New lung cancer treatment modalities and their adverse effects

New treatment modalities for lung cancer, including targeted therapy and immunotherapy, have contributed to improved patient survival rates. However, these treatments come with unique adverse effects. The nurse’s role in managing symptoms of these adverse effects requires an understanding of treatment mechanisms of action and common side effects.

Most oncogenic drivers (gene mutations responsible for the initiation and maintenance of cancer) with corresponding Food and Drug Administration (FDA)–approved molecular targeted therapies are found in non-small cell lung cancer (NSCLC), adenocarcinoma subtype. Significantly fewer FDA-approved targeted therapies exist to treat squamous cell subtype. This article focuses on treatment of meta­static NSCLC.

The FDA has approved several types of targeted therapies for treating lung cancer, including angiogenesis inhibitors, signal transduction inhibitors, and immunotherapies. Each type of targeted therapy has unique and distinct adverse effect profiles. (See Targeted therapy defined.)

Angiogenesis inhibitors

Tumors require a blood supply for continued growth. Tumor angiogenesis (the formation and continued growth of blood vessels into tumors) plays a crucial role in tumor growth, progression, and metastasis. Vascular endothelial growth factor (VEGF), a signaling protein, stimulates the formation of new blood vessels and is overexpressed in tumors. Angiogenesis inhibitors (including bevacizumab and ramucirumab) block VEGF action. Providers may use these anti-VEGF therapies as first-line treatment or along with other targeted therapies. The distinctive adverse effects of angiogenesis inhibitors stem from targeting blood vessel formation and growth rather than the tumor itself. (See Angiogenesis inhibitor adverse effects.)

Nursing considerations

Adverse effects of angiogenesis inhibitors include hypertension, slow-healing wounds, proteinuria, increased risk of internal bleeding. Rarely, these treatments result in intestinal perforation. Education before and during therapy includes encouraging patients to keep a blood pressure log and report abnormal readings. In addition, they should be instructed to notify their nurse or provider if they experience any bleeding or bruising issues or nonhealing wounds. Patients should consult with their oncology team before any surgery while receiving angiogenesis inhibitor therapy.

Signal transducing inhibitors

Signal transduction transmits cellular signals from outside the cell to inside to effect an appropriate response. Advances in the knowledge of signal transduction pathways have allowed for the development of a new class of drugs, signal transduction inhibitors, which block the activities of these pathways. Researchers have identified many targetable pathways in the treatment of lung cancer, and several drugs targeting these pathways have been developed but are beyond the scope of this article. The most common signal transducing inhibitors used to treat lung cancer belong to a class of drugs that target the epidermal growth factor (EGF)/epidermal growth factor receptor (EGFR) signaling pathway cascade.

Signaling pathway cascade

As the EGF protein circulates in the blood, it attaches to the EGFR (or ligand), which activates the EGFR cascade. EGFR is a type of tyrosine kinase (TK) receptor. TKs play a critical role in cell signaling. Once bound to its ligand, EGFR-TK can phosphorylate (activate) other proteins, allowing the signal to go into the cell nucleus and aid gene transcription. Mutations of any of the proteins in this tightly controlled system may affect the regulation of cell growth processes, resulting in uncontrolled cell growth or cancer.
TK inhibitors (TKIs), a group of pharmacologic agents, disrupt the signal transduction pathways of protein kinases via several modes. The FDA has approved more than 50 TKIs, but this article focuses on the most common EGFR-TKIs effective for treating metastatic NSCLC (erlotinib, afatinib, gefitinib, osimertinib, and dacomitinib). EGFR-TKIs are the primary treatment option for NSCLCs that harbor an EGFR mutation.

Nursing considerations

Successful management of treatment-related adverse events requires knowledge of the standardized toxicity grading criteria. Although EGFR-TKIs may cause anorexia, alopecia, and stomatitis, the most common adverse effects include dermatologic toxicity and diarrhea. Less common but serious adverse effects include hepatotoxicity and interstitial lung disease. (See EGFR-TKI adverse effects.)

Dermatologic toxicity.

Potentially painful acneiform rash, the most common dermatologic toxicity (90% of patients), typically appears on the face, scalp, upper back, and chest. Other symptoms include xerosis (abnormally dry skin or membranes [mouth, eyes]) and pruritus (itching). Paronychia (finger or toenail inflammation) can develop when bacteria enter broken skin near the cuticle and nail fold, resulting in infection.

Patient education includes discussion of good skincare, daily use of a light lotion and antiseptic-containing soap substitute, and minimal sun exposure. Toxicity prevention, early recognition, and intervention help minimize subsequent bacterial infections and mitigate debilitating effects. Depending on the severity or grading of the toxicity, treatment recommendations include good skincare with or without the use of prophylactic antibiotics, steroids with or without antibiotics, and EGFR-TKI interruptions.

Diarrhea.

