The Pulmonary Toxicity of Antineoplastic Agents
Terry L. Stonich, Pharm.D.
(with modifications by L. Bressler)
Spring , 1998
OBJECTIVES
1. List five proposed mechanisms of pulmonary injury induced by antineoplastic agents.
2. List five risk factors for development of antineoplastic induced pulmonary toxicity.
3. Discuss three clinical syndromes of pulmonary toxicity identified with the antineoplastic agents.
4. Discuss the incidence, risk factors, treatment and outcome of bleomycin induced pulmonary toxicity.
5. List the major categories of antineoplastic agents reported to cause pulmonary injury.
REQUIRED READING
NONE
SUGGESTED READING
1. Cooper J et al: Drug induced pulmonary disease - Part I: Cytotoxic drugs; Am Rev Resp Dis 133:321-340 (1986)
2. DeVita V et al (eds): Cancer - Principles and Practice of Oncology, 3rd Edition, 2162-2219 (1989)
3. Ginsbery S et al: The pulmonary toxicity of antineoplastic agents; Sem Oncol 9(1):34-51 (1982)
4. Batist G, Andrews J: Pulmonary toxicity of antineoplastic drugs; J Am Med Assoc 246(13):1449-1453 (1981)
Although antineoplastic agents play an invaluable role in the treatment of malignancies, there are toxicities inherent to their use. A serious and sometimes dose limiting toxicity is pulmonary injury.
II. MECHANISMS OF PULMONARY INJURY
Pulmonary toxicity secondary to antineoplastic drugs may be due to a variety of mechanisms. There are five major postulates to explain the development of this toxicity. Generally it is thought that antineoplastics induce pulmonary injury by disturbing homeostatic mechanisms (ie. causing an imbalance between inflammatory reactions that may cause pulmonary damage and protective detoxification reactions) for the following systems:
A. Oxidant/Antioxidant System
Oxidant molecules (eg. O2, H2O2, OH, HOCl) that are formed within phagocytic cells such as monocytes, macrophages and neutrophils may participate in redox reactions resulting in fatty acid oxidation that can lead to membrane instability and perhaps autologous cytotoxicity. Similarly, it is thought that these oxidant species may initiate damaging inflammatory reactions. Normally, antioxidant defense mechanisms (superoxide dismutase, glutathione peroxidase, alpha tocopherol) provide the necessary balance to offset the oxidant effects. When antineoplastic drugs are administered, there may be a disturbance of this homeostasis resulting in pulmonary injury.
B. Immunologic System
Even in the "healthy" state, pulmonary host cells can exaggerate toxic reactions caused by exposure to substances that initiate or activate the immunologic system. Pulmonary cells release mediators that activate and attract inflammatory cell types like eosinophils, monocytes, neutrophils, etc. To counterbalance the amplified effects of the immunologic system that may result in pulmonary tissue damage, other tolerant cells (eg. lymphocytes, alveolar macrophages) exist. It is postulated that when cytotoxic drugs are administered, there is a disturbance of this usual homeostasis of toxic reaction and tolerant suppressor cells, resulting in pulmonary injury.
C. Matrix Repair System
Normally, proliferation of fibroblasts leading to collagen deposition is helpful in repairing or limiting cell injury. However, excessive deposition of collagen can result in structure impairment. It has been postulated that when antineoplastic drugs are administered, the homeostatic control of fibroblast proliferation and collagen deposition is disrupted.
D. Proteolytic System
Neutrophils, macrophages, and other inflammatory cells produce a number of proteolytic enzymes that are associated with a myriad of pulmonary disturbances. Proteolytic enzymes are normally controlled or inactivated by protease inhibitors that are mediated by oxidant molecules. It is thought that although antineoplastic drug parent molecules do not affect this homeostasis, their oxidant radicals may inactivate protease inhibitors, thereby allowing proteolytic enzymes to function unopposed.
