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Clinical study (Prospective, Retrospective, Case Series)

Surveillance Chest X-Ray and Pulmonary Function Testing in Patients Undergoing Intralesional Bleomycin in the Treatment of Vascular Malformations

DeHart, Austin N.a; Mack, Joana M.b; Garner, Annsleyc; Nicholas, Richardd; Smith, Ambera; Lewis, P. Spencere; Crary, Shelley E.b

Author Information
Journal of Vascular Anomalies: December 2021 - Volume 2 - Issue 4 - p e024
doi: 10.1097/JOVA.0000000000000024
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Bleomycin, an antibiotic with antineoplastic properties widely used for Hodgkins lymphoma and testicular cancer, has gained traction in the treatment of vascular malformations.1 It exerts cytotoxic effects by inhibiting DNA synthesis and cleaving DNA, leading to cellular apoptosis, and a subsequent inflammatory response.2 This results in vascular occlusion, fibrosis, and injury to vessels.3 Sclerotherapy is an effective treatment option for vascular malformations, although multiple sclerosant agents exist.4 Of popular agents, bleomycin has been associated with a favorable short-term side effect profile, with transient fever, swelling, or nausea, and a very low risk of ulceration or nerve damage.4,5

One of the most significant, albeit rare, side effects of bleomycin is pulmonary toxicity.6 An endogenous enzyme, bleomycin hydrolase, inactivates bleomycin and is commonly found in the liver, spleen, and bone marrow, but is not present in the lungs, hence this organ’s vulnerability to injury.7 Pulmonary toxicity can take multiple forms, either as interstitial pneumonitis or more severe progression to pulmonary fibrosis.7 Symptoms typically occur gradually and include dyspnea, tachypnea, and hypoxia.8 Risk factors include smoking, kidney failure, and age >40 years.9,10

In patients being treated for cancer, pulmonary function testing (PFT) has been shown to have a linear, dose-dependent decrease in the diffusion capacity of the lung for carbon monoxide (DLCO) with increasing cumulative bleomycin exposure.11,12 The mean DLCO remains decreased for several months and has been shown to be the most sensitive indicator of pulmonary injury.11 However, in chemotherapy, bleomycin is frequently used in combination with other agents, which may attenuate its pulmonary toxicity and abnormal PFT results.12,13 When used as a sclerosant for vascular anomalies, the concurrent use of other agents is avoided, so the overall risk may be lower.


This study was approved by the University of Arkansas for Medical Sciences Institutional Review Board (IRB no. 202187). Retrospective chart review of patients with a vascular malformation who underwent sclerotherapy with bleomycin between the years 2011 to 2018 at Arkansas Children’s Hospital was performed. Patients included were required to have undergone treatment with bleomycin and have either documented CXR or PFT results. Statistical analysis was performed using the Real Statistics Resource Pack software (Release 6.8).14


A total of 64 patients were identified who met inclusion criteria. Diagnosis treated is shown in Table 1. The majority of patients had venous malformation (29, 45.3%), arteriovenous malformation (14, 21.9%), and lymphatic malformation (19, 29.7%), with the remainder having mixed lesions with capillary component (2, 3.1%). Median age of patients at first treatment was 12 years old (range <1 year to 65 years). The median cumulative bleomycin dose per patient was 10.9 U/m2 (range 1.8–106.8 U/m2).

Table 1. - Diagnosis Treated
Diagnosis Number of Patients (% of Total)
Venous malformation 31, 58.5%
Arteriovenous malformation 11, 20.8%
Lymphatic malformation 7, 13.2%
Other 3, 5.8%

Chest x-ray film

A total of 30 CXR were available for review, 10 baseline and 20 posttreatment. Of baseline CXR, 6 (60%) were normal and 4 (40%) were abnormal. Of posttreatment CXR, 14 (70%) were normal and 6 (30%) were abnormal. The majority of findings were concerning for an underlying acute infectious process. All abnormal results are described in Table 2. Chi-square testing was performed, and there was no significant difference in the distribution of patients with a normal or abnormal CXR result between the baseline and follow up groups (X2 [2, N = 30] = 0.3; P = 0.6). Further analysis with a two-sample t-test was performed for the follow-up group, and there was no difference in mean cumulative bleomycin dose between patients with a normal compared with an abnormal CXR (38.1 versus 39.9 U/m2, P = 0.9). No patients had CXR findings which disrupted the treatment plan or precluded the administration of bleomycin in the future.

