Bleomycin

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Mechanism of Action

• causes DNA strand scission through formation of an intermediate metal complex requiring a metal ion cofactor such as copper or iron.

• results in inhibition of DNA synthesis, and to a lesser degree, in inhibition of RNA and protein synthesis.

• cell-cycle specific for G phase, M-phase and S phase

Uses

• Primary uses:

  • *Cervical cancer

  • *Larynx and paralarynx

  • *Lymphoma, Hodgkin’s

  • *Lymphoma, non-Hodgkin’s

  • *Malignant pleural effusion

  • *Penile cancer

  • *Renal cancer

  • *Soft tissue sarcoma

  • *Testicular cancer

  • *Vulva cancer

  • *Lung cancer

• Other uses:

  • Dysplastic oral leukoplakia7

  • Head and neck6

  • Kaposi’s sarcoma6

  • Melanoma8

  • Mycosis fungoides8

  • Osteosarcoma8

  • Skin cancer8

  • Thyroid cancer8

  • Trophoblastic, gestational8

  • Cystic craniopharyngioma9

*Health Canada approved indication

Contraindicated in: patients who have a history of hypersensitivity reaction to bleomycin.2

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.

Carcinogenicity: Bleomycin is carcinogenic in animals.2

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

Fertility: no information found.

Pregnancy: 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).11

Breastfeeding is not recommended due to the potential secretion into breast milk.12

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/immunology4 hypersensitivity reactions (fever, anaphylaxis, eosinophilic

pulmonary infiltrates)

I

blood/bone marrow

febrile neutropenia

anemia (mild) I E

leukopenia I E

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Revised: 1 December 2004

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)

myelosuppression (uncommon, mild) I E

thrombocytopenia I E

cardiovascular (general) edema of hands and feet E

hypotension3 I

myocardial infarction (rare) E

phlebitis (uncommon) E

thrombotic microangiopathy (rare) E

constitutional symptoms chills (common) I

fever (50%) less frequent with continued use8 I

malaise I E

weakness, general I E

weight loss (common) E

dermatology/skin extravasation hazard: rare

alopecia, diffuse D

desquamation4 E

erythema E

facial flushing3 I E

hyperkeratosis of hands and nails E

hyperpigmentation especially in creases and folds in the areas of

trauma3 (frequent)

E

hypoesthesia progressing to hyperesthesia E

ichthyosis, peeling and bleeding E

induration13 E

paresthesia E D

prorates E D

rash on pressure areas and abdominal skin creases (8%) E

Raynaud’s phenomenon4 (rare) E D

scaling3 E D

stomatitis E

striae E

tenderness of skin E

thickening of skin3 E D

ulcerations, tongue, lips (rare) E D

urticaria E

vesiculation E

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Revised: 1 December 2004

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)

emetogenic potential: Low Moderate

anorexia (common) I E

mucositis (30%) E

nausea I E

stomatitis (30%) E

gastrointestinal

vomiting (common) I

hepatic hepatic toxicity (rare)8 E

musculoskeletal arthritis, acute13 E D

neurology aggressive behaviour (rare) I

cerebrovascular accident (rare) E

cerebral arteritis (rare) E

disorientation (rare) I

ocular/visual periorbital edema4 E

pain chest pain4, acute, suggestive of pleuropericarditis (rare) I E

myalgias3 (less frequent) E

pulmonary bronchospasm4 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 used2, but have not produced uniform results in reducing bleomycin

associated fever.6

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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

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.10,18

Identification 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:

1. 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.

2. 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.

3. Preoperative anaesthesia consultation should be mandatory for patients with a history of bleomycin therapy.

4. Recreational use of high flow oxygen (e.g., scuba diving) should be discouraged.

5. Patients should be encouraged to carry wallet cards or wrist bracelets alerting caregivers to possible toxicity

associated with oxygen therapy.

cisplatin1 may increase risk of

bleomycin toxicity

reduced bleomycin

elimination

monitor for bleomycin

toxicity

digoxin19 may decrease digoxin

levels

changes to intestinal

mucosa may decrease

digoxin absorption

monitor for decrease in

pharmacological effect of

digoxin

phenytoin19 may decrease phenytoin

levels

decreased absorption,

increased metabolism of

phenytoin

monitor serum levels of

phenytoin

vincristine8 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

Bleomycin

BC Cancer Agency Cancer Drug Manual©

Developed: September 1994 Page 6 of 12 Bleomycin

Revised: 1 December 2004

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 2-8°C, 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.

