BLENOXANE(r), generic available
Antitumour antibiotic, cytotoxic
Special pediatric considerations are noted when applicable, otherwise adult provisions apply.
Bleomycin causes DNA strand scission through formation of an intermediate metal complex requiring a metal ion cofactor such as copper or iron.3 This action results in inhibition of DNA synthesis, and to a lesser degree, in inhibition of RNA and protein synthesis.2 The drug is cell-cycle specific for G phase, M-phase and S phase.1
| Interpatient variability | no information found | |
| Distribution | mainly in the skin, lungs, kidneys, peritoneum and lymphatics | |
| cross blood brain barrier? | no | |
| volume of distribution 1 | 20 L | |
| plasma protein binding 1 | less than 10% | |
| Metabolism | activated by microsomal reduction, degraded by hydrolase found in multiple tissues especially in liver and kidneys 1 | |
| active metabolite(s) | no information found | |
| inactive metabolite(s) | no information found | |
| Excretion | renal: 45-70% in first 24 h 4 | |
| urine | 60-70% active drug (less than 20% in patients with moderate renal impairment [creatinine clearance less than 35 mL/min]) | |
| feces | no information found | |
| terminal half life 3 | 2-4 h (may be prolonged with renal dysfunction); 3 h (intrapleural); 5 h (intraperitoneal) | |
| clearance 3 | 3 L/h/m2 | |
| Gender | no information found | |
| Elderly | no information found | |
| Children 5 | terminal half life | 3 h |
| clearance | 2.5 L/h/m2 | |
| renal clearance | 65% | |
| Ethnicity | no information found | |
Adapted from standard references2,6 unless otherwise specified.
Primary uses:
*Cervical cancer *Larynx and paralarynx
Other uses:
Dysplastic oral leukoplakia7 Head and neck6 *Lymphoma, Hodgkin's *Lymphoma, non-Hodgkin's *Malignant pleural effusion *Penile cancer *Renal cancer *Soft tissue sarcoma *Testicular cancer *Vulva cancer *Lung cancer
*Health Canada approved indication
Kaposi's sarcoma6 Melanoma8 Mycosis fungoides8 Osteosarcoma8 Skin cancer8 Thyroid cancer8 Trophoblastic, gestational8 Cystic craniopharyngioma9 Bleomycin
patients who have a history of hypersensitivity reaction to bleomycin.
Use with caution in patients2,6,8: with compromised pulmonary function, with compromised renal function, with an age greater than 40 years,10 receiving concomitant chest radiation, receiving concomitant administration of cisplatin, cyclophosphamide, methotrexate or doxorubicin, receiving positive fluid balance during prolonged surgical procedures and who smoke. These are all risk factors that can predispose the patient to bleomycin pulmonary toxicity (BPT), which can be severe and life threatening. A cumulative dose of greater than 450 units of bleomycin is also a known risk factor for developing BPT.
Bleomycin is carcinogenic in animals.
Mutagenicity: Bleomycin is not found to be mutagenic when using the Ames test8, but has been shown to be mutagenic in vitro and in vivo using other mutation tests.6
no information found.
FDA Pregnancy Category D. There is positive evidence of human fetal risk, but the benefits from use in pregnant women may be acceptable despite the risk (e.g., if the drug is needed in a life-threatening situation or for a serious disease for which safer drugs cannot be used or are ineffective).
is not recommended due to the potential secretion into breast milk.
