Continuing Education Activity

Bleomycin has approval for adult use in treating squamous cell cancer of head and neck regions, Hodgkin's lymphoma, testicular carcinoma. It is also used as a sclerosing agent for malignant pleural effusions. Off-label use includes treatment of germ cell tumors and pediatric Hodgkin's lymphoma. Bleomycin is in the cytotoxic chemotherapy class of medications. This activity describes the indications, action, and contraindications for bleomycin as a valuable agent in treating various malignant cancers. This activity will highlight the mechanism of action, adverse event profile, and other key factors (e.g., off-label uses, dosing, pharmacodynamics, pharmacokinetics, monitoring, relevant interactions) pertinent for members of the interprofessional team in the treatment of patients with various cancers.

Objectives:

• Describe the pathophysiology of bleomycin toxicity.
• Review the risk factors for developing bleomycin pulmonary toxicity.
• Summarize appropriate monitoring of bleomycin therapy.
• Outline some interprofessional team strategies for improving care coordination and communication when administering bleomycin.

Indications

Bleomycin belongs to a subfamily of glycopeptide antibiotics and is utilized primarily as an antineoplastic agent. Glycopeptide antibiotics, a drug class that includes vancomycin, are derived from bacterial species and contain glycosylated peptide cores which are thought to contribute to their mechanism of action in disrupting cellular functions. Bleomycin is part of combination cytotoxic chemotherapy regimens, including ABVD ([adriamycin], doxorubicin, bleomycin, vinblastine, dacarbazine) and BEACOPP (bleomycin, etoposide, adriamycin, cyclophosphamide, oncovin, procarbazine, prednisone). [1] It first received approval from the FDA in 1975 for the treatment of squamous cell carcinomas, malignant lymphomas, and testicular cancers. [2] Bleomycin has since received a wide array of FDA-approved therapeutic indications, including germinal cell tumors, gestational trophoblastic disease, Hodgkin lymphoma, and non-Hodgkin lymphoma. Non-FDA-approved indications include AIDS-associated Kaposi sarcoma, osteosarcoma, malignant melanoma, and advanced stages of mycosis fungoides. [3] Another non-FDA-approved indication for bleomycin is pleural effusion in patients requiring chemical pleurodesis due to metastatic disease. In pleurodesis, bleomycin can be injected into the pleural space, causing the lung to adhere to the chest wall, thus preventing the collection of fluid or air. Pleurodesis is typically reserved for use in patients with recurrent malignant effusions after more conservative management, such as repeat thoracocentesis, has proven unsuccessful in preventing effusion recurrence. [4] Due to factors discussed below, including the high risk of adverse effects with this drug, newer chemotherapy regimens including less dangerous alternatives to bleomycin and chemotherapy in combination with biologics or targeted immunotherapies are increasingly preferred in many cases. 

Mechanism of Action

The primary mechanism of action of bleomycin involves the drug's ability to oxidatively damage DNA by binding to metal ions, including iron, forming metallobleomycin complexes. [5] The reactive oxygen species generated by these complexes cause DNA single-strand and double-strand breaks between 3'-4' bonds in deoxyribose. These strand breaks produce free base propenals particularly thymine. The production of these free base propenals is known to result in cell cycle arrest at the G2 phase. Arrest in this phase halts the progression of cell replication and thus prevents tissue growth and repair. [6] As a result of these effects, chromosomal aberrations, fragments, and chromatid breaks can be observed cytologically after bleomycin exposure. Translocations can also be detected. Resistance to bleomycin in normal tissues correlates with the presence of an enzyme known as bleomycin hydrolase, a member of the cysteine proteinase family. This enzyme substitutes a terminal amine with a hydroxyl group, thereby inhibiting cytotoxic activity by reducing iron-binding and prohibiting the aforementioned cellular effects. The low concentration of hydrolase in the skin and lung tissue has contributed to the hypothesis for the unique bleomycin sensitivity found in these sites. It should be noted, however, that studies designed to discover a correlation between hydrolase levels in tumor cells and tumor sensitivity to bleomycin have not yielded definitive conclusions thus far. [7]

Administration

Bleomycin administration is via the parenteral route, as the GI tract does not significantly absorb it. Bleomycin is quickly absorbed following intramuscular, subcutaneous, intraperitoneal, or intrapleural administration and reaches peak plasma concentrations in approximately 60 minutes. The half-life of bleomycin varies between patients and depends on a variety of factors, including the route of administration. Less than 1% of the drug given intravenously binds to plasma proteins, leading to high bioavailability. [8] Although the metabolic fate of bleomycin remains poorly understood, the elimination of bleomycin has been described in several studies by first-order rate kinetics. In one such study, renal clearance of bleomycin has been strongly correlated to creatinine clearance, suggesting the importance of assessing renal function in patients exposed to the medication. Additionally, a mean plasma drug clearance approaching 70 mL/min/m2 has been calculated for bleomycin. [9] These pharmacokinetics demonstrate that bleomycin possesses a high plasma elimination rate and high urinary excretion rate.