Diarrhea, the second most common (20% to 90% of patients) adverse effect of EGFR-TKIs, typically occurs within the first 2 weeks of treatment. The etiology is unclear but electrolyte imbalances may occur without appropriate management. Most patients experience lower grades of toxicity but long durations of Grades 1 and 2 may cause significant problems.

Diarrhea management begins with pre-treatment patient education. Dietary recommendations include increasing daily fluid intake, eating frequent small meals, and avoiding fried, high-fiber, greasy, and spicy foods. Depending on the toxicity grade, treatment includes dietary management, loperamide, hospitalization, parenteral hydration, and EGFR-TKI interruption. No evidence exists for the efficacy of octreotide in EGFR-TKI–induced diarrhea.

Hepatotoxicity.

Hepatotoxicity, a less-frequent adverse effect, occurs in about 10% of patients. Most have no symptoms and don’t require management. Clinical manifestations include transitional mild-to-moderate increases in alanine transaminase, aspartate aminotransferase, and bilirubin. Most cases don’t require treatment interruption. In the presence of Grade 3 toxicity, temporary EGFR-TKI interruption can be effective. Treatment restart can occur when the toxicity reaches ≤Grade 1. However, if ≥Grade 3 recurs, the treatment dose may require modification.

Interstitial lung disease.

Interstitial lung disease, a rare (0–5.7%) adverse effect, is fatal in approximately one-third of patients. Symptoms include acute onset of dyspnea, hypoxia, cough, and possibly fever within the first 4 weeks of treatment. Prompt recognition ensures proper treatment, so patients should immediately contact their provider with any of these symptoms. The provider will discontinue EGFR-TKI therapy until ruling out infection or another etiology. If ruled out, the provider may order high-dose steroid therapy and withhold EGFR-TKI treatment indefinitely.

Immune checkpoint inhibitors

Immunotherapies trigger a patient’s immune system to destroy cancer cells. They’re primarily used to strengthen and regulate the immune system and microenvironment so immune cells can attack and clear tumor cells. Many immune checkpoint inhibitors (ICIs), the most common type of immunotherapy used to treat lung cancer, involve inhibiting the interaction of the PD-L1 protein and the PD-1 receptors on the T-cell. PD-L1 and PD-1 interaction prevents the immune system from recognizing and attacking cancer cells. Current FDA-approved lung cancer immunotherapy drugs disrupt that interaction, so T-cells can recognize and respond to cancer cells.

Durvalumab and atezolizumab target the PD-L1 protein, and nivolumab and pembrolizumab target the PD-1 receptor. Ipilimumab, another immunotherapy, can block the CTLA4 pathway so the body can ramp up the number of immune cells available to respond to cancer cells.

Nursing considerations

ICIs rely on increased use of the body’s immune system to identify and treat cancer. They upregulate the body’s immune system so much that it begins attacking healthy cells, resulting in immune-related adverse events (irAEs). irAEs can occur in any organ system at any point after treatment begins, even after discontinuation. (See Immune-related adverse events.)

The most commonly affected organs are the lungs, GI tract, thyroid, liver, and skin. Most irAEs are mild to moderate, but severe irAEs can be life-threatening. Relative to chemotherapy-induced toxicities, irAEs have a delayed onset and a prolonged duration. Unlike chemotherapy-induced toxicities, irAEs require early and prompt intervention for patient safety. Treatment may include dose reduction or interruption, permanent ICI cessation, and systemic corticosteroid therapy. With prompt detection and intervention, most patients can remain on ICI therapy. Although severe irAEs are rare, they can result in harm if left untreated.

Adverse events differ among specific immunotherapy agents. Many common ICIs (nivolumab, pembrolizumab, atezolizumab, and ipilimumab) may cause colitis/diarrhea, dermatitis, endocrinopathies (hyper- or hypothyroidism and hypophysitis), hepatitis, and pneumonitis. These irAEs are managed differently and more promptly relative to other targeted therapies and chemotherapy.

Nurses should contact the oncology team if the patient exhibits a Grade 2 or higher adverse event while receiving immunotherapy. Nurses also should provide patient education to ensure prompt recognition of irAE signs and symptoms and immediate communication with providers.

Understand the basics

Understanding the basics of new lung cancer treatment modalities helps nurses perform proper assessments and recognize adverse effects that may impact patient quality of life and ongoing therapy. Providing patient education and communicating promptly with a patient’s oncology team aid care coordination in all settings and improve patient outcomes.

Monica L. Beck is an assistant professor at the University of Alabama Huntsville College of Nursing in Huntsville. Haley Hoy is a professor at the University of Alabama Huntsville College of Nursing. Rachel McMahill is a clinical nurse navigator at Clearview Cancer Center in Huntsville, Alabama.

American Nurse Journal. 2023; 18(2). Doi: 10.51256/ANJ022306

Key words: lung cancer, metastatic non-small cell lung cancer (NSCLC), targeted therapy, immunotherapy, treatment adverse effects

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