| ORGAN SITE | SIDE EFFECT | ONSET | |||
| Dose-limiting side effects are in bold, italics I = immediate (onset in hours to days); E = early (days to weeks); D = delayed (weeks to months); L = late (months to years) | |||||
| allergy/immunology 4 | hypersensitivity reactions (fever, anaphylaxis, eosinophilic pulmonary infiltrates) | I | |||
| blood/bone marrow febrile neutropenia | anemia (mild) | I | E | ||
| leukopenia | I | E | |||
| myelosuppression (uncommon, mild) | I | E | |||
| thrombocytopenia | I | E | |||
| cardiovascular (general) | edema of hands and feet | E | |||
| hypotension 3 | I | ||||
| ORGAN SITE | SIDE EFFECT | ONSET | |||
| Dose-limiting side effects are in bold, italics I = immediate (onset in hours to days); E = early (days to weeks); D = delayed (weeks to months); L = late (months to years) | |||||
| myocardial infarction (rare) | E | ||||
| phlebitis (uncommon) | E | ||||
| thrombotic microangiopathy (rare) | E | ||||
| constitutional symptoms | chills (common) | I | |||
| fever (50%) less frequent with continued use 8 | I | ||||
| malaise | I | E | |||
| weakness, general | I | E | |||
| weight loss (common) | E | ||||
| dermatology/skin | extravasation hazard: rare | ||||
| alopecia, diffuse | D | ||||
| desquamation 4 | E | ||||
| erythema | E | ||||
| facial flushing 3 | I | E | |||
| hyperkeratosis of hands and nails | E | ||||
| hyperpigmentation especially in creases and folds in the areas of trauma 3 (frequent) | E | ||||
| hypoesthesia progressing to hyperesthesia | E | ||||
| ichthyosis, peeling and bleeding | E | ||||
| induration 13 | E | ||||
| paresthesia | E | D | |||
| prorates | E | D | |||
| rash on pressure areas and abdominal skin creases (8%) | E | ||||
| Raynaud's phenomenon 4 (rare) | E | D | |||
| scaling 3 | E | D | |||
| stomatitis | E | ||||
| striae | E | ||||
| tenderness of skin | E | ||||
| thickening of skin 3 | E | D | |||
| ulcerations, tongue, lips (rare) | E | D | |||
| urticaria | E | ||||
| vesiculation | E | ||||
| gastrointestinal | emetogenic potential: Low Moderate | ||||
| anorexia (common) | I | E | |||
| mucositis (30%) | E | ||||
| nausea | I | E | |||
| ORGAN SITE | SIDE EFFECT | ONSET | |||
| Dose-limiting side effects are in bold, italics I = immediate (onset in hours to days); E = early (days to weeks); D = delayed (weeks to months); L = late (months to years) | |||||
| stomatitis (30%) | E | ||||
| vomiting (common) | I | ||||
| hepatic | hepatic toxicity (rare) 8 | E | |||
| musculoskeletal | arthritis, acute 13 | E | D | ||
| neurology | aggressive behaviour (rare) | I | |||
| cerebrovascular accident (rare) | E | ||||
| cerebral arteritis (rare) | E | ||||
| disorientation (rare) | I | ||||
| ocular/visual | periorbital edema 4 | E | |||
| pain | chest pain 4 , acute, suggestive of pleuropericarditis (rare) | I | E | ||
| myalgias 3 (less frequent) | E | ||||
| pulmonary | bronchospasm 4 | I | |||
| dyspnea | E | ||||
| pleuropericarditis (rare) 8 | I | ||||
| pneumonitis (10%) | E | D | |||
| pulmonary fibrosis (1%) | E | D | |||
| rales | I | ||||
| renal/genitourinary | cystitis (rare) | E | |||
| hematuria (rare) | E | ||||
| hemorrhagic cystitis (rare) | E | ||||
| renal toxicity (rare) | E | ||||
Adapted from standard references2,6 unless specified otherwise. Dermatologic effects are the most frequent adverse effects of bleomycin, occurring in 50% of patients2 usually occurring 2-4 weeks after initiation of therapy.8 Adverse mucocutaneous effects including erythema, rash, striae, vesiculation, hyperpigmentation, and tenderness of skin usually develop in the second or third week of bleomycin therapy. Mucocutaneous effects appear to be dose related, usually occurring after 150-200 units of bleomycin. Discontinuation of therapy due to these toxicities occurs in about 2% of patients.6 Febrile reactions are seen in 50% of patients treated with bleomycin given IV and in 25% of patients where bleomycin is given IM. This reaction can be prevented by hydrocortisone premedication. Pre-treatment with antipyretics or antihistamines can also be used,2 but have not produced uniform results in reducing bleomycin associated fever.6 Hypersensitivity reactions occur in 1% of lymphoma patients receiving bleomycin. This anaphylactic reaction can include hypotension, fever, chills, mental confusion, and wheezing.6 This idiosyncratic reaction can occur immediately or be delayed for several hours. This reaction usually occurs after the first or second dose. The manufacturer