What is the appropriate dose of bleomycin when used for sclerotherapy by vascular interventional radiology? When used for this indication is pulmonary monitoring or testing recommended?

Comment by InpharmD Researcher

Dosing experience for intralesional bleomycin sclerotherapy is primarily presented in small retrospective studies, lacking a single consensus recommendation. While dosing varies across the studies, commonly utilized doses appear to range between 0.4 to 1.0 mg/kg (see tables). While most studies found belomycin to be safe and effective in this setting, monitoring for onset of pulmonary toxicity is still recommended with belomycin injection.

Background

A retrospective chart review (Table 4) evaluated the utility of routine chest X-ray (CXR) and pulmonary function testing (PFT) in patients receiving intralesional bleomycin sclerotherapy. Utilizing data from the Arkansas Children’s Hospital, the investigation involved 64 patients (age <1 to 65 years) who underwent sclerotherapy with bleomycin between 2011 and 2018 and had documented CXR or PFT results. A majority of the patients had venous malformation (n= 29), and the median cumulative bleomycin dose per patient was 10.9 U/m2 (range: 1.8 - 106.8 U/m2). A total of 20 post-treatment CXRs were reviewed, of which 14 (70%) were normal. There was no significant difference in the distribution of patients with a normal or abnormal CXR result between baseline and post-treatment imaging (p= 0.6), and no mean difference in cumulative bleomycin dose between patients with a normal versus abnormal CXR (p= 0.9). Per the hospital’s protocol, PFTs were performed for patients 6 years or older before receiving bleomycin, with repeat PFTs at a cumulative dose of 60 U/m2 and again at 100 U/m2. A total of 41 PFTs were completed (including baseline and post-treatment tests), of which 39 (95.1%) were normal. There was no decrease in the mean diffusion capacity of the lungs for carbon monoxide (DLCO) between baseline and post-treatment PFT groups (94.1 vs. 101.8, p= 0.17). The authors concluded that pulmonary testing and monitoring in this setting seem to be of limited clinical utility, but remain important as cumulative bleomycin doses increase. [1]

References:

[1] DeHart AN, Mack JM, Garner A, et al. Surveillance chest x-ray and pulmonary function testing in patients undergoing intralesional bleomycin in the treatment of vascular malformations. Journal of Vascular Anomalies. 2021;2(4):e024.
Relevant Prescribing Information

Adverse Reactions [2]
Pulmonary
To monitor the onset of pulmonary toxicity, roentgenograms of the chest should be taken every 1 to 2 weeks. If pulmonary changes are noted, treatment should be discontinued until it can be determined if they are drug related. Recent studies have suggested that sequential measurement of the pulmonary diffusion capacity for carbon monoxide (DLCO) during treatment with Bleomycin for Injection, USP may be an indicator of subclinical pulmonary toxicity. It is recommended that the DLCO be monitored monthly if it is to be employed to detect pulmonary toxicities, and thus the drug should be discontinued when the DLCO falls below 30% to 35% of the pretreatment value.

References:

[2] Bleomycin injection. Prescribing information. Hospira, Inc.; 2022
Literature Review

A search of the published medical literature revealed 9 studies investigating the researchable question:

What is the appropriate dose of bleomycin when used for sclerotherapy by vascular interventional radiology? When used for this indication is pulmonary monitoring or testing recommended?

Level of evidence

C - Multiple studies with limitations or conflicting results  Read more→


Please see Tables 1-9 for your response.

