Pulmonary Complications of Systemic Anticancer Therapies - An Overview

Introduction

A variety of anticancer medications can induce pulmonary toxicity; cytotoxic agents are the medications that are primarily linked to pulmonary toxicity. The administration of chemotherapeutic agents such as Bleomycin, Methotrexate, Cytosine arabinoside, Mitomycin, and Nitrosoureas, particularly Carmustine. The immunotherapeutic drugs also carry the potential danger of pneumonopathy. The incidence and course of the phenomenon are even more unexpected compared to conventional cytotoxic drugs; the mentioned treatment exhibits a higher efficacy.

What Are the Potential Hazards of Pneumotoxicity?

The potential hazards associated with pneumo toxicity are present, although it is important to note that the manifestation of these risks may vary among different patients.

• Severe pulmonary complications resulting from exposure to any causative substance.

• In contrast to thoracic radiation therapy, which typically has a limited impact on the segment of the pulmonary organ that falls within the scope of radiation exposure, as well as the pharmaceutical substances administered throughout the body. Frequently, these agents induce diffuse pneumonitis or other alterations.

• While drug-induced lung injury is less common than respiratory pneumonia, it can nevertheless occur.

• The condition can become severe and pose a significant risk to a patient's life, especially if it is not identified in its early stages.

• Corticosteroids are frequently employed in treating RP and have demonstrated potential efficacy.

• Radiation-induced damage and drug-induced lung toxicity may manifest together when it becomes feasible to cease the use of the problematic agent. These are several systemic agents that are linked to pulmonary toxicity.

What Is Chemotherapy for Cytotoxicity?

Cytotoxicity chemotherapy is a medical treatment that involves the use of drugs to treat cancer. The various medicines include:

• Bleomycin: Bleomycin, a chemotherapy medication, is widely recognized for its propensity to cause pulmonary injury and its notable affinity for lung tissue. The occurrence of pneumonopathy encompasses pneumonitis and chronic or permanent fibrosis. These types of malignancies primarily affect younger individuals who have less pre-existing medical conditions compared to those with lung cancer. There exist numerous similarities between Bleomycin lung injury and radiation lung injury, encompassing the presence of both pneumonitic and fibrotic phases, as well as a time lag of several weeks to months between the administration of treatment and the detection of harmful effects. Lung infiltrates generated by Bleomycin can exhibit diffuseness; however, they may also be confined to the basilar and subpleural regions of the lungs. Similar to radiation, dyspnea is the predominant symptom of Bleomycin-induced lung damage. However, symptoms such as cough and fever also manifest in affected individuals.

Alongside the comorbidities associated with age and cumulative Bleomycin dosage, renal insufficiency represents a significant risk factor due to the renal excretion of Bleomycin. This issue is especially problematic in individuals who may be undergoing therapy with nephrotoxic drugs, such as Cisplatin, which is frequently administered in conjunction with Bleomycin for the management of germ-cell tumors. Cigarette smoking, along with a prior history of thoracic radiation, are other factors that contribute to increased risk. There exists a significant correlation between Bleomycin-induced pulmonary toxicity.

The potential risks associated with exposure to elevated oxygen levels, particularly in the context of a surgical intervention, should be considered. It is required that the patients and their surgical teams are aware of minimizing the fraction of inspired oxygen (FiO2) to the minimum required throughout any medical treatment. It is strongly recommended that patients exercise great caution when considering the elective prescription of supplementary oxygen for patients receiving treatment with Bleomycin. This is particularly important for those who are now undergoing or have recently completed Bleomycin therapy, as well as those with a confirmed diagnosis of Bleomycin pneumonopathy.

The majority of patients get a full or nearly full recovery. Certain instances of steroid-responsive Bleomycin pneumonitis or fibrosis may indicate an initial hypersensitivity, resembling episodes of bronchiolitis obliterans with organizing pneumonia. Following Bleomycin chemotherapy, those who have undergone treatment may experience notable decreases in pulmonary function for around six months. Several chemotherapeutic agents from different classes have been linked to lung injury. Usually, these agents elicit interstitial pneumonitis.

Which Are the Other Drugs Involved?