suggests using a test dose of 2 units or less for the first 2 doses.14 If no acute reaction occurs after 2 to 4 hours, then regular dosing may commence.1,4 The use of a test dose is not universally accepted.15-17 Bleomycin Respiratory effects are the most serious side effects for bleomycin.6 Bleomycin pulmonary toxicity BPT occurs in 10% of treated patients.2 In approximately 1%, the non-specific pneumonitis induced by bleomycin progresses to pulmonary fibrosis and death. Non-productive cough, dyspnea, basal rales, pleuritic chest pain and fever are frequently first signs of toxicity. Pulmonary fibrosis from bleomycin can develop insidiously during treatment.18 Patients should be questioned carefully for new dry unproductive cough or new respiratory limitation of exercise tolerance at each visit. Persistence of either of these symptoms for longer than one week without other explanation, such as infection, should prompt consideration of discontinuation of the bleomycin. Some authors have recommended serial measurement of carbon monoxide diffusing capacity by pulmonary function testing, however, this has not proved to be a reliable predictor of bleomycin toxicity and its use must be individualized. A normal chest x-ray is unreliable to exclude BPT.10,18Identification of patients with bleomycin induced pulmonary toxicity can be very difficult due to the non- specific signs and symptoms.6 Treatment includes corticosteroids for pneumonitis to prevent pulmonary fibrosis and antibiotics for infectious pneumonitis. See Special Precaution section for risk factors which can predispose a patient to BPT. In addition to these risk factors oxygen therapy after treatment with bleomycin is considered a risk factor to developing BPT. The following recommendations have been developed regarding the use of oxygen therapy in patients who have been treated with bleomycin10:
Although the evidence is inconsistent with regards to the relationship between supplemental oxygen therapy and bleomycin lung toxicity, patients should not be denied oxygen therapy if hypoxia is documented or anticipated.
If supplemental oxygen is required, the lowest FIO2 that maintains adequate tissue oxygenation (as measured by arterial blood gasses or pulse oximetry) should be provided.
Preoperative anaesthesia consultation should be mandatory for patients with a history of bleomycin therapy.
Recreational use of high flow oxygen (e.g., scuba diving) should be discouraged.
Patients should be encouraged to carry wallet cards or wrist bracelets alerting caregivers to possible toxicity associated with oxygen therapy.
(More information under "A Guideline for Oxygen Therapy for Patients who have Received Bleomycin Systemic Therapy" after References)
| AGENT | EFFECT | MECHANISM | MANAGEMENT |
| cisplatin 1 | may increase risk of bleomycin toxicity | reduced bleomycin elimination | monitor for bleomycin toxicity |
| digoxin 19 | may decrease digoxin levels | changes to intestinal mucosa may decrease digoxin absorption | monitor for decrease in pharmacological effect of digoxin |
| phenytoin 19 | may decrease phenytoin levels | decreased absorption, increased metabolism of phenytoin | monitor serum levels of phenytoin |
| vincristine 8 | sequential administration of vincristine given before bleomycin may improve bleomycin efficacy | vincristine arrests cells in mitosis so that they are more susceptible to the actions of bleomycin | can be used for therapeutic advantage |
Injection: Supplied as single dose vials containing 15 units of bleomycin.2 Bleomycin is a mixture of peptides and should be described in units rather than mg.3 Mayne Pharma's formulation contains 1.5-2.0 units of bleomycin per milligram, while Bristol Laboratories' formulation contains 1 unit of bleomycin per milligram.20 Store vials between 2-8degC, and protect from light. Intact vials are stable for 28 days at room temperature.21
Reconstitution is based on administration. For IM or SC injection dissolve the contents of the vial in 1-5mL of either SWI or NS to give a solution of 3 to 15 units/mL.2 For IV or intra-arterial administration dissolve the contents of the vial in 5-10 mL SWI or NS to give a solution of 1.5-3 units/mL. For intra-pleural administration dissolve the contents of 1-8 vials (15-120 units) in 100 mL of either NS or D5W. For intra-peritoneal administration dissolve the contents of 4- 8 vials (60-120 units) in 100 mL of NS.
is stable for 24 hours at room temperature or refrigerated for 48 hours.
