Bleomycin

Indications


Contraindications

  • xxxx

Pharmacology

  • Bleomycin is an Antibiotic Derived from Streptomyces Verticillus: in 1962

Anti-Neoplastic Mechanisms

  • Direct Cytotoxic Effect
  • Prevention of Tumor Angiogenesis
  • Stimulation of Cytokine Production
  • Free Radical generation Via Formation of Complex Between Ferrous Iron and Oxygen: this mechanism probably plays a role in the synergism between bleomycin and oxygen (which may persist for months-years after bleomycin administration)

Myelosuppression

  • Bleomycin is Not Considered Myelosuppressive

Bleomycin Pulmonary Toxicity

  • Likely Involves Oxidative Injury in the Lung: as bleomycin hydrolase (the enzyme which inactivates bleomycin) is not active in the lung or skin
    • Activation of Alveolar Macrophages
    • Inflammatory Cytokines

Metabolism

  • xxx

Administration

  • IV: xxx
  • Intrapleural (For Malignant Pleural Effusion)

Dose Adjustment

  • Hepatic
  • Renal

Adverse Effects

Allergic/Immunologic Adverse Effects

Anaphylaxis-Like Syndrome (see Anaphylaxis, [[Anaphylaxis]])

  • Epidemiology: occurs in 1% of lymphoma patients treated with bleomycin
  • Clinical
    • Usually occurs after first or second dose
    • Onset: may be immediate or delayed (for several hours)

Cardiovascular Adverse Effects

Acute Chest Pain During Bleomycin Infusion (see Chest Pain, [[Chest Pain]])

  • Epidemiology: occurs in 3% of cases
  • Physiology: due to pleuropericarditis

Dermatologic Adverse Effects

Skin Toxicity

  • Epidemiology: usually a late manifestation, developing in the 2nd-3rd week of treatment (after patient receives 150-200 U of bleomycin)
    • Related to cumulative dose
  • Clinical

Gastrointestinal Adverse Effects

Nausea/Vomiting (see Nausea and Vomiting, [[Nausea and Vomiting]])

  • Epidemiology: common

Weight Loss

  • Epidemiology: may persist after cessation of bleomycin

Otolaryngologic Adverse Effects

Stomatitis (see Stomatitis, [[Stomatitis]])

  • Epidemiology: common

Pulmonary Adverse Effects

General Comments

  • Prevalence: bleomycin-inducred lung toxicity is the most prevalent and best understood chemotherapy-induced lung disease
  • Incidence: between 0-46% of Bleomycin-treated patients develop lung toxicity
    • By PFT’s and CXR: 20% of Bleomycin-treated patients develop lung toxicity
  • Average Latency Between Bleomycin Administration and Onset of Lung Toxicity: 4 months
  • Risk Factors for Bleomycin Lung Toxicity
    • Age >70 y/o: known risk factor
    • High FIO2 Administration (in OR, PACU, etc.): synergistically increases incidence of bleomycin lung toxicity
      • Although duration of risk after receiving bleomycin is not known (risk may extend for years), bleomycin within the last 6 months probably poses greatest risk
      • Toxicity associated with oxygen use begins about 18 hrs after exposure to oxygen (and may progress to acute lung injury-ARDS)
    • Concomitant Cyclophosphamide Administration (see Cyclophosphamide, [[Cyclophosphamide]]): increases risk of bleomycin lung toxicity
    • Concomitant Granulocyte Colony Stimulating Factor (GSCF) Administration (see Granulocyte Colony Stimulating Factor, [[Granulocyte Colony Stimulating Factor]]): controversial as to whether this increases risk of bleomcyin lung toxicity
    • Cumulative Bleomycin Dose: increased risk of toxicity with cumulative dose >450 U
      • Cumulative Dose >550 U: death rate increases to 10%
      • However, doses as low as 50 U may be toxic, in conjunction with other risk factors
    • Pediatric Age Group
      • 70% of children treated with Bleomycin for rhabdomyosarcoma developed pumonary toxicity in one study
    • Pre-Existing Lung Disease
    • Prior or Concomitant Thoracic Radiation Therapy: markedly and synergistically increases incidence of severe Bleomycin lung toxicity
    • Rapid Intravenous Bleomycin Infusion: may be a risk factors (slower infusion rates and IM injection have been suggested to address this issue)
    • Renal Failure (see Chronic Kidney Disease, [[Chronic Kidney Disease]]): 80% of Bleomycin is eliminated renally