• Methotrexate: It is the antimetabolite that exhibits the strongest correlation with pneumonopathy. Gemcitabine, a substance frequently used in contemporary medical practice, is infrequently linked to pneumonitis when administered as a standalone treatment. However, it has the potential to enhance the development of drug-induced pneumonopathy when taken with other medications that have pneumotaxic properties. The concurrent administration of Gemcitabine with a taxane has been observed to result in an elevated risk of pulmonary damage in comparison to the individual use of either drug.

Pneumonopathy can also be linked to the administration of alkylating drugs, especially when administered in high dosages for bone marrow or stem cell transplant procedures. Determining the specific impact of these drugs in the context of transplantation poses challenges due to various additional factors that may potentially affect the lungs. Pulmonary toxicity is regarded as a potential limitation in terms of dosage, and apprehensions regarding this issue have restricted the utilization of the entire class of drugs. The characteristic manifestation of lung damage is a gradual development of pulmonary fibrosis, which is influenced by both age and the total amount of exposure. This disorder does not seem to be responsive to steroids.

• Mitomycin: Mitomycin is an alternative chemotherapeutic to induce pulmonary toxicity, manifesting in many forms, such as the development of pleural effusions. The occurrence of lung toxicity generated by Mitomycin is challenging to anticipate and does not exhibit a clear correlation with dosage. It is widely believed that pulmonary toxicity generated by Mitomycin is typically amenable to steroid treatment.

• Anthracycline: It is a medication widely recognized for its potential to cause cardiac complications, although its association with direct lung harm is comparatively less established. Nevertheless, the coadministration of Anthracyclines and concurrent thoracic radiation has the potential to induce significant pneumonitis. Concurrent and sequential chemoradiotherapy, incorporating Doxorubicin, for small cell lung cancer was prematurely terminated due to a significant occurrence of fatal pneumonopathy events.

• Taxanes: The taxanes exhibit a comparable level of risk for causing direct lung injury. Additionally, weekly administration schedules of taxanes may be more likely to cause pneumo toxicity than every three-week schedule. The concurrent treatment regimens involving taxanes and radiotherapy may carry a slightly higher risk of pneumonitis than those involving Cisplatin and radiotherapy.

Biologically targeted agents refer to therapeutic substances designed to specifically interact with and modulate molecular targets involved in biological processes. These agents are developed based on a deep understanding.

In contemporary medical practice, alternative therapeutic agents targeting cancer cells through processes that do not rely solely on inducing DNA damage are utilized, reducing reliance on traditional cytotoxic medicines like chemotherapy and radiotherapy. The pharmaceutical agents in question can be classified as either small-molecule inhibitors targeting intracytoplasmic or intranuclear biologic molecules or as antibodies specifically designed to bind to receptors located on tumor cells or vascular cells within or near the tumor.

• Tyrosine Kinase Inhibitor: Tyrosine kinase inhibitors, such as Gefitinib and Erlotinib, have been extensively investigated as targeted therapy targeting the intracytoplasmic segment of the epidermal growth factor receptor (EGFR). Due to their predominant application in combating lung cancer, considerable scholarly attention has been directed towards investigating the impact of orally delivered pharmaceuticals on pulmonary function.

The tyrosine kinase inhibitors (TKIs) have the potential to induce lung damage, exhibiting a similar pattern to the antiEGFR drugs. Conversely, some inhibitors target many kinases, including those present in tumor cells and those found in vascular cells associated with tumors, such as Sunitinib. This includes the presence of interstitial lung infiltrates, a ground-glass appearance, and dyspnea as the primary symptom. Additionally, it possesses the ability to induce pulmonary hypertension directly.

Idelalisib, a recently developed tyrosine kinase inhibitor (TKI), has shown efficacy in targeting PI3K and has received approval for the treatment of specific recurring B-cell hematologic malignancies; it has been linked to a relatively elevated incidence of pneumotoxicity.

Less frequent occurrences include acute or subacute pneumonitis and other indications of direct pulmonary harm. Vascular-targeted antibodies, such as Bevacizumab, which specifically target vascular endothelial growth factor, have been found to have a potential risk of pulmonary hemorrhage. This may be attributed to the presence of a bronchovascular fistula close to the visible tumor. Thalidomide and Lenalidomide, which are intricate drugs with antiangiogenic and immunomodulatory properties, have been linked to venous thromboembolic illness and pulmonary emboli, as direct lung harm is not very prevalent while using these medicines.