Bleomycin solution reconstituted with NS has been reported to be stable for four weeks when refrigerated, for two weeks or longer when stored at room temperature, and for ten days at 37degC, but as the formulation is preservative- free, Trissels recommends that solutions be used within 24 hours.21 Mayne Pharma reports their product is stable for 24 hours when reconstituted with NS, BWI or SWI and stored at room temperature and the product is stable for 10 days when reconstituted with NS or SWI, refrigerated and protected from light.22
No information provided by Bristol Laboratories of Canada.20 Diluted solution for infusion: Bristol states the diluted solution is stable for 8 hours in NS at room temperature.20 Intermittent infusion is given in 50-100mL of solution.1 Diluted in NS to concentrations of 15units/100mL in PVC bags and 60 units/100mL in polypropylene syringes, bleomycin lost 4 and 6%, respectively, in 28 days at room temperature in the dark.21 At concentration of 15 units/mL in D5W a 54% loss occurred in PVC bags in 28 days at room temperature protected from light.
No information provided by Mayne Pharma.22
Bleomycin with single drug compatibility at Y-site21
| bleomycin 1 unit/mL | bleomycin 3unit/mL |
| allopurinol 3 mg/mL amifostine 10 mg/mL aztreonam 40 mg/mL cefepime 20 mg/mL doxorubicin liposomal 0.4 mg/mL etoposide 5 mg/mL filgrastim 30 mcg/mL fludarabine 1 mg/mL gemcitabine 10 mg/mL granisetron 0.05 mg/mL melphalan 0.1 mg/mL ondansetron 1 mg/mL paclitaxel 1.2 mg/mL piperacillin-tazobactam 40 + 5 mg/mL sargramostim 10 mcg/mL teniposide 0.1 mg/mL vinorelbine 1 mg/mL | cisplatin 1 mg/mL cyclophosphamide 20 mg/mL doxorubicin 2 mg/mL droperidol 2.5 mg/mL fluorouracil 50 mg/mL heparin 1000 units/mL leucovorin 10 mg/mL methotrexate 25 mg/mL metoclopramide 5 mg/mL mitomycin 0.5 mg/mL vinblastine 1 mg/mL vincristine 1 mg/mL |
Bleomycin with single drug compatibility in 1 L NS21 Bleomycin with single drug compatibility in syringe21
| bleomycin 20 and 30 units | bleomycin 1.5 units/0.5 mL |
| amikacin 1.25 g | cisplatin 0.5 mg/0.5 mL |
| dexamethasone 50 mg | cyclophosphamide 10 mg/0.5 mL |
| diphenhydramine 100 mg | doxorubicin 1 mg/0.5 mL |
| fluorouracil 1 g | droperidol 1.25 mg/0.5 mL |
| gentamicin 50, 100, 300, 600 mg | fluorouracil 25 mg/0.5 mL |
| heparin 10,000 to 200,000 units | furosemide 5 mg/0.5 mL |
| hydrocortisone sodium phosphate 100 mg, 500 mg, 1 g, 2 g | heparin 500 units/0.5 mL |
| phenytoin 500 mg | leucovorin 5 mg/0.5 mL |
| streptomycin 4 g | methotrexate 12.5 mg/0.5 mL |
| tobramycin 500 mg | metoclopramide 2.5 mg/0.5 mL |
| vinblastine 10 and 100 mg | mitomycin 0.25 mg/0.5 mL |
| vincristine 50 and 100 mg | vinblastine 0.5 mg/0.5 mL |
| vincristine 0.5 mg/0.5 mL |
The following are incompatible in the same infusion solution: aminophylline 0.25 mg/mL, ascorbic acid 2.5 mg/mL, 5 mg/mL, cefazolin 1 mg/mL, dexamethasone 0.05 mg/mL, hydrocortisone sodium succinate 0.3
mg/mL, 0.75 mg/mL, 1 mg/mL, 2.5 mg/mL, methotrexate 0.25 mg/mL, 0.5 mg/mL, mitomycin 0.01 mg/mL, 0.05 mg/mL, penicillin G 2000 units/mL, 5000 units/mL, terbutaline 0.5 mg/mL.21
| BCCA administration guideline noted in bold , italics | |
| Subcutaneous 1 | has been given |
| Intramuscular 1 | has been given |
| Direct intravenous | give slowly over 10 min |
| Intermittent infusion | in 50 mL over 10-15 min |
| Continuous infusion | has been given |
| Intrapericardium 3 | has been given |
| Intraperitoneal 2 | has been given |
| Intrapleural 21 | by physician only |
| Intrathecal | no information found |
| Intra-arterial 1 | has been given |
| Intravesical 5 | has been given |
| Intratumoral 1,9 | instilled into Ommaya reservoir |
There is some evidence that administration of bleomycin by continuous infusion over 24 hours rather than intermittently may be associated with less pulmonary and idiosyncratic toxicity, although mucocutaneous toxicity may be increased.8
Refer to protocol by which patient is being treated. Numerous dosing schedules exist and depend on disease, response and concomitant therapy. Guidelines for dosing also include consideration of absolute neutrophil count (ANC). Dosage may be reduced, delayed or discontinued in patients with bone marrow depression due to cytotoxic/radiation therapy or with other toxicities.