E. Central Nervous System
The CNS is thought to provide some control over pulmonary capillary permeability. It has been postulated that cytotoxic drugs may affect the hypothalamus and medulla in such a way that permeability is increased.
III. RISK FACTORS FOR DEVELOPMENT OF PULMONARY TOXICITY
As has been discussed, antineoplastic drugs do induce pulmonary toxicity. However, it should be realized that not all patients receiving these agents experience this toxicity. To identify those patients at risk, five major predisposing factors for development of pulmonary toxicity should be noted.
A. Cumulative Dose
Cytotoxic agents that are directly toxic to the lungs generally exhibit increasing toxicity with increasing dose. This is believed to be a result of drug accumulation in the lung itself. Two patterns of dose related pulmonary toxicity are usually clinically observed:
1. A threshold effect wherein there is a marked increase beyond a specific amount of drug received. For example, when total lifetime dose of bleomycin exceeds 450-500 units, there is a definite increase in risk for development of pulmonary toxicity. Pulmonary toxicity secondary to busulfan, in the absence of other predisposing factors, has only been noted with total doses >500mg.
2. A linear effect wherein there is a constantly increasing risk for the development of pulmonary toxicity as more drug is administered (eg. carmustine).
B. Age
A normal physiologic phenomenon that has been observed with aging is a decrease in the effectiveness of the antioxidant defense system. Therefore, as a patient ages, he/she would be expected to be more susceptible to pulmonary toxicity from certain cytotoxic drugs. To date, however, age has been shown to be a risk factor only for the development of bleomycin-induced pulmonary disease.
C. Radiation
Radiation therapy results in the production of oxidant species that lead to pulmonary damage. When antineoplastic agents (eg. bleomycin, mitomycin, busulfan) that also affect the oxidant/antioxidant homeostasis are administered, there may be synergistic toxicity.
D. Oxygen Therapy
Reactive oxidant metabolites (eg. O2, H2O2, OH) are produced when high concentrations of oxygen are administered. Synergistic toxicity may also be possible between high concentrations of O2 and drugs that can disrupt the normal oxidant/antioxidant homeostasis. This appears to be the case with bleomycin, cyclophosphamide and mitomycin.
E. Multidrug Regimens
Although not clearly defined, the incidence and severity of pulmonary toxicity may increase with multidrug regimens. Typically, these chemotherapy regimens include bleomycin, mitomycin, cyclophos- phamide, methotrexate, or carmustine. It has not been determined whether any single drug is the causative agent or if the interaction of these antineoplastics results in enhanced toxicity.
IV. CLINICAL SYNDROMES IDENTIFIED
Pulmonary toxicity induced by antineoplastic agents is manifested in three typical clinical patterns. Although they will be described individually, there may be certain patients that present with symptoms from more than one pattern.
A. Chronic Pneumonitis/Fibrosis
This presentation is observed most frequently and has been reported with virtually all antineoplastic drugs associated with pulmonary toxicity. However, it should be noted that it is not usually associated with antimetabolites. With this manifestation of pulmonary damage, the patient experiences slow, progressive (ie. weeks to months) dyspnea on exertion, a nonproductive cough and fatigue. Based on clinical utility and assessment of severity, the antineoplastic drug may be discontinued in an attempt to manage this toxicity. Steroids have been administered to enhance resolution of this syndrome, but documentation of their efficacy is anecdotal.
B. Hypersensitivity Reactions
These reactions are commonly associated with bleomycin, methotrexate, and procarbazine, and are manifested as an acute syndrome (ie. hours to days) consisting of dyspnea, fever, and nonproductive cough. Peripheral and/or pulmonary eosinophilia with pulmonary infiltrates can be observed. Usual treatment of these hypersensitivity reactions includes drug discontinuation and steroid administration, resulting in a good prognosis for the affected patient.
C. Noncardiogenic Pulmonary Edema
This pattern of pulmonary toxicity is a very rare and acute complication associated with the use of cytarabine, methotrexate, and cyclophosphamide. Prognosis in these instances is variable.