Intralesional injection of bleomycin in the management of low flow vascular malformations: Results and factors affecting the outcome
Design

Single-center prospective cohort study

N= 50
Objective To evaluate the safety and efficacy of bleomycin intralesional injection for the treatment of low-flow vascular malformations and determine the different factors affecting the outcome
Study Groups All patients (n= 50)
Inclusion Criteria Symptomatic patients with extratruncular low-flow vascular malformations (venous, lymphatic, or combined lympho-venous) diagnosed clinically and by duplex ultrasound and confirmed by contrast-enhanced MRI
Exclusion Criteria Surgically accessible localized lesions, total thrombosis, significant soft tissue component, pregnant women, and drug hypersensitivity
Methods Patients underwent preoperative duplex ultrasound and MRI. The procedure was performed under ultrasound and fluoroscopic guidance using a double-needle technique. Bleomycin powder was reconstituted with 15 mL of normal saline, yielding a 1 mg/mL fluid solution and it was injected at 0.5 mg/kg, not exceeding 15 mg per session. Post-procedure compression bandage was applied, and patients were advised to wear compression garments during follow-up. 
Duration April 2020 to March 2022
Outcome Measures Objective improvement rate, ultrasound assessment of size reduction or obliteration, patient-reported outcomes (pain, symptoms, self-confidence)
Baseline Characteristics   All patients (n= 50)
Age, years 19.3 ± 11.4
Female 29 (58%)

Type -

Venous malformations

Lymphatic malformations

 

42 (84%)

8 (16%)

Region

Lower limb

Head and neck

Upper limb

Genital

Trunk

 

17 (34%)

16 (32%)

11 (22%)

4 (8%)

2 (4%)
Results   All patients (n= 50)
Objective improvement rate 79.53%
Ultrasound size reduction or obliteration 81.25%
Patient-reported improvement in pain, symptoms, self-confidence Statistically significant
Adverse Events Fever (16%), skin pigmentation (10%), thrombophlebitis (6%), vomiting (4%), painful lymphadenopathy (2%). No major complications recorded
Study Author Conclusions Bleomycin intralesional injection is a safe and effective treatment for low-flow vascular malformations. Diffuse lesions are associated with poor outcomes. 
Critique The study's prospective design and use of blinded assessment are strengths, providing reliable data on bleomycin's efficacy. However, the lack of randomization and post-intervention MRI limits the robustness of the findings. The study's focus on a single center may affect generalizability. The PRO may be subject to bias due to patient self-reporting. 
References:

Abdelaty MH, Badran AI, Aborahma AM, Elheniedy MA, Kamhawy AH. Intralesional injection of bleomycin in the management of low flow vascular malformations: Results and factors affecting the outcome. J Vasc Surg Venous Lymphat Disord. 2024;12(2):101694. doi:10.1016/j.jvsv.2023.101694

The Treatment of Lymphangiomas with Bleomycin in Childhood: A Retrospective Observational Study
Design

Retrospective observational study

N= 20
Objective To present the results of ultrasonography-guided intralesional bleomycin treatment of lymphangioma
Study Groups All patients (n= 20)
Inclusion Criteria Patients with lymphangioma treated with intralesional bleomycin between January 2012-July 2018; diagnosed with macrocystic or mixed type lymphangiomas
Exclusion Criteria Patients with microcystic lymphangiomas (<1cm)
Methods Retrospective evaluation of 20 patients treated with 0.4-0.6 mg/kg bleomycin injected under ultrasonography guidance. The patients received a minimum dose of 0.4 mg/kg and a maximum dose of 2 mg/kg bleomycin. The response was graded as 'excellent response' (>90% reduction), 'good response' (>50% reduction), and 'poor response' (<50% reduction or no change).
Duration January 2012 to July 2018
Outcome Measures Response to treatment graded as excellent, good, or poor
Baseline Characteristics   All patients (n= 20)
Age, years 3.1
Female 11

Location

Neck

Trunk

Axillary region

Neck to mediastinum and retropharynx

Anterior surface of thigh

Anterior surface of leg

 