Adults:
Intravenous:
Cycle Length:
BCCA usual dose noted in bold, italics
Dosage in myelosuppression:
modify according to protocol by which patient is being treated; if no guidelines
available, refer to Appendix 6 "Dosage Modification for Myelosuppression"
Dosage in renal failure2:
| Creatinine clearance (mL/min) | Dose |
| >50 | 100% |
| 10-50 | 75% |
| <10 | 50% |
* For males N = 1.23; for females N=1.05
Dosage in hepatic failure:
no adjustment required
Dosage in dialysis1 : not effectively hemodialyzed Intra-arterial: 30-60 u once or twice a week, to a total recommended dosage of 300 u.2 Intra-arterial bleomycin serum concentration peaks were reported to be three times higher then levels from comparable IV doses.1 Intrapleural2: 50-60 u in 100 mL NS or D5W. (not exceeding 1 unit/kg or 40 units/m2 in geriatric patients). Intra-tumoral1: small doses are diluted in a minimal volume of NS and combined with lidocaine. Local skin reactions and soft tissue toxicity may be severe. Intravesical1: 30-120 u in 30-60 mL water.
Maximum lifetime dose8 : 400 units (less for patients with renal or pulmonary function impairment) due to the risk of pulmonary toxicity. Doses greater than this must be given with great caution. Count intraperitoneal and intrapleural doses as half. For bleomycin given intravesically the systemic absorption is minimal.
Children5: Bleomycin 10-20 units/m2 IV by bolus or infusion, IM, or SC. Intrapleural and intravesicular administration are used. Intratumoral dosing is 2.5-5 units instilled into Ommaya reservoir three times weekly aiming for 12 doses.
9,23
Dosage in renal failure:
45-65% dosage reduction has been recommended for children with a creatinine clearance of less than 30 mL/min/m2.
Oral, topical administration1,7: 1% bleomycin in dimethylsulfoxide applied once daily for fourteen consecutive days. The solution is applied directly to the lesions on the oral mucosa. Topical application1: 1% ointment in petrolatum applied to affected area followed by an occlusive dressing.
Dorr RT, Von-Hoff DD. Drug monographs. Cancer chemotherapy handbook. 2nd ed. Norwalk, Conneticut: Appleton and Lange; 1994. p. 227-236.
Faulding Canada Inc. Bleomycin sulfate product monograph. 2002.
Perry M. The Chemotherapy Source Book. Philadelphia: Lippincott Williams & Wilkins; 2001. p. 237-239.
Chabner BA, Longo DL. Cancer Chemotherapy & Biotherapy. Philadelphia: Lippincott Williams & Wilkins; 2001. p. 466-481.
Pizzo PA. Principles and Prectice of Pediatric Oncology. 4th ed. Philadelphia: Lippincott Williams & Wilkins; 2002. p. 274-275.
McEvoy GK, editor. AHFS 2002 Drug Information. Bethesda, Maryland: American Society of Health-System Pharmacists, Inc.; 2004.
