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Bleomycin Pulmonary Toxicity
(BPT)
Dr/Khaled Abulkhair, PhD
Consultant Medical Oncology
IMC
FDA bleomycin official data release revised on Dec, 2010 was the main source
of this presentation unless mentioned otherwise
Drug Induced Lung Disease
Drug induced lung disease is increasing being
recognized with over 150 drugs described as
causing adverse pulmonary reactions.
All of the respiratory system can be affected.
Parenchyma Bleomycin, Amiodarone
Airways
Aspirin, Penicillamine
Pleura
All trans retinoic acid
Vasculature Fenfluramine
Patterns of Toxicity
(Parenchymal Disease)
Interstitial pneumonitis/fibrosis (commonest).
Hypersensitivity pneumonitis.
Non cardiac pulmonary edema (ATRA).
Acute pneumonia (mitomycin, vinca alkaloids,
Gefitinib).
Pulmonary renal syndrome.
Pulmonary venocclusive disease.
Drug Induced Lung Disease
Problems in Recognition
 Drugs are given as part of multidrug regimens
and offending agent may not be clear.
 Other conditions, such as pulmonary infection or
progression of cancer, occur considerably more
frequently.
 No pathognomonic clinical, radiographic or
pathologic findings.
 New agents or new combinations are frequently
being used and unrecognized or new types of
toxicity occur.
Chemotherapy Induced Lung Disease
Toward Better Recognition
High index of suspicion:
exercise intolerance, SOB, unexplained cough,
new findings on chest examination or X-rays.
Knowledge of patterns of toxicity associated
with each drug in use.
Exclusion of other likely entities Patterns:
infection or disease progression.
Pay special attention for high risk patients.
Bleomycin*
 A family member of polypeptides macrolides
secreted by Streptomyces verticillus works by
Intercalation into DNA strands causing breaks.
 DNA degradation needs O2 and Fe2+ or Cu+,
another pathway makes strand(s) susceptible to
alkylating agents (dacarbazine).
 Drug is rapidly eliminated, mostly by kidneys.
 Resistance to bleomycin correlates with bleomycin
hydrolase enzyme »» Inhibits iron binding, and
decrease cytotoxicity
 Low conc’n of hydrolase in skin, lung » »
Mechanism for sensitivity to toxic effects.
*Hecht SM. J Nat Prod 2000;63(1):158-68
Bleomycin Pulmonary Toxicity (BPT)
 Why does Bleomycin deserve special attention?
“Grasp defeat from the jaws of victory” it could be
disabling and fatal in curable cancers.
– Late pulmonary nodules do not necessarily represent
recurrent disease – needs a biopsy.
– Once exposed to bleomycin ALWAYS at risk of toxicity
(patient should NEVER get 100% FiO2).
 Incidence:
- Incidence of toxicity is 6-10% but subclinical toxicity
based on PFTS reaches up to25%1.
- Approximately 2% of patients treated have died of
pulmonary fibrosis2.
1-O’Sullivan et al, Annals of Oncology 14:91-96, 2003
2-Simpson et al, Br J Cancer 78: 1061-1066, 1998
BPT
Risk factors?
various clinical trials. However, few of them have sufficient statistical
power, most of them are case reports or retrospective with few events.
1- increased Cumulative dose ; between 100 and 400 IU toxicity is sporadic,
while at doses above this range the incidence rises steeply .
2- Low GFR.
3- Older age.
4- Supplemental oxygen exposure (no safe threshold).
5- Bolus drug delivery (as opposed to continuous infusion).
6- Extent of lung involvment and prior lung disease.
Cumulative dose and reduced renal function are the most well established risk
factors.
Cigarette smoking is suggested however, patient numbers are small.
Other suggested factors include combination with other drugs e.g. cisplatin, and
the use of growth factors ??
Pathology*
 Interstitial edema with influx of inflammatory and
immune cells Leads to pulmonary fibrosis with
enhanced collagen deposition (fibrosing alveolitis).
 BAL in animals and humans in bleomycin induced
toxicity shows increased number of neutrophils
and in some cases eosinophils.
 Direct toxicity with imbalance in
oxidantantioxidant systems.
 Vascular damage with influx of inflammatory cells
and fibroblasts; induction of cytokines.
 Increased TGF- Beta.
* Hay J, et al. Arch Toxicol 1991;65(2):81-94
Clinical presentation *
First symptom S.O.B === First sign wheezes.