8

7

2

1

1

1
Results   Number of Patients
Excellent response (>90% reduction) 10
Good response (>50% reduction) 8
Poor response (<50% reduction or no change) 1
Adverse Events Discoloration in one patient; induration in another patient; no serious life-threatening complications observed
Study Author Conclusions Bleomycin injection is very effective for the treatment of macrocystic and mixed type lymphangioma of the neck and other body areas. It is suitable for cases with previous surgery showing recurrence or incomplete resection.
Critique The study is limited by its small sample size and retrospective design, which may introduce bias. The lack of a control group and the exclusion of microcystic lymphangiomas limit the generalizability of the findings. However, the study provides valuable insights into the effectiveness of bleomycin for treating lymphangiomas, especially in cases with previous surgical interventions.
References:

Bilici S. The treatment of lymphangiomas with bleomycin in childhood: a retrospective observational study. Haydarpasa Numune Med J. Published online 2019.

Treatment of Early-stage Extracranial Arteriovenous Malformations with Intralesional Interstitial Bleomycin Injection: A Pilot Study
Design

Prospective study

N= 34
Objective To assess the efficacy and safety of intralesional interstitial bleomycin injection in the treatment of early-stage (Schobinger stage I or II) extracranial arteriovenous malformations (AVMs)
Study Groups All patients (n= 34)
Inclusion Criteria Patients with early-stage AVMs (Schobinger stage I or II) diagnosed with digital subtraction angiography (DSA)
Exclusion Criteria Stage III AVM, maximum lesion diameter >15 cm, age <2 or >60 years, previous treatments in the past year
Methods Patients received intralesional interstitial bleomycin injected at a maximum dose of 15,000 IU or 1000 IU/kg for children under 15 kg, once every month for 6 months. The mean dose per procedure was 14,200 ± 2,300 IU (range, 4,500–15,000 IU). The cumulative mean dose per patient was 79,700 ± 16,000 IU (range, 45,000–90,000 IU) over a mean of 5.6 procedures. Therapeutic outcome was evaluated by the degree of devascularization at angiography and clinical outcome 3 months after the last treatment. Adverse events were recorded according to the Society of Interventional Radiology classification. 
Duration April 2014 to May 2015
Outcome Measures Degree of devascularization at angiography, clinical outcome 3 months after last treatment
Baseline Characteristics   All patients (n= 34)
Age, years 20.5 ± 10.9 (2–44)
Female 24 (75%)

Position

Craniofacial region

Extremity

 

29 (90.6%)

3 (9.4%)

Therapeutic history

No

Yes

 

18 (56.2%)

14 (43.8%)

AVM stage

I

II

 

10 (31.2%)

22 (68.8%)

Cho classification

I

II

IIIa

IIIb

 

1 (3.1%)

2 (6.3%)

25 (78.1%)

4 (12.5%)
Size at angiography, cm 4.5 ± 2.6 (1.5–15)
Results   All patients (n= 32)
Complete response 9 (28.1%)
Partial response 18 (56.3%)
No response 4 (12.5%)
Worsening 1 (3.1%)
Stable outcome at follow-up 31 (96.9%)
Major complication - Anaphylactic shock 1 (3.1%)
Adverse Events A major complication, anaphylactic shock, was observed in one (3.1%) patient. Common minor complications included hyperpigmentation, nausea, pruritus, and bullae
Study Author Conclusions Intralesional interstitial bleomycin injection is a feasible approach for early-stage AVMs and yields safe and effective outcomes.
Critique The study was limited by its small sample size and lack of diversity, as all patients were from Asia. The follow-up period may not be sufficient to determine long-term outcomes. Additionally, the evaluation methods were not entirely objective, relying on previously published standards that may not be precise enough for fair assessment.
References:

Jin Y, Zou Y, Hua C, et al. Treatment of Early-stage Extracranial Arteriovenous Malformations with Intralesional Interstitial Bleomycin Injection: A Pilot Study. Radiology. 2018;287(1):194-204. doi:10.1148/radiol.2017162076