Epstein JB, Gorsky M, Wong FL, et al. Topical bleomycin for the treatment of dysplastic oral leukoplakia. Cancer. 1998; 83(4):629-34.
Bleomycin. USP DI. Volume 1. Drug information for the health care professional. 20th ed. Englewood, Colorado: Micromedex, Inc.; 2000.
Hader WJ ea. Intratumoral therapy with bleomycin for cystic craniopharyngiomas in children. Pediatric Neurosurgery 2000; 33(4):211-18.
Judy Sutherland, MD. Bleomycin Associated Lung Toxicity. A Guideline for Oxygen Therapy for Patients who have Received Bleomycin Systemic Therapy. 2001.
Briggs GG, Freeman RK, Yaffe SJ. Drugs in Pregnancy and Lactation. 5th ed. Baltimore: Williams & Wilkins; 1998.
BC Cancer Agency Genitourinary Tumour Group. (GUBEP) BCCA Protocol Summary for Bleomycin, Etoposide, Cisplatin for Nonseminoma Germ Cell Cancers. Vancouver: BC Cancer Agency; 1 February 2002.
De Vita V, Hellman S, Rosenberg SA. Cancer Principles & Practise of Oncology. Philadelphia: Lippincott Williams & Wilkins; 2001.
Mayne Pharma Canada Inc. Bleomycin Product Monograph. 2002.
B.C. Cancer Agency Lymphoma Tumour Group. BCCA Protocol Summary for treatment of Hodgkin's disease with doxorubicin, bleomycin, vinblastine and dacarbazine (LYABVD). Vancouver, British Columbia: BC Cancer Agency; 1 May 2002.
B.C. Cancer Agency Lymphoma Tumour Group. BCCA Protocol Summary for lymphoma palliative chemotherapy (LYPALL). Vancouver, British Columbia: BC Cancer Agency; 1 Nov 2002.
B.C. Cancer Agency Lymphoma Tumour Group. BCCA Protocol Summary for treatment of Hodgkin's disease with vincristine, doxorubicin, bleomycin, etoposide and prednisone (LYODBEP). Vancouver, British Columbia: BC Cancer Agency; 1 September 2002.
Joseph Connors MD. Personel Communication. Chair, Lymphoma Tumour Group, BC Cancer Agency Chair, Research Ethics Board, BC Cancer Agency; 23 September 2004.
Tatro D editor. Drug Interactions Facts. St. Louis: Facts and Comparisons; 2002.
Bristol-Myers Squibb Canada Inc. Blenoxane product monograph. 1999.
Trissel LA. Handbook on Injectible Drugs. 12th ed. ; 2003.
Sheila Ahmed. Personal Communication. Regulatory Affairs Associate, Mayne Pharma; 2 July 2004.
Roberta Esau. Personal Communication. Pharmacist BC Childrens Hospital. 17 November 2004.
Guyatt GH, Sackett DL, Sinclair JC, et al. Users' guides to the medical literature. IX. A method for grading health care recommendations. Evidence-Based Medicine Working Group [published erratum appears in JAMA 1996 Apr 24; 275(16):1232]. Jama 1995; 274(22):1800-4.
Blum RH, Carter SK, Agre K. A clinical review of bleomycin--a new antineoplastic agent. Cancer 1973; 31(4):903-14.
Yagoda A, Mukherji B, Young C, et al. Bleomycin, an antitumor antibiotic. Clinical experience in 274 patients. Annals of Internal Medicine 1972; 77(6):861-70.
Jules-Elysee K, White DA. Bleomycin-induced pulmonary toxicity. Clinics in Chest Medicine 1990; 11(1):1-20.
Comis RL. Bleomycin pulmonary toxicity: current status and future directions. Seminars in Oncology 1992; 19(2 Suppl 5):64-70.
Goldiner PL, Carlon GC, Cvitkovic E, et al. Factors influencing postoperative morbidity and mortality in patients treated with bleomycin. BMJ 1978; 1(6128):1664-7.
Hulbert JC, Grossman JE, Cummings KB. Risk factors of anesthesia and surgery in bleomycin-treated patients. Journal of Urology 1983; 130(1):163-4.