Reconstituted solution for injection: is stable for 24 hours at room temperature or refrigerated for 48 hours.2

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 37°C, but as the formulation is preservativefree,

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.

Bleomycin with single drug compatibility at Y-site21

allopurinol 3 mg/mL cisplatin 1 mg/mL

amifostine 10 mg/mL cyclophosphamide 20 mg/mL

aztreonam 40 mg/mL doxorubicin 2 mg/mL

cefepime 20 mg/mL droperidol 2.5 mg/mL

doxorubicin liposomal 0.4 mg/mL fluorouracil 50 mg/mL

etoposide 5 mg/mL heparin 1000 units/mL

filgrastim 30 mcg/mL leucovorin 10 mg/mL

fludarabine 1 mg/mL methotrexate 25 mg/mL

gemcitabine 10 mg/mL metoclopramide 5 mg/mL

granisetron 0.05 mg/mL mitomycin 0.5 mg/mL

melphalan 0.1 mg/mL vinblastine 1 mg/mL

ondansetron 1 mg/mL vincristine 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

Bleomycin

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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

Incompatibility: 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

Subcutaneous1 has been given

Intramuscular1 has been given

Direct intravenous give slowly over 10 min

Continuous infusion has been given

Intrapericardium3 has been given

Intraperitoneal2 has been given

Intrapleural21 has been given

Intrathecal no information found

Intra-arterial1 has been given

Intravesical5 has been given

Intratumoral1,9 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.

Bleomycin

BC Cancer Agency Cancer Drug Manual©

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BCCA usual dose noted in bold, italics

Intravenous: Cycle Length:

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"

>50 100%

10-50 75%

<10 50%

Calculated creatinine clearance = N* x (140 - Age) x weight (kg)

Serum Creatinine in μmol/L

* 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.

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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.

1. 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.

2. Faulding CI. Bleomycin sulfate product monograph. 2002.

3. Perry M. The Chemotherapy Source Book. Philadelphia: Lippincott Williams & Wilkins; 2001. p. 237-9.

4. Chabner BA, Longo DL. Cancer Chemotherapy & Biotherapy. Philadelphia: Lippincott Williams & Wilkins; 2001. p. 466-81.

5. Pizzo PA. Principles and Prectice of Pediatric Oncology. 4th ed. Philadelphia: Lippincott Williams & Wilkins; 2002. p. 274-5.

6. McEvoy GK, editor. AHFS 2002 Drug Information. Bethesda, Maryland: American Society of Health-System Pharmacists, Inc.;

2004.

7. Epstein JB, Gorsky M, Wong FL, et al. Topical bleomycin for the treatment of dysplastic oral leukoplakia. Cancer

1998;83(4):629-34.

8. Bleomycin. USP DI. Volume 1. Drug information for the health care professional. 2Oth ed. Englewood, Colorado: Micromedex,

Inc.; 2000.

9. Hader WJ ea. Intratumoral therapy with bleomycin for cystic craniopharyngiomas in children. Pediatr Neurosurg 2000;33(4):211-

18.

10. Judy Sutherland, MD. Bleomycin Associated Lung Toxicity. A Guidline for Oxygen Therapy for Patients who have Received

Bleomycin Systemic Therapy. 2001.

11. Briggs GG, Freeman RK, Yaffe SJ. Drugs in Pregnancy and Lactation. 5th ed. Baltimore: Williams & Wilkins; 1998.

12. B.C. Cancer Agency Genitourinary Tumour Group. BCCA Protocol Summary for bleomycin, etoposide, cisplatin for

nonseminoma germ cell cancers (GUBEP). Vancouver, British Columbia: BC Cancer Agency; 1 February 2002.

13. De Vita VT, Hellman S, Rosenberg SA. Cancer Principles & Practise of Oncology. Philadelphia: Lippincott Williams & Wilkins;

2001. p. 453-4.