Adverse Effects

The most common serious adverse effect of bleomycin is pulmonary toxicity, often referred to as bleomycin pulmonary toxicity or BPT. This adverse effect sometimes leads to pulmonary fibrosis, a chronic and irreversible disease with a poor prognosis. In observing the development of pulmonary fibrosis, inflammatory cell infiltration into pulmonary endothelial cells is seen after one week of exposure to bleomycin, and fibrotic changes with elevated collagen content are seen after three weeks of exposure to bleomycin. Other changes include increased expression of fibrogenic mediators such as transforming growth factor (TGF)-beta, connective tissue growth factor, and platelet-derived growth factor (PGDF)-C in endothelial cells exposed to bleomycin. Additionally, thapsigargin-induced prostaglandin I2 and nitric oxide, which are both vasodilatory agents, are seen to decrease in endothelial pneumocytes exposed to bleomycin. The administration of bleomycin is thus seen to induce functional changes in endothelial cells of the lung leading to respiratory damage, although the exact mechanism of these changes is not entirely understood. Other adverse reactions include fever, chills, faintness, chest pain, and shortness of breath. Less serious reactions include skin pigmentation changes, itching, hypogeusia, rash, nausea, vomiting, and weight loss. Some of these symptoms appear to correlate with a hypersensitivity-type reaction. [10]

Contraindications

Although absolute contraindications for bleomycin have not been established, it is crucial to assess lung disease history and renal function before administration. Because of the aforementioned numerous adverse effects of bleomycin on pulmonary tissue, patients with a history of smoking are at elevated risk for pulmonary complications due to bleomycin. In addition, elderly patients and patients with stage IV disease have demonstrated to be more likely to experience lung toxicity with bleomycin exposure. This is also true of patients who receive bolus drug delivery as opposed to continuous infusion. Patients who require supplemental oxygen administration have also been shown to be at increased risk for serious adverse effects of bleomycin exposure. Although studies regarding teratogenic effects of bleomycin exposure in humans are limited, some sources consider antineoplastic therapy during gestation to be generally harmful to fetal development, especially during the first trimester. [11]

Monitoring

As well as checking vital signs and monitoring laboratory values commonly measured during chemotherapeutic treatment, such as liver enzymes, blood cell counts, plasma proteins, and electrolytes, recommendations are that physicians acquire periodic chest imaging of patients receiving bleomycin. This is due to the high risk of pulmonary toxicity associated with the drug and the ability to detect signs of resultant fibrosis on a number of imaging modalities. Such imaging modalities include magnetic resonance imaging (MRI), computed tomography (CT), and plain film X-rays. However, it bears mentioning that according to some sources, imaging alone is considered a nonspecific test for detecting bleomycin pulmonary toxicity, and additional diagnostic tools may be required. In addition to imaging, baseline and post-treatment pulmonary function tests are often part of the patient treatment and monitoring plan. [12] Such pulmonary function tests typically involve measuring a number of respiratory characteristics including lung volume, the quantity of gas exchange, and airflow rates. 

Toxicity

Since early clinical trials in the 1960s, bleomycin pulmonary toxicity (BPT) has been a recognized adverse effect of this drug. Recent studies have described BPT rates of approximately 10% in patients taking bleomycin, with 14% of these BPT cases proving fatal. For this reason, careful monitoring for toxicities accompanied by bleomycin levels is essential. As previously described, BPT can include a serious condition known as pulmonary fibrosis. Risk factors for BPT include cumulative dose, raised creatinine, advanced age, supplemental oxygen, and reduced glomerular filtration rate. While many cases of BPT are irreversible or fatal, evidence suggests that in some surviving patients, pulmonary parameters can improve to baseline in approximately two years. Although there are no well-established therapies for reversing BPT, studies involving alternative formulations of the drug have shown promise. Numerous studies have also demonstrated that bleomycin can sometimes be substituted for less toxic chemotherapy and immunotherapy agents as a part of a multi-drug regimen, producing similar outcomes. This approach is especially useful for patients with multiple BPT risk factors and patients whose low-grade disease does not merit the risk of BPT. [11] In addition to substituting less toxic drugs for bleomycin in chemotherapy regimens, efforts to reduce the risk of pulmonary damage have also included the investigation of lipophilic bleomycin analogs, such as liblomycin. These investigations have not yielded promising results in animal models. [13] Thus, it remains to be seen as to whether the role of bleomycin will continue to diminish in the setting of chemotherapeutic treatment regimens. 

Enhancing Healthcare Team Outcomes

Due to its low therapeutic index and high toxicity, the administration of bleomycin should only be performed in dedicated treatment centers under expert supervision with an interprofessional team. Improper management of patients at high risk for adverse effects, including those with pulmonary and renal dysfunction, can lead to avoidable instances of drug-related harm and death. For these reasons, regular interprofessional communication involving online charting tools, verbal confirmation of prescribed dosages and infusion rates, and regular patient monitoring must take place. Clinicians, pharmacists, and nursing staff should be knowledgeable regarding individual patient histories and risk factors; whenever possible, these interprofessional team members should have specialty oncology training. Notably, patients with previous bleomycin treatment are predisposed to developing rapid pulmonary deterioration due to the sensitization of pulmonary tissue to oxygen. As with other chemotherapy agents, close monitoring of patients' symptoms during treatment with bleomycin is necessary. Monitoring measures include pulmonary function tests, regular lab value assessment, and periodic chest radiographs. [14] [Level 1]