Hay JG, Haslam PL, Dewar A, et al. Development of acute lung injury after the combination of intravenous bleomycin and exposure to hyperoxia in rats. Thorax 1987; 42(5):374-82.
Simpson AB, Paul J, Graham J, et al. Fatal bleomycin pulmonary toxicity in the west of Scotland 1991-95: a review of patients with germ cell tumours. British Journal of Cancer 1998; 78(8):1061-6.
Donat SM, Levy DA. Bleomycin associated pulmonary toxicity: is perioperative oxygen restriction necessary? Journal of Urology 1998; 160(4):1347-52.
Waid-Jones MI, Coursin DB. Perioperative considerations for patients treated with bleomycin. Chest 1991; 99(4):993-9.
Donohue JP, Rowland RG. Complications of retroperitoneal lymph node dissection. Journal of Urology 1981; 125(3):338-40.
Allen SC, Riddell GS, Butchart EG. Bleomycin therapy and anaesthesia. The possible hazards of oxygen administration to patients after treatment with bleomycin. Anaesthesia 1981; 36(1):60-3.
Douglas MJ, Coppin CM. Bleomycin and subsequent anaesthesia: a retrospective study at Vancouver General Hospital. Canadian Anaesthetists Society Journal 1980; 27(5):449-52.
Strickland RA, Spackman TN, Wedel DJ. Anesthetic management of bleomycin-treated patients [letter; comment]. Mayo Clinic Proceedings 1991; 66(5):548.
Bleomycin Associated Lung Toxicity. A Guideline for Oxygen Therapy for Patients who have Received Bleomycin Systemic Therapy.
| Effective date: | 27 July 2000 |
| Prepared by: | Dr. Judy Sutherland on behalf of GU Tumour Group |
| Approved by: | Provincial Systemic Program Committee |
The objective of this guideline is to provide recommendations for oxygen therapy based on the quality of available published evidence relating bleomycin pulmonary toxicity (BPT) to supplemental oxygen therapy. The diagnosis and treatment of BPT have been reviewed elsewhere and will not be reported in this guideline. A MEDLINE literature search of all published abstracts, case reviews and clinical trials using the search terms "Bleomycin" (adverse effects, poisoning, toxicity) and "Lung diseases" (chemically induced) was undertaken. Documents retrieved were limited to those published in English and related to human exposure. Seventy-three publications since 1970 were identified and reviewed. The strength of the data were graded according to standard criteria.24 Bleomycin has been used in combination chemotherapy for patients with germ cell tumours, Hodgkin's disease and non-Hodgkin's lymphoma for more than 20 years. Overall response rates of 50-90% have been achieved. Reported toxicities have included mucositis, hypersensitivity reactions, skin rashes and BPT.1,25,26 The reported incidence of non fatal BPT is dependent on the diagnostic criteria used but appears to be 5-10% and fatal BPT has been reported in approximately 2% of treated cases.27,28 Pulmonary toxicity may occur in the form of acute pneumonitis, chronic pulmonary fibrosis or acute respiratory distress syndrome (ARDS) which is most commonly seen in the postoperative setting.29,30 Risk factors that have been associated with BPT include age >40 years, cumulative dose of >450 units, renal failure, concomitant administration of cisplatin, cyclophosphamide, methotrexate and doxorubicin, chest irradiation, and positive fluid balance during prolonged surgical procedures.27,28 Animal studies have demonstrated that supplemental oxygen may be an additional risk factor for lung toxicity 31, but human data based on case reports, and retrospective reviews are less clear. Multivariate analyses in two large retrospective reviews have not identified high flow oxygen as an additional risk factor for BPT.32,33 Prospective randomized studies evaluating pulmonary morbidity in bleomycin treated patients have not been reported. The vast majority of the data relating BPT to oxygen therapy has been obtained from patients undergoing general anesthesia and surgical resections following chemotherapy with multiagent regimens containing bleomycin. Very little published data are available reporting the safety of chronic or short-term supplemental oxygen in non-surgical patients who have received bleomycin. In 1978, Goldiner et al. published the first report of postanesthetic complications in patients who received bleomycin for germ cell tumours and later underwent retroperitoneal lymph node dissection