 Develops subacutely btw 1 and 6 months
 Nonspecific, overall
 Nonproductive cough, Dyspnea, tachypnea,
hypoxemia
 Pleuritic or substernal CP
 Fever
 Rales
 Restrictive lung physiology and decreased DLCO
*Lasky JA, Ortiz L. Up-To-Date, Bleomycin-induced lung injury. [2/19/07]
Two different clinical syndromes
Intersitial Pneumonitis/Fibrosis
 Common
 Subacute to chronic
(over weeks to months)
 Symptoms: Dyspnea and dry
cough;
 Fever and systemic symptoms rare
 Physical exam: Bibasilar crackles
 Chest radiographs: Increased
reticular infiltrates; advanced
cases showing fibrosis and
honeycombing.
 PFT show low DLCO
Hypersensitivity Pneumonitis
 Rare
 Acute to subacute (earlier onset)
 fever, fatigue, myalgias and
arthralgia;
 cough and dyspnea occur latter
 Eosinophilia may be present
 Various findings
 Radiographs show air space
disease, which may be focal, lobar
or diffuse’ peripheral
predominance in some cases
 PFT show decreased FEV1.
Diagnosis
 Gold standard for diagnosis is re-challenge
which is impractical and could be dangerous.
 Compatible clinical, radiographic and pathologic
picture with reasonable exclusion of other
entities.
– Clinical & radiographs.
– PFTs
– Bronchoscopy & BAL.
– Open biopsy
 No pathognomonic findings??
Interstitial Pneumonitis/Fibrosis
Bibasilar crackles
Radiographs show increased
markings, peripherally in
Basescan progressing to
honeycombing
Implicated drugs:
Bleomycin.
Mitomycin.
Cyclophosphamide.
Interstitial Pneumonitis/Fibrosis
How could we improve Early Detection?*
 To monitor the onset of pulmonary toxicity, chest X-rays
should be taken every 1 to 2 weeks. If pulmonary changes
are noted, treatment should be discontinued until it can be
determined if they are drug related or not.
 Recent studies have suggested that sequential measurement
of the pulmonary diffusion capacity for carbon monoxide
(DLCO) during treatment with Bleomycin may be an
indicator of subclinical pulmonary toxicity.
 It is recommended that the DLCO be monitored monthly if
it is to be used to detect pulmonary toxicities, and thus the
drug should be discontinued when the DLCO falls below
30% to 35% of the pretreatment value.
*FDA bleomycin official data release revised on7/2006 (warning section)
Pulmonary function tests (PFTs)
It is just a good standard of care to follow pulmonary
function in patients who are getting bleomycin, either through
simple means, such as asking the patient about their pulmonary
function, or through pulmonary function tests. (Dr. George Bosl
at ASCO 2007).
Principles of using PFTs:*
 Screening ; if >15% drop in DLCO, exercise your patient:
- If no exercise desaturation and no clinical or radiologic
toxicity, continue bleomycin.
- If exercise desaturation and no other explanation, stop
bleomycin.
 If unexplained dyspnea occurs with decrease in DLCO, stop
bleomycin.
 Drop more than 30-35% in DLCO stop bleomycin.
* www.pneumotox.com.
Management
Mainly conservative:
 Discontinue bleomycin. if the
 pulmonary diffusion capacity for carbon monoxide (DLCO) falls to 30-35% of initial value.
 forced vital capacity (FVC) falls significantly.
 any clinical or radiographic features indicating pulmonary toxicity.
 Supportive care:
- I.V.F
- O2 should not be given if O2 sat >80-85%.1
 Steroids. in an effort to prevent progression to fibrosis
 Pentoxifylline would help patients resistant to steroids2,
start as 400 mg po bid to be increased in 1-2 days to 400 mg tid.
 Avoid future RT (if necessary cover with steroids)
 Avoid unnecessary O2 supplement, maintain low O2 sat. during anesthesia .
 Patients should be warned that uncontrolled oxygen should be avoided except briefly in
an emergency and to avoid increased oxygen pressure as in scuba diving.
1- Martin Dreyling head of lymphoma program, Ludwig Maximillian University, Germany, LyFE, 2008.
2- Goffin et al, Journal of Clinical Oncology, Vol 19, Issue 2 (January), 2001: 597-598
Conclusion
 Should we plan a strategy for prevention of BPT ??
 Could we establish at least a baseline PFTs for those
patients going to receive Bleomycin?
 Never under estimate the words “I am really having S.O.B”.
 Pay special attention for those patients with high risk
factors.
 Consider dose reduction or omitting Bleomycin in patients
with renal impairment.
 Maximum lifetime doses should not exceed 400 U
(200mg/m2). Not to exceed 100 mg/m2 in patients with
prior or concurrent lung radiation and in patients over 70
years.