Continuing Education Activity

Bleomycin has approval for adult use in the treatment of 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 the treatment of 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. Bleomycin is part of combination cytotoxic chemotherapy regimens, including ABVD ([adriamycin], doxorubicin, bleomycin, vinblastine, dacarbazine). It first received approval from the FDA in 1975 for the treatment of squamous cell carcinomas, malignant lymphomas, and testicular cancers. 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. 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. Due to factors discussed below, including the high risk of adverse effects with this drug, chemotherapy regimens, including less dangerous alternatives to bleomycin, are increasingly preferred in many cases.[1][2][3][4]

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. 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 of thymine, causing cell cycle arrest at the G2 phase. Chromosomal aberrations, fragments, chromatid breaks, and translocations can be observed cytologically after bleomycin exposure. Resistance to bleomycin in normal tissues correlates with the presence of bleomycin hydrolase enzyme, a member of the cysteine proteinase family. This enzyme substitutes a terminal amine with a hydroxyl group, thereby inhibiting cytotoxic activity by reducing the binding of iron. 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.[5][6][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. Although the metabolic fate of bleomycin remains poorly understood, the elimination of bleomycin has been described in several studies by first-order rate kinetics with a mean plasma drug clearance approaching 70 mL/min/m2. These pharmacokinetics demonstrate that bleomycin possesses a high plasma elimination rate and high urinary excretion rate.[8][9]

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. Administration of bleomycin is likely to induce functional changes in endothelial cells of the lung, although the exact mechanism of these changes 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. Patients with a history of smoking are at elevated risk for pulmonary complications due to bleomycin. Additionally, 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, and those who require supplemental oxygen delivery. 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 monitoring laboratory values commonly measured during chemotherapeutic treatment, such as liver enzymes, blood counts, plasma proteins, and electrolytes, recommendations are that physicians acquire periodic chest imaging of patients receiving bleomycin. Methods for imaging include magnetic resonance imaging (MRI), computed tomography (CT), and plain film X-rays. It bears mentioning, however, that 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]

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 level 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]

Enhancing Healthcare Team Outcomes

Due to its low therapeutic index and high toxicity, the administration of bleomycin should only be in dedicated treatment centers with expert supervision. 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 must take place. Physicians, pharmacists, and nursing staff should be knowledgable regarding individual patient histories and risk factors. 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.[13] [Level 1]