or resection of pulmonary metastases.29 Five patients died of rapidly progressive respiratory failure. In a subsequent prospective study of 12 similar patients, the mean FIO2 was reduced to 0.24 from 0.39 and the crystalloid administration was significantly reduced from 5.86 mg/kg/h to 3.87. These patients experienced no postoperative pulmonary complications. Goldiner et al. concluded that the FIO2 during and after surgery should be kept as low as possible and that fluid status should be closely monitored to avoid excessive crystalloid administration. {Goldiner, 1978 #122} These recommendations for anesthetic management remain the guidelines used by most anesthesiologists today.34 Several similar case studies have been reported.30,35 Other investigators attribute the absence of postoperative complications to the administration of a low FIO2 and limited fluids.36 Contrary to these recommendations, several more recent publications, which have reviewed over 300 patients undergoing general anesthesia following bleomycin containing regimens for germ cell tumors, have indicated no excess in pulmonary toxicity related to intraoperative or postoperative oxygen therapy.32,33,37 There has been no substantial change in the anesthetic guidelines for these patients, despite the data obtained from these more recent studies. Several of these investigators have stressed that safe anesthesia for these patients may demand high flow oxygen to avoid risk of intraoperative hypoxia, particularly when one lung anesthesia and ventilation is required for lobectomy.
34,38
Published data regarding the safety of exposure to high flow oxygen during recreational activities such as scuba diving are limited and patients should be counselled that safety cannot be assured during these activities. Implementation of this guideline may reduce treatment-related morbidity and mortality. The magnitude of the benefit is expected to be modest given the overall low rate of BPT in current clinical practice. The success of this guideline should be evaluated by careful reporting of treatment-related toxicity in all at risk patients as it is unlikely that prospective clinical trials will be done. RECOMMENDATIONS
The conflicting evidence suggests that caution regarding oxygen therapy be continued, but that patients should not be denied oxygen therapy if hypoxia is documented or anticipated.
If supplemental oxygen is required, the lowest FIO2 that maintains adequate tissue oxygenation (as measured by arterial blood gasses or pulse oximetry) should be provided.
Preoperative anesthesia consultation should be mandatory for patients with a history of bleomycin therapy.
Recreational use of high flow oxygen (e.g., scuba diving) should be discouraged.
Patients should be encouraged to carry wallet cards or wrist bracelets alerting caregivers to possible toxicity associated with oxygen therapy.
References:
Guyatt GH, Sackett DL, Sinclair JC, et al. Users' guides to the medical literature. IX. A method for grading health care recommendations. Evidence-Based Medicine Working Group [published erratum appears in JAMA 1996 Apr 24; 275(16):1232]. JAMA 1995; 274(22):1800-4.
Blum RH, Carter SK, Agre K. A clinical review of bleomycin--a new antineoplastic agent. Cancer 1973; 31(4):903-14.
Yagoda A, Mukherji B, Young C, et al. Bleomycin, an antitumor antibiotic. Clinical experience in 274 patients. Ann Intern Med 1972; 77(6):861-70.
Dorr RT, Von-Hoff DD. Drug monographs. In: Dorr R, Von-Hoff D, editors. Cancer chemotherapy handbook. 2nd ed. Norwalk, Conneticut: Appleton and Lange; 1994. p. 227-36.
Jules-Elysee K, White DA. Bleomycin-induced pulmonary toxicity. Clin Chest Med 1990; 11(1):1-20.
Comis RL. Bleomycin pulmonary toxicity: current status and future directions. Semin Oncol 1992; 19(2 Suppl 5):64-70.
Goldiner PL, Carlon GC, Cvitkovic E, et al. Factors influencing postoperative morbidity and mortality in patients treated with bleomycin. BMJ 1978; 1(6128):1664-7.
Hulbert JC, Grossman JE, Cummings KB. Risk factors of anesthesia and surgery in bleomycin-treated patients. J Urol 1983; 130(1):163-4.
Hay JG, Haslam PL, Dewar A, et al. Development of acute lung injury after the combination of intravenous bleomycin and exposure to hyperoxia in rats. Thorax 1987; 42(5):374-82.
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