Risk factors – Risk factors for bleomycin toxicity include:

Older age

Chronic kidney disease

Higher cumulative bleomycin dose

Concurrent thoracic radiation

Concurrent cisplatin

Thoracic procedures, particularly including high levels of supplemental oxygen and/or high intraoperative tidal volumes

Surveillance of asymptomatic patients

The most important step of surveillance for bleomycin toxicity is careful direct questioning and physical examination of the patient to identify symptoms and signs of toxicity that are not initially evident. (See 'Clinical presentation' above.)

We assess baseline spirometry and diffusing capacity for carbon monoxide (DLCO) prior to treatment for all patients with planned bleomycin-containing regimens. For patients with known or suspected parenchymal pulmonary disease or risk factors for bleomycin pulmonary toxicity (table 2), we also suggest serial testing at intervals during therapy. (See 'Surveillance of asymptomatic patients for lung toxicity' above.)

For patients with germ cell tumors, we monitor pulmonary function tests (PFTs) prior to each new treatment cycle. For older adults with Hodgkin lymphoma receiving a bleomycin-containing regimen such as ABVD (doxorubicin, bleomycin, vinblastine, dacarbazine), we assess PFTs after two to four cycles of therapy. (See 'Pulmonary function tests (PFTs)' above.)

A decrease in DLCO by 15 to 25 percent from baseline should prompt close interval follow-up, while a decrease in DLCO by 25 percent or more requires further evaluation and possible cessation of therapy. (See 'When to suspect bleomycin toxicity' above.)

We do not use imaging to surveil asymptomatic patients. Suggestive imaging abnormalities on interim scans for disease monitoring may warrant further evaluation. (See 'Is there a role for imaging?' above and 'When to suspect bleomycin toxicity' above.)

Evaluation of patients with suspected bleomycin toxicity

Patients with suspected bleomycin toxicity should receive high-resolution computed tomography (HRCT). Typical findings include bibasilar subpleural opacities with volume loss; honeycombing may develop as fibrosis progresses. Radiographic patterns suggestive of eosinophilic or organizing pneumonia may also occur. (See 'Imaging' above.)

We suggest obtaining spirometry, lung volumes, and DLCO in patients with suspected bleomycin pulmonary toxicity; a restrictive pattern or isolated decrease in DLCO is typically seen.

Invasive testing is rarely needed, but bronchoalveolar lavage (BAL) can be used in some patients to exclude infection or malignancy. (See 'Bronchoalveolar lavage' above and 'Lung biopsy' above.)

Diagnosis - The diagnosis of bleomycin-induced pulmonary toxicity is usually made based on compatible clinical findings during bleomycin treatment and the exclusion of infectious or malignant causes. (See 'Diagnosis and differential diagnosis' above.)

Treatment

Bleomycin discontinuation – We recommend permanently discontinuing bleomycin therapy in patients with suspected bleomycin-induced lung injury, including an asymptomatic decrease in the DLCO of 25 percent or more. (See 'Permanent discontinuation of bleomycin' above.)

Use of glucocorticoids

-For most patients with bleomycin-induced pulmonary toxicity accompanied by symptoms or hypoxemia, we suggest systemic glucocorticoids rather than discontinuation of bleomycin alone (Grade 2C). We typically initiate therapy using prednisone 0.5 to 1 mg/kg ideal body weight (IBW) for four to six weeks, followed by a taper based on radiographic pattern and clinical response. (See 'Glucocorticoids, for symptomatic patients with most patterns of injury' above.)

-For asymptomatic patients without hypoxemia, we suggest monitoring for development of symptoms or further decline in pulmonary function rather than initiation of glucocorticoids (Grade 2C).

-For patients with chronic pulmonary fibrosis due to bleomycin toxicity, we suggest avoiding glucocorticoid therapy (Grade 2C). Symptomatic patients with progressive pulmonary fibrosis may benefit from antifibrotic therapy, although this has not been well studied in this population. (See 'Avoidance of glucocorticoids, in patients with late-onset interstitial fibrosis' above.)

Future perioperative management – Although the evidence is anecdotal, current practice is to minimize excess supplemental oxygen in hypoxemic patients and practice lung-protective ventilation in patients requiring general anesthesia after bleomycin administration. (See 'Supplemental oxygen and future perioperative management' above.)

ACKNOWLEDGMENTS — The editorial staff at UpToDate acknowledge Philip W Kantoff, MD, Sumanta Pal, MD, and Nicholas Vander Els, MD, who contributed to earlier versions of this topic review.

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Topic 4316 Version 38.0

References

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