Lung cancer is the second most common malignancy and the leading cause of cancer death in the U.S and worldwide (1, 2). The American Cancer Society estimates 238,340 new diagnoses and 127,000 lung cancer-related deaths in 2023 (2). Although these numbers highlight the significant disease burden of lung cancer worldwide, there are reasons for optimism. From 1999-2019, the age-adjusted annual rate of new lung cancer decreased from 70.8 to 52.9 per 100,000 people, and the age-adjusted annual rate of death decreased from 55.4 to 33.4 per 100,000 people (3). This downturn in the rate of new cancers is likely due to the decline in smoking prevalence (1). Moreover, due to advancements in chemotherapeutics, the 5-year relative survival rate has increased from 11.7% in 1975 to 22.9% in 2018 (4).

As patients live longer due to advancements in early cancer detection and effective anticancer therapies, other medical challenges arise. One such challenge is the development of coexistent comorbidities, paramount of which is CVD. CVD has been identified as the second leading cause of death in patients with NSCLC (5). In this paper, we review the shared risks factors for developing lung cancer and CVD and discuss in depth the therapies for lung cancer that have adverse CV effects. Furthermore, we explore strategies for prevention, management, and surveillance of CVD in patients with NSCLC and SCLC.

CVD and lung cancer share a number of risk factors: smoking, hypertension, diabetes mellitus (DM), advanced age, obesity, and racial and socioeconomic status (SES) (6–9). Preexisting CV comorbidities in lung cancer patients are common given these overlapping risk factors (10, 11). A population-based study found hypertension, arrhythmia, coronary artery disease (CAD), dyslipidemia, and heart failure (HF) to be the most prevalent CV conditions in patients with lung and bronchus cancer (10). Coexistent CVD portends worse prognosis in these patients (10). Patients with NSCLC and comorbid HF, myocardial infarction (MI), or cardiac arrhythmias had the lowest overall survival (11). Interestingly, lung cancer was found to be an independent risk factor for the development of CVD, specifically CAD and MI, in a meta-analysis (6). Additionally, low SES is a well-documented risk factor for both lung cancer and CVD (9).

There are notable health inequities observed in lung cancer and CVD across various races and SES groups (9). In the United States, non-Caucasians are at an increased risk of developing lung cancer and dying from CVD (9). African Americans have 50-70% greater risk of developing HF compared with Caucasians, and African American men are 12% more likely to develop lung cancer compared with Caucasian men (12, 13). The incidence rate for lung cancer in African American population has been estimated to be 71.2/100,000 compared with 35.1–65./100,000 in other racial groups (14). Lower SES has been associated with increased smoking, lack of exercise, and lower life expectancy (15). One pooled analysis of case-control studies found a correlation between low SES and lung cancer. The highest effect was observed in men in the lowest vs. highest SES category: calculated OR for lung cancer was 1.84, 95% CI: 1.61–2.09. For women, OR was 1.54, 95% CI: 1.20–1.98 (16). Population-based studies have yielded similar results with CVD showing that lower income levels, lower educational attainment, and unemployment increase the risk of developing CVD and lead to worse clinical outcomes (17). These studies highlight the complex interrelationship between CVD and lung cancer.

Antineoplastic regimens for both NSCLC and SCLC, including immune checkpoint inhibitors, targeted therapies, cytotoxic chemotherapy, or mediastinal radiation can have profound CV effects. Arrhythmia, left ventricular (LV) dysfunction, HF, hypertension, ischemia/MI, pulmonary hypertension, thromboembolic disease, and pericarditis have been reported as side effects associated with anticancer treatment (30). Common CV adverse effects of anticancer regimens for NSCLC and SCLC are summarized in Table 1 .

Given the high prevalence of preexisting CVD and CV risk factors in patients with lung cancer, management of these patients is particularly challenging. Patients with underlying CV conditions should have them optimally managed prior to starting cancer treatment. Smoking cessation using a combination of behavioral interventions together with pharmacotherapy should be recommended (75). Underlying hypertension, DM, and hyperlipidemia should be optimally managed prior to, during, and after cancer treatment. Cancer survivors should continue to be screened for modifiable CV risk factors as these patients are more likely to be underdiagnosed and undertreated compared with the general population (76, 77). Patients with a history of cancer are less likely to receive cardioprotective therapies, especially antiplatelets and statins (77).

Management of BP is paramount because hypertension is highly prevalent in lung cancer patients and accounts for more ASCVD deaths than any other modifiable risk factor (10, 11, 75). The 2019 ACC/AHA guidelines recommend controlling BP to <130/80 for patients with hypertension and ASCVD or 10-year ASCVD risk ≥10% (75). These recommendations for BP targets are extrapolated from the general population and not well-studied in patients with cancer. Initial management of hypertension involves a low sodium diet and a minimum of 150 minutes of moderate-intensity, or 75 minutes of vigorous-intensity, aerobic exercise per week (75). The choice of antihypertensive regimen is dependent on patient characteristics and comorbidities similar to the general population (78). Patients with known diabetes, diabetic nephropathy, proteinuria, or chronic kidney disease (CKD) should be managed with an angiotensin converting enzyme inhibitors (ACE-I) or angiotensin II receptor blockers (ARB). Patients with CHF and LV systolic dysfunction should receive guideline-directed medical therapy, i.e. ACE-I/ARB/angiotensin receptor-neprolysin inhibitor (ARNI), sodium-glucose cotransporter-2 (SGLT2) inhibitor, beta blocker (BB), and mineralocorticoid receptor antagonist (MRA) as tolerated. For those with CAD, BB, ACE-I/ARB, and/or nitrates