Serious or Life Threatening Effects: Pulmonary toxicity: The most serious toxicity of Bleomycin is a subacute or chronic pneumonitis that progresses to interstitial fibrosis and may be fatal. This occurs in approximately 10% of treated patients, about 1% of whom have died of pulmonary fibrosis. Pulmonary toxicity is both age and dose related, being more common in patients over 70 years of age and in those receiving over 400,000 IU total dose. This toxicity, however, is unpredictable and has been seen occasionally in young patients receiving low doses. Also, when used in combination with other antineoplastic agents, pulmonary toxicities may occur at lower doses.
This toxicity is frequently seen in those with underlying lung disease such as emphysema and in those previously treated with pulmonary or mediastinal irradiation.
The identification of patients with pulmonary toxicity due to bleomycin has been extremely difficult. The clinical symptoms and x-ray findings of bleomycin pulmonary toxicity are not easily distinguished from other syndromes commonly observed in cancer patients, including progressive metastatic tumor (especially lymphangitic tumor), infectious processes such as Pneumocystis carinii or cyto-megalovirus, or radiation injury.
The first symptoms to appear are dyspnoea, with cough, and low grade fever, commonly occurring 4-10 weeks after initiation of therapy, although the time of onset of pulmonary toxicity may vary from during therapy to up to six months after the cessation of therapy.
The microscopic tissue changes due to bleomycin toxicity are frequently present as bronchiolar squamous metaplasia, reactive macrophages, atypical alveolar epithelial cells, fibrinous edema, and interstitial fibrosis. The acute stage may involve capillary changes and subsequent fibrinous exudation into alveoli producing a change similar to hyaline membrane formation and progressing to a diffuse interstitial fibrosis resembling the Hamman-Rich syndrome.
These microscopic findings are non-specific and are similar to the changes produced in radiation pneumonitis, pneumocystic pneumonitis, and at times reaction to long standing malignant pulmonary disease.
Pulmonary function tests have revealed some alteration in the pulmonary status such as decreased total lung volume and decreased vital capacity, but these tests have proved to be of limited value in predicting pulmonary fibrosis. It has been suggested that Bleomycin should be discontinued if forced vital capacity decreases rapidly.
Pulmonary toxicity is seen more commonly in smokers.
Idiosyncratic Effects: Hypersensitivity reactions consisting of hypotension, fever, chills, mental confusion and wheezing have occurred in approximately 1% of patients receiving bleomycin.
This idiosyncratic reaction occurs mainly in lymphoma patients (5%), may be immediate or delayed for several hours, and usually occurs after the first or second dose. The reaction has resulted in death. Treatment of anaphylactoid reactions is supportive and symptomatic and may include volume expansion, vasopressor therapy, antihistamines, and corticosteroids.
Cardiovascular: Vascular toxicities coincident with the use of bleomycin in combination with other antineoplastic agents have been reported rarely. The events are clinically heterogeneous and may include myocardial infarction, cerebrovascular accident, thrombotic microangiopathy (haemolytic - uremic syndrome) or cerebrovascular arteritis. Acute chest pain syndrome, acute pericarditis, fulminant fatal hyperpyrexia and fulminant, fatal angioedema have been reported.
More Common Effects: Body as a whole: Fever, chills and headache frequently follow parenteral administration of bleomycin (20-50%). These reactions have been reported to occur most frequently with large single doses and occur within a few hours of administration lasting 4-12 hours. Usually, febrile reactions become less frequent with continued use of the drug but may occur sporadically and re occur later in the treatment course.
Gastrointestinal: Anorexia, nausea and vomiting (20-50%) (anorexia and weight loss may persist after discontinuing therapy), tiredness.
Mucocutaneous (50%): Hypoesthesia which may progress to hyperesthesia, urticaria, erythematous swelling, tenderness, pruritis, hyperpigmentation (particularly in those areas subject to friction or pressure and in skin folds, nail cuticles, scars, and I.M. injection sites), patchy hyperkeratosis, alopecia, ichthyosis, rash, striae, vesiculation, peeling, and bleeding, stomatitis, ulcerations of the tongue and lips. This toxicity is usually evident within 1-3 weeks following initiation of therapy and appears to be reversible and dose related, usually after 150,000 to 200,000 IU of bleomycin has been administered and, in general, is related to total cumulative dose. In 0.2% of patients it was necessary to discontinue treatment because of this toxicity.
When bleomycin is administered intra-arterially, dermal lesions are most common in the region supplied by the artery used. The incidence of mucocutaneous adverse events is increased when bleomycin sulfate is given in combination with radiotherapy to head and neck.
Less Common Effects: Body as a whole: Idiosyncratic reactions occurring in1% of patients (5% of lymphoma patients) (see Serious or Life Threatening Effects as previously mentioned).
Cardiovascular: Diverse vascular toxicities (see Serious or Life Threatening Effects as previously mentioned), hypotension (more common after intra-pleural administration), sudden onset of an acute chest pain syndrome, suggestive of pleuropericarditis (although each patient must be individually evaluated, further courses of bleomycin do not appear to be contraindicated), occular haemorrhage.
There are isolated reports of Raynaud's phenomenon occurring in patients treated with a combination of bleomycin and vinblastine with or without cisplatin, or, in a few cases, with bleomycin as a single agent. It is currently unknown if the cause of the Raynaud's phenomenon in these cases is the disease, underlying vascular compromise, bleomycin, vinblastine, cisplatin-induced hypomagnesaemia or a combination of any or all of these.
Central Nervous System: CNS toxicity is rare, but monitoring is advised. Disorientation and aggressive behaviour have been reported.
Haematologic: Thrombocytopenia, leukopenia, slight depression of haemoglobin levels. Bleomycin does not frequently produce serious bone marrow toxicity.
Hepatic: Liver toxicity beginning as deterioration in liver function tests has been reported infrequently.
Injection site: Pain at injection site, phlebitis, other local reactions.
Renal: Renal toxicity beginning as deterioration in renal function tests has been reported infrequently.
Haematuria and cystitis have been reported.
Respiratory: Pulmonary toxicity (10%) (see Serious or Life Threatening Effects as previously mentioned).