Classic Bleomycin Pneumonitis

  • Epidemiology: most common pattern
  • Diagnosis
    • Pulmonary Function Tests (PFT’s) (see Pulmonary Function Tests, [[Pulmonary Function Tests]]): restrictive pattern
      • DLCO
        • Detection of Decreased DLCO on Pre-Bleomycin Screening: predicts the subsequent development of clinical pulmonary disease
        • Progressive Decrease in DLCO During Bleomycin Treatment: further bleomycin administration should stopped
      • VC and Pulmonary Capillary Blood Flow: may be better predictors of lung toxicity
    • CXR/Chest CT
      • Alveolar or interstitial pattern with lower-lobe predominance
      • Primarily subpleural location
      • Chest CT Scan Has Better Sensitivity Than CXR: CXR is positive in only 15% of cases, while CT is positive in 38% of cases
    • Bronchoscopy (see Bronchoscopy, [[Bronchoscopy]]): useful to exclude infection
      • Bronchoalveolar Lavage: polymophonuclear or lymphocyte or eosinophil predominance
    • Lung Biopsy
      • Diffuse alveolar damage: non-specific
      • End-stage bleomycin-induced fibrosis resembles usual interstitial pneumonitis (see Usual Interstitial Pneumonia, [[Usual Interstitial Pneumonia]])
  • Clinical
  • Treatment
    • Withdraw Drug Permanently: if progressive decrease in DLCO
    • Corticosteroids (see Corticosteroids, [[Corticosteroids]]): indicated
  • Prognosis
    • Mild-Moderate Pulmonary Toxicity: if patient survives the acute event, pulmonary function test and radiographic changes are fully reversible within 6 mo-2 yrs
    • Moderate-Severe Pulmonary Toxicity (with Severe Hypoxemia Due to Pulmonary Fibrosis): usually progresses despite corticosteroids
    • Mortality Rate: up to 3% of bleomycin-treated patients die from pulmonary toxicity

Bleomycin-Induced Pulmonary Infiltrates with Eosinophilia-Type Pattern (see Drug-Induced Pulmonary Eosinophilia, [[Drug-Induced Pulmonary Eosinophilia]])

  • Epidemiology: less common pattern
  • Physiology: hypersensitivity reaction
  • Diagnosis
    • CXR/Chest CT: alveolar or interstitial pattern with lower-lobe predominance
    • Bronchoscopy (see Bronchoscopy, [[Bronchoscopy]])
      • Bronchoalveolar Lavage: eosinophilia
  • Clinical
    • Fever (see Fever, [[Fever]]): acute onset
    • Bronchoalveolar Lavage Fluid Eosinophilia (see Bronchoscopy, [[Bronchoscopy]])
    • Peripheral Eosinophilia (see Peripheral Eosinophilia, [[Peripheral Eosinophilia]])
  • Treatment
    • Withdraw Drug + Corticosteroids (see Corticosteroids, [[Corticosteroids]]): usually rapidly responsive to corticosteroids

Bleomycin-Induced “Radiation Recall” Phenomenon (see Radiation Therapy, [[Radiation Therapy]])

  • Epidemiology: bleomycin may reactivate prior radiation-induced lung disease

Bleomycin-Induced Lung Nodules (Cryptogenic Organizing Pneumonia-Type Pattern) (see Cryptogenic Organizing Pneumonia, [[Cryptogenic Organizing Pneumonia]] and Lung Nodule or Mass, [[Lung Nodule or Mass]])

  • Epidemiology
    • Rare pattern
    • First reported in Cancer, 1989
    • Seen mostly in the setting of lymphoma and seminoma
  • Diagnosis
    • CXR/Chest CT: lung nodules
    • Lung Biopsy: cryptogenic organizing pneumonia
  • Clinical: nodular pattern mimics tumor metastases (may require surgical biopsy to differentiate these lesions from metastases

Acute Chest Pain During Bleomycin Infusion (see Chest Pain, [[Chest Pain]])

  • Epidemiology: occurs in 3% of cases
  • Physiology: due to pleuropericarditis

Pneumothorax (see Pneumothorax, [[Pneumothorax]])

  • Epidemiology: case reports

Pneumomediastinum (see Pneumomediastinum, [[Pneumomediastinum]])

  • Epidemiology: case reports

Pulmonary Veno-Occlusive Disease (see Pulmonary Veno-Occlusive Disease, [[Pulmonary Veno-Occlusive Disease]])

  • Epidemiology: case reports

Rheumatologic Adverse Effects

Scleroderma-Like Syndrome (see Scleroderma, [[Scleroderma]])

  • Epidemiology: case reports

Other Adverse Effects

  • Fever (see Fever, [[Fever]])

References

  • Pulmonary veno-occlusive disease due to bleomycin therapy for lymphoma. Case reports. S Afr Med J. 1983 Oct 8;64(16):636-8
  • Pulmonary veno-occlusive disease after chemotherapy. Human Pathology, Volume 14, Issue 1, January 1983, Pages 88-91