• mTOR: The drugs targeting the mammalian Rapamycin (mTOR) target may be associated with pneumonitis. The cause of this phenomenon remains uncertain. The clinicopathologic manifestations encompass interstitial pneumonitis, which may or may not be accompanied by fibrosis, bronchiolitis obliterans organizing pneumonia, or alveolar hemorrhage. Lung biopsies, bronchoalveolar lavage results, and the documented clinical improvement following corticosteroid treatment substantiate the presence of immune-mediated processes of pneumonitis. Radiographic signs indicative of drug-induced pneumonitis were observed in patients who were administered temsirolimus for the treatment of advanced neuroendocrine tumors and endometrial cancer. The patients exhibiting radiographic alterations demonstrated clinical manifestations of pneumonitis, and in several instances, pharmacological therapy was sustained without exacerbating the pneumonitis.

• Steroid Treatment: The biologic-drug-induced pneumopathy is diagnosed in patients exhibiting dyspnea. The implementation of steroids should be considered in the majority of instances involving biological drug-induced effects.Pneumonitis is sensitive to steroid treatment, so the appropriate timing to initiate a challenge must be determined. Individualizing therapy with an alternative agent within a comparable pharmacological class is significant.

What Are Pulmonary Toxicity Associated With Immunotherapy?

Immunomodulatory drugs with anticancer properties represent one of the first categories of biological treatments. In the past, the primary immunotherapeutics employed were interleukins and interferons. However, their usage has significantly declined due to concerns regarding their toxicity profile. Pneumonopathy, linked to interleukins or interferons, is known to occur infrequently. Additionally, there are instances of noncardiogenic pulmonary edema syndrome.

Over recent years, there has been a significant surge in attention and numerous indications for using monoclonal antibody therapeutics targeting immune-checkpoint proteins found on T lymphocytes or antigen-presenting cells. Significantly, they encompass antibodies like Ipilimumab that target the CTLA-4 receptor on cytotoxic T-cells or the PD-1 receptor on T cells.

The presence of these antibodies has been linked to an increased likelihood of noninfectious pneumonitis and several other toxicities such as dermatologic, gastrointestinal, neurologic, endocrinologic, and others. Similar to other drug-induced pneumonitis syndromes, this condition manifests with interstitial infiltrates that commonly appear as ground-glass opacities. In extreme cases, it can lead to the development of significant dyspnea. The available data on the absolute risk of pneumonitis associated with these drugs is still being developed. A proposition exists that increased doses of Ipilimumab may have a greater propensity to induce pneumonitis. The duration of immune-checkpoint inhibitor pneumonitis exhibits significant variability, as seen by studies from as little as one week after initiating the treatment to one year or even longer after its commencement.

The management of pneumonitis generated by immunotherapy is more complex than pneumonitis induced by radiation or other medications. This is mostly because the main treatment for immunotherapy-induced pneumonitis, corticosteroids, is believed to counteract the anticancer effects of the causative agent. Patients with grade 3 or higher immunotherapy-induced pneumonitis should quit the medication completely and get treatment using high-dose steroids, following a similar approach as indicated for small-molecule medicines. However, there is a lack of certainty regarding managing immunotherapy-induced pneumonitis in patients classified as grade 1 to 2. The potential course of action could entail a temporary cessation of the medication, followed by a resumption of therapy with a reduced dosage after a course of steroids. A patient who has experienced pneumonitis, even of a mild nature, as a result of immunotherapy should only be considered for rechallenge with great care and careful consideration of the potential for a recurrence of severe pneumonitis. The potential hazards associated with the therapy must be meticulously weighed against the anticipated advantages, which might be remarkable in the context of immunotherapy.

Conclusion

The lungs are frequently the focus of adverse medication reactions brought on by antineoplastic drugs, which are a prevalent type of iatrogenic damage. While certain reactions (such as those caused by Bleomycin) depend on the total dose, most are unique and unpredictable.

The most prevalent lung toxicity patterns include interstitial pneumonitis, organizing pneumonia, and diffuse alveolar damage. The risk of lung toxicity associated with each medicine is typically low, and the adverse reaction to the respiratory system is typically reversible with drug withdrawal, even though there have been fatalities present.