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

Retrospective chart review

N= 64
Objective To analyze the utility of routine chest x-ray (CXR) and pulmonary function testing (PFT) in a pediatric patient population receiving intralesional bleomycin sclerotherapy
Study Groups All patients (n= 64)
Inclusion Criteria Patients with a vascular malformation who underwent sclerotherapy with bleomycin between 2011 to 2018 and have either documented CXR or PFT results
Exclusion Criteria Not specified
Methods Retrospective chart review was conducted of CXR and PFT results in patients who underwent bleomycin intralesional injection for the treatment of vascular malformations. Statistical analysis was performed using the Real Statistics Resource Pack software
Duration 2011 to 2018
Outcome Measures

Primary: Utility of routine CXR and PFT in detecting bleomycin-induced pulmonary toxicity
Baseline Characteristics   All patients (n= 64)
Median age, years 12 (range <1 to 65)
Venous malformation 31 (58.5%)
Arteriovenous malformation 11 (20.8%)
Lymphatic malformation 7 (13.2%)
Other 3 (5.8%)
Results   All patients (n= 64)
Median cumulative bleomycin dose per patient, U/m2 10.9 (range 1.8–106.8)
Normal CXR 14 (70%)
Abnormal CXR 6 (30%)
Normal PFT 39 (95.1%)
Abnormal PFT 2 (4.9%)
Adverse Events No acute pulmonary toxicity was observed in the cohort. Two patients had abnormal PFTs with obstructive patterns, but no diffusion abnormalities were seen.
Study Author Conclusions Routine CXR for the surveillance of bleomycin-induced pulmonary toxicity seems to be of limited clinical utility. No diffusion abnormalities on PFT were seen in this patient cohort to date; however, as cumulative bleomycin doses increase, follow-up PFT monitoring will remain important.
Critique The study provides valuable insights into the utility of CXR and PFT in monitoring bleomycin-induced pulmonary toxicity. However, the retrospective design and the small sample size may limit the generalizability of the findings. The study also lacks a control group and detailed exclusion criteria, which could affect the robustness of the conclusions.
References:

DeHart AN, Mack JM, Garner A, et al. Surveillance chest x-ray and pulmonary function testing in patients undergoing intralesional bleomycin in the treatment of vascular malformations. Journal of Vascular Anomalies. 2021;2(4):e024.

Single center experience with intralesional bleomycin sclerotherapy for lymphatic malformations
Design Retrospective study N= 10
Objective To evaluate the efficacy of percutaneous sclerotherapy using bleomycin in treatment of lymphatic malformations
Study Groups All patients (n= 10)
Inclusion Criteria Classification by pre-procedural radiological and clinical findings as LM consistent with the classification of ISSVA, available documentation of patient and clinician evaluation of outcome, treatment by percutaneous sclerotherapy with bleomycin, minimum of 6 months follow-up
Exclusion Criteria Not specified
Methods Intralesional bleomycin was administered by percutaneous injection through 21–23 Gauge needles with a dose of 1 mg/kg body weight. Patients were clinically and radiologically assessed at baseline and followed at first and third months after treatment. Response to treatment was measured visually by using photographs and by radiological images. Symptomatic improvement was also evaluated either by patients or parents
Duration January 2009 to January 2013
Outcome Measures

Visual and radiological resolution of lymphatic malformations 
Baseline Characteristics   All patients (n= 10)
Age, mean years (range) 9.3 (2 days–32 years)
Sex - Male 6
Sex - Female 4
Lesion location - Head and neck 6
Lesion location - Calf 2
Lesion location - Thigh 1
Lesion location - Leg 1
Results   Percentage of patients
Excellent resolution 80%
Significant improvement 20%
No major side effects 100%
Minor side effects - Fever 10%
Minor side effects - Transient erythema 10%
Adverse Events No major side effects were recorded. Minor side effects included fever in one patient and transient injection site erythema in another patient.
Study Author Conclusions Intralesional bleomycin is a safe and effective treatment for patients with lymphatic malformations, with excellent results and no major complications.
Critique The study was limited by its retrospective nature and small sample size. Symptomatic improvement was evaluated subjectively by patients or their parents, and the follow-up period was short, which may not capture long-term complications such as pulmonary fibrosis or recurrence. Despite these limitations, the study supports the efficacy and safety of bleomycin sclerotherapy for lymphatic malformations.
References:

Yılmaz H, Yılmaz Ö, Çamlıdağ İ, Belet Ü, Akan H. Single center experience with intralesional bleomycin sclerotherapy for lymphatic malformations. Jpn J Radiol. 2017;35(10):590-596. doi:10.1007/s11604-017-0672-5

Bleomycin Foam Treatment of Venous Malformations: A Promising Agent for Effective Treatment with Minimal Swelling
Design

Retrospective review

N= 20
Objective To report clinical and radiographic outcomes of patients with venous malformations (VMs) treated with bleomycin foam
Study Groups All patients (n= 20)
Inclusion Criteria Patients with venous malformations treated with bleomycin foam at the institution between June 2012 and October 2013
Exclusion Criteria Not specified
Methods Retrospective review conducted of electronic medical records. Patients underwent bleomycin foam embolization with a mean of 1.7 treatments per patient. An average of 0.45 U/kg of bleomycin foam (range 0.1–2.3 U/kg [9–60 U]) was used per procedure. Pre- and post-procedural MR imaging was used to assess outcomes.
Duration June 2012 to October 2013
Outcome Measures

Primary: Clinical improvement in symptoms

Secondary: Radiographic volume reduction of lesions on MR imaging
Baseline Characteristics   All patients (n= 20)
Age, years (range) 32 (2-68)
Female 14 (70%)
Lesion location - Head and neck 17 (85%)
Lesion location - Extremities 2 (10%)
Lesion location - Mediastinum 1 (5%)
Results   All patients (n= 20)
Improvement in symptoms 100%
Mean lesion volume reduction 66%
MR imaging volume reduction 93%
Decreased enhancement on MR imaging 79%
Decreased T2 signal intensity on MR imaging 86%
Adverse Events Minor complications in 22% of procedures; major complications in 7% of procedures. One case of significant swelling treated with steroids. Flagellate hyperpigmentation in one patient.
Study Author Conclusions The use of bleomycin foam for the percutaneous treatment of VMs is safe and effective. Foaming bleomycin may be used to address the dose limitations of the liquid.
Critique The study is limited by its retrospective design and small sample size. Lack of direct comparison with other sclerosing agents limits the ability to assess relative efficacy and safety. The subjective nature of some outcome measures may introduce bias.
References:

Ul Haq F, Mitchell SE, Tekes A, Weiss CR. Bleomycin Foam Treatment of Venous Malformations: A Promising Agent for Effective Treatment with Minimal Swelling. J Vasc Interv Radiol. 2015;26(10):1484-1493. doi:10.1016/j.jvir.2015.05.007

Safety and Efficacy of Bleomycin Sclerotherapy for Microcystic Lymphatic Malformation
Design Retrospective review N= 31
Objective To evaluate the safety and efficacy of bleomycin sclerotherapy in microcystic lymphatic malformation
Study Groups All patients (n= 31)
Inclusion Criteria Patients with microcystic or combined lymphatic malformation who underwent percutaneous image-guided sclerotherapy using bleomycin with pre- and postprocedure imaging
Exclusion Criteria Patients without pre- and postprocedure imaging
Methods Retrospective review conducted of medical records and imaging studies. Patients underwent percutaneous image-guided sclerotherapy using bleomycin. Up to 1 U/kg of bleomycin was injected per session, with a maximum of 15 U. Pulmonary function tests and chest X-rays were performed before the procedure, repeated at 6 months and 1 year postprocedure, and annually thereafter.
Duration Mean follow-up period: 3.2 years (range 1.5–5 years)
Outcome Measures