14. Mayne Pharma CI. Bleomycin Product Monograph. 2002.

15. 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.

16. B.C. Cancer Agency Lymphoma Tumour Group. BCCA Protocol Summary for lymphoma palliative chemotherapy (LYPALL).

Vancouver, British Columbia: BC Cancer Agency; 1 Nov 2002.

17. 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.

18. Joseph Connors, MD. Personel Communication. Chair, Lymphoma Tumor Group, BC Cancer Agency

Chair, Research Ethics Board, BC Cancer Agency 2004;23 September 2004.

19. Tatro D, editor. Drug Interactions Facts. St. Louis: Facts and Comparisons; 2002.

20. Bristol-Myers Squibb Canada I. Blenoxane product monograph. 1999.

21. Trissel LA. Handbook on Injectible Drugs. 2003;12th ed.

22. Sheila Ahmed. Personal Communication. Regulatory Affairs Associate, Mayne Pharma 2004;2July2004(reference JUN-128-

2004).

23. Roberta Esau. Pharmacist BC Childrens Hospital. 17 November 2004 2004.

24. 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.

25. Blum RH, Carter SK, Agre K. A clinical review of bleomycin--a new antineoplastic agent. Cancer 1973;31(4):903-14.

Bleomycin

BC Cancer Agency Cancer Drug Manual©

Developed: September 1994 Page 10 of 12 Bleomycin

Revised: 1 December 2004

26. 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.

27. Jules-Elysee K, White DA. Bleomycin-induced pulmonary toxicity. Clin Chest Med 1990;11(1):1-20.

28. Comis RL. Bleomycin pulmonary toxicity: current status and future directions. Semin Oncol 1992;19(2 Suppl 5):64-70.

29. 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.

30. Hulbert JC, Grossman JE, Cummings KB. Risk factors of anesthesia and surgery in bleomycin-treated patients. J Urol

1983;130(1):163-4.

31. 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.

32. 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. Br J Cancer 1998;78(8):1061-6.

33. Donat SM, Levy DA. Bleomycin associated pulmonary toxicity: is perioperative oxygen restriction necessary? J Urol

1998;160(4):1347-52.

34. Waid-Jones MI, Coursin DB. Perioperative considerations for patients treated with bleomycin. Chest 1991;99(4):993-9.

35. Donohue JP, Rowland RG. Complications of retroperitoneal lymph node dissection. J Urol 1981;125(3):338-40.

36. 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.

37. Douglas MJ, Coppin CM. Bleomycin and subsequent anaesthesia: a retrospective study at Vancouver General Hospital. Can

Anaesth Soc J 1980;27(5):449-52.

38. Strickland RA, Spackman TN, Wedel DJ. Anesthetic management of bleomycin-treated patients [letter; comment]. Mayo Clin

Proc 1991;66(5):548.

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Revised: 1 December 2004

Therapy.

Effective date: 27 July 2000

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 toxicity31, 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.29 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

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BC Cancer Agency Cancer Drug Manual©

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Revised: 1 December 2004

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

1. 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.

2. 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.

3. Preoperative anesthesia consultation should be mandatory for patients with a history of bleomycin therapy.

4. Recreational use of high flow oxygen (e.g., scuba diving) should be discouraged.

5. Patients should be encouraged to carry wallet cards or wrist bracelets alerting caregivers to possible toxicity

associated with oxygen therapy.

References

1. 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.

2. Blum RH, Carter SK, Agre K. A clinical review of bleomycin--a new antineoplastic agent. Cancer 1973;31(4):903-14.

3. 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.

4. 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.

5. Jules-Elysee K, White DA. Bleomycin-induced pulmonary toxicity. Clin Chest Med 1990;11(1):1-20.

6. Comis RL. Bleomycin pulmonary toxicity: current status and future directions. Semin Oncol 1992;19(2 Suppl 5):64-70.

7. 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.

8. Hulbert JC, Grossman JE, Cummings KB. Risk factors of anesthesia and surgery in bleomycin-treated patients. J Urol

1983;130(1):163-4.

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