Table 2. - Description of Abnormal CXR Results
Age/Diagnosis Timing of CXR CXR Finding Cumulative Dose per m2
11 y male with AVM Baseline Prominent pulmonary interstitial pattern 22.9
8 y male with lymphatic malformation Follow up Findings most consistent with viral bronchiolitis vs reactive airway process. No pneumonia. 5.0
15 y male with lymphatic malformation Baseline Retrocardiac opacity could represent atelectasis or pneumonia. 3.7
9 y female with lymphatic malformation Baseline Minimal bronchial wall thickening, most compatible with viral bronchial airway disease. 12.3
8 y male with lymphatic malformation Follow up Left lower lobe airspace disease with likely effusions. 63.3
7 y female with venous malformation Follow up Right lung pulmonary nodule. 25.3
3 y male with AVM Follow up Bronchial wall thickening, otherwise normal chest findings, may be due to viral illness or reactive airway disease. 59.8
7 mo male with lymphatic malformation Follow up Left-sided perihilar thickening and interstitial prominence which may be related to developing infectious process. 75.6
1 y male with lymphatic malformation Baseline Mild Cardiomegaly. Prominence of the interstital markings could represent pulmonary edema, infiltrate or findings of chronic lung disease. 39.3
8 y male with lymphatic malformation Follow up Prominent vascularity. Minimal bronchial wall thickening. Otherwise normal chest. 11.0

Pulmonary function testing

Per institutional protocol, PFTs are performed at baseline before receiving bleomycin if a patient’s age is 6 years or older. They are also obtained for surveillance when a child who has received bleomycin turns 6 years old, if a patient’s cumulative bleomycin dose reaches 60 U/m2, and again at a cumulative dose of 100 U/m2. The first threshold of 60 U/m2 was chosen loosely, based off published data that showed an increase in detectable toxicity around that level.8,15 The maximum cumulative dose of 100 U/m2 was calculated by halving the adult oncologic dose of 400 U, with an assumed adult body surface area of 2 m2.15-17 These thresholds are somewhat arbitrary due to a lack of published information in this patient population. After reaching this maximum bleomycin dose, PFTs are considered again 2–3 years after the last bleomycin administration to monitor for long-term sequelae, and sooner if respiratory symptoms develop. A total of 62 PFTs were attempted in this population, with 41 successfully completed and 21 (33.9%) unable to be completed due to poor patient compliance with testing. Twenty nine (70.7%) of these were baseline tests and 12 (29.3%) were follow-up tests after bleomycin administration.

Of the 41 completed PFTs, 39 (95.1%) were normal and 2 (4.9%) were abnormal. The first patient was an adult smoker who had an abnormal baseline PFT results with a DLCO(Hg) % predicted of 73% (Figure 1). The decision was made to avoid bleomycin use in this patient due to this abnormal result.

Figure 1.:
Abnormal baseline PFT. PFT indicates pulmonary function testing.

The second patient was a 16-year-old male with a mixed capillary-venous malformation of his parotid, which was swelling, growing, and getting progressively more discolored. He underwent two treatment sessions, both with the flash pulse dye laser, gentle YAG laser, and with interstitial injection of 4 units (total cumulative dose of 5.71 units/m2) of bleomycin. His PFTs at 4 months after his initial treatment demonstrated an abnormal DLCO (Hg) of 28.6 (78% predicted) and DLCO/VA 4.31 (69% predicted) (Figure 2). There was good effort for SVC and DLCO. No baseline PFT had been obtained before treatment due to distance to travel for the patient. He remained asymptomatic with no shortness or breath, dyspnea, or hypoxia. He had excellent response in his malformation size and color after two treatment sessions. Further bleomycin treatment will be avoided in the future given his abnormal PFT result.

Figure 2.:
Abnormal post-procedure PFT. PFT indicates pulmonary function testing.

In the patient cohort analyzed, there was no difference in the mean DLCO (Hg) % predicted between the baseline PFTs and the follow-up PFTs obtained to monitor for bleomycin toxicity (94.1 versus 101.8, P = 0.17). The patients with an abnormal PFT did have a statistically significant lower cumulative bleomycin dose than those with normal PFTs (5.3 versus 10.1, P = 0.002). This is attributed to stopping treatment with bleomycin once an abnormal PFT was obtained and switching to alternative therapies.