The definitive diagnosis of cytotoxic drug induced pulmonary toxicity is difficult since a detailed history of drug administration in the absence of other situations that may lead to pulmonary damage is required. However, the following have been reported:
A. Chest X-ray changes consistent with progressive pulmonary fibrosis; however, a patient may have a normal X-ray even when histologically demonstrated pulmonary damage is present.
B. Pulmonary histopathologic features including endothelial cell damage, fibroblast proliferation, and epithelial abnormalities
C. Arterial blood gases revealing hypoxia with hypocapnia
D. Pulmonary function abnormalities: typically a restrictive process is seen, with a reduced diffusion capacity for carbon monoxide, decreased total lung capacity, and other ventilatory defects.
The model for antineoplastic-induced pulmonary damage, both interstitial pneumonitis/pulmonary fibrosis and hypersensitivity, is bleomycin, which will be used for illustrative purposes.
A. Incidence -
Literature reports of the incidence of bleomycin pulmonary toxicity vary from 2-40% of all patients receiving the drug. It is thought that these differences in occurrence may be due to differences in risk factors in the populations studied. It has been suggested that a realistic estimate of patients affected is near 10% of those receiving bleomycin. Of this population, 10% will die due to pulmonary toxicity, resulting in an overall fatality of 1% of patients treated.
B. Risk Factors
1. Age - older patients (ie. >70) are more sensitive to bleomycin-induced pulmonary toxicity. However, younger patients, especially those receiving high cumulative doses, are still at risk.
2. Cumulative Dose - at approximately 450-500 total units, the incidence of pulmonary toxicity sharply increases. It should be noted, however, that caution should be exercised in all patients at even lower cumulative doses since contributing risk factors may be present.
3. Radiotherapy - lowest effective doses of radiotherapy should be administered since there is a synergistic phenomenon that occurs. It should be noted that this synergism is seen regardless of sequence of therapy administration (ie. radiation followed by bleomycin or bleomycin followed by radiation).
4. Oxygen Therapy - only clinically necessary oxygen supplementation should be provided to patients who have received bleomycin since this contributes to the development of pulmonary fibrosis.
5. Multidrug Regimens - close monitoring is warranted when bleomycin is administered as part of a multidrug regimen, especially those containing cyclophosphamide.
6. Route of Administration - although further documentation is required, it is thought that continuous infusion of bleomycin may decrease the incidence of pulmonary toxicity.
7. Organ Failure - Delayed excretion of bleomycin is seen in patients with renal failure. This has been reported to lead to an increased sensitivity to pulmonary toxicity. This relationship is inconclusive.
C. Treatment
No single or specific treatment is accepted as a standard in managing bleomycin-induced pulmonary toxicity. For those patients experiencing chronic pneumonitis/fibrosis, discontinuation of the drug should be considered when a rapid decline in pulmonary function (especially CO diffusion capacity) is observed. For those patients experiencing hypersensitivity reactions, bleomycin discontinuation with steroid therapy is usually recommended.
VII. OTHER ANTINEOPLASTIC AGENTS REPORTED TO INDUCE PULMONARY
DAMAGE
Several other antineoplastic drugs or drug classes have been reported in the literature to induce pulmonary damage. These include: MITOMYCIN, NITROSOUREAS (BCNU, CCNU), ALKYLATING AGENTS (BUSULFAN, CYCLOPHOSPHAMIDE, CHLORAMBUCIL, MELPHALAN), ANTIMETABOLITES (METHOTREXATE, AZATHIOPRINE, 6-MERCAPTOPURINE, CYTARABINE), VINCA ALKALOIDS, PROCARBAZINE, and FLUDARABINE.
The pulmonary toxicities associated with chemotherapy administration can pose significant problems in the management of cancer patients. Methods to prevent pulmonary toxicity and standard, effective management of the toxicity once it occurs must still be developed.
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