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

Dose Adjustment

• Hepatic
• Renal

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
  • Erythema (see Erythroderma, [[Erythroderma]])
  • Hyperkeratosis
  • Hyperpigmentation
  • Nail Changes
  • Pruritus (see Pruritus, [[Pruritus]])
  • Skin Tenderness
  • Striae (see Striae, [[Striae]])
  • Vesicular Rash (see Vesicular-Bullous Skin Lesions, [[Vesicular-Bullous Skin Lesions]])

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
  • Acute Lung Injury-ARDS (see Acute Lung Injury-ARDS, [[Acute Lung Injury-ARDS]])
  • Crackles
  • Dry Cough (see Cough, [[Cough]])
  • Dyspnea (see Dyspnea, [[Dyspnea]])
  • Fever (see Fever, [[Fever]])
• 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]])