Linear regression was performed on the follow-up PFT group to determine if a relationship could be detected between DLCO(Hg) % predicted and cumulative bleomycin dose at time of PFT (Figure 3). The line of best fit demonstrated a slightly positive slope coefficient, which was not statistically significant (0.37; P = 0.75; 95% CI, –2.2 to 2.9). The coefficient of determination was low (R2 = 0.01) due to variability in the data. For this dataset, no meaningful relationship could be detected between the DLCO (Hg) % predicted and the cumulative bleomycin dose.

Figure 3.:
Relationship between DLCO(Hg) % predicted and cumulative dose. DLCO indicates diffusion capacity of the lung for carbon monoxide.


Bleomycin has demonstrated good efficacy in the treatment of vascular anomalies although concerns about pulmonary toxicity remain.5,18-21 These data represent a large cohort of patients treated with bleomycin sclerotherapy and supports existing literature describing safety with this application. Jin et al and Chaudry et al have used interstitial bleomycin to treat early arteriovenous malformations and lymphatic malformations with good results and no reported pulmonary toxicities.20,21 While these data overall are reassuring, the optimal monitoring protocol for toxicities has yet to be established.

In this study, the utility of screening and follow-up CXR was limited. There was a high incidence of abnormal findings with minimal clinical significance, which did not affect patient management. Baseline and follow-up CXR had similar rates of abnormal results, none of which precluded bleomycin administration. This supports findings in the literature that CXR has poor sensitivity in screening for bleomycin pulmonary toxicity.6

PFTs offer an alternative way to monitor for bleomycin pulmonary toxicity and a dose-dependent relationship has been described in the oncologic literature.10-12 The generalizability of these findings to the vascular anomaly patient population is questioned due to differences in patient factors including age, smoking, and kidney disease, as well as differences in treatment factors, including coincident exposure to radiation and chemotherapy agents, which may potentiate toxicities.13 In this study, a significant relationship could not be detected between DLCO(Hg)% predicted and cumulative bleomycin dose, although caution is advised when interpreting these results.

Pulmonary fibrosis does not usually develop until doses greater than 400 mg are reached.5,22,23 Few patients in this study received high doses of bleomycin, in part, because the patient population is biased toward children and adolescents, where dosing is limited by body surface area. Although patients frequently received multiple treatments of bleomycin, it remains a relatively newer sclerosant in use at this institution and has demonstrated good efficacy, so the aggregate exposure needed per patient remains low. While still preliminary, it is reassuring that bleomycin has been well tolerated by this patient population overall with few pulmonary side effects.

While no patients in this cohort developed acute pulmonary toxicity, this rare but serious complication has been described following intralesional administration of low doses of bleomycin in three recent case reports.23-25 These events occurred after receiving intralesional bleomycin injections of 0.4 units per kilogram and 1.8 units per kilogram in a 5-year-old child and an 8-month-old infant, respectively, with eventual recovery after extended hospital stays.23,24 One fatality has been reported in a 15-month old after the injection of 7 units of bleomycin into a cheek macrocystic lymphatic malformation, who developed respiratory distress and diffuse alveolar damage 1 week after therapy.25 This potentially life-threatening side effect needs to be discussed with patients and more research is necessary to better predict patients at risk.


Bleomycin has been shown to be an effective agent in the treatment of vascular anomalies, although caution must be used due to the risk of pulmonary fibrosis. CXR shows minimal benefit as a routine screening test and instead may have better utility in symptomatic patients with a history of bleomycin exposure. PFTs show more promise as a method of screening and monitoring for toxicities. In this study’s patient population, no acute pulmonary fibrosis developed, although this risk remains a concern. Optimum bleomycin dosing regimens and safe monitoring protocols remain an elusive challenge in the treatment of patients with vascular malformations.


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Bleomycin; Sclerotherapy; Vascular malformation; Venous malformation; Toxicity; Lymphatic malformation; Arteriovenous malformation; Chest x-ray film; Pulmonary function testing; Monitoring bleomycin

Copyright © 2021 the Author(s). Published by Wolters Kluwer Health, Inc. on behalf of The International Society for the Study of Vascular Anomalies.