Primary: Response to sclerotherapy (complete, partial, minimal/no response) 
Baseline Characteristics   All patients (n= 31)
Mean age, years 13.4
Age range, months-years 3 months–31 years
Male:Female ratio 10:21
Location of malformation - Head and neck 27
Location of malformation - Trunk 4
Results   Number of patients (%)
Complete response (>90% size reduction) 12 (38%)
Partial response (25-90% size reduction) 18 (58%)
No response (<25% size reduction) 1 (3%)
Adverse Events No complications were identified
Study Author Conclusions Preliminary results indicate that sclerotherapy of microcystic lymphatic malformations using bleomycin is effective and safe.
Critique The study is limited by its retrospective design and small sample size. The follow-up period is relatively short, with the longest being 5 years, which may not capture long-term risks such as bleomycin-induced pulmonary fibrosis. Larger multicenter studies with extended follow-up are needed to confirm these findings.
References:

Chaudry G, Guevara CJ, Rialon KL, et al. Safety and efficacy of bleomycin sclerotherapy for microcystic lymphatic malformation. Cardiovasc Intervent Radiol. 2014;37(6):1476-1481. doi:10.1007/s00270-014-0932-z

 

Acute Lung Toxicity After Intralesional Bleomycin Sclerotherapy

Design

 Case report

Case presentation

A 5-year-old girl underwent intralesional bleomycin sclerotherapy and was administered a low dose of bleomycin (7 mg:0.28 mg/kg; 10 U: 0.4 U/kg). However, this resulted in significant respiratory distress 24 hours post-procedure. Radiographic imaging revealed bilateral opacities and diffuse lung ground-glass opacities, necessitating intravenous methylprednisolone and montelukast treatment. Despite no prior risk factors or apparent systemic drainage during the procedure, the patient developed acute hypersensitivity pneumonitis, a rare but serious complication. Eventually, the patient showed significant improvement both clinically and radiographically after a prolonged tapering of corticosteroid therapy, illustrating the potential reversibility of acute pulmonary toxicity when identified and managed swiftly.

Study Author Conclusions

This is the second case of pulmonary toxicity observed in a child after bleomycin intralesional administration, and the first reported after the lowest dose of this drug to date (7 mg: 0.28 mg/kg; 10 U: 0.4 U/kg). A delay in the diagnosis and treatment of this complication can be fatal. Any physician who treats these patients must be alert and consider this complication in children with respiratory symptoms after bleomycin sclerotherapy. Early detection of pulmonary toxicity would allow prompt therapy and could avoid pulmonary damage.
References:

Méndez-Echevarría A, Fernandez-Prieto A, de la Serna O, et al. Acute Lung Toxicity After Intralesional Bleomycin Sclerotherapy. Pediatrics. 2018;141(1):e20161787. doi:10.1542/peds.2016-1787

 

Fatal Lung Toxicity After Intralesional Bleomycin Sclerotherapy of a Vascular Malformation

Design

 Case report 

Case presentation

A 15-month-old girl presented with a left cheek macrocystic lymphatic malformation. Following two sessions of needle aspiration, she underwent sclerotherapy with an injection of 7 U of bleomycin under ultrasound guidance. During extubation, she required positive pressure ventilation due to laryngospasm but was subsequently stabilized and discharged. However, she returned five days later with respiratory distress, secondary to a left tension pneumothorax and pneumomediastinum, as shown by chest imaging. Despite meticulous management, including the administration of escalating doses of methylprednisolone and other supportive therapies, her condition deteriorated, ultimately leading to death from respiratory failure.

Study Author Conclusions

 This case report underscores the potential for acute bleomycin-induced pulmonary toxicity, even in recommended pediatric doses.
References:

Cho AL, Kiang SC, Lodenkamp J, Tritch WTH, Tomihama RT. Fatal Lung Toxicity After Intralesional Bleomycin Sclerotherapy of a Vascular Malformation. Cardiovasc Intervent Radiol. 2020;43(4):648-651. doi:10.1007/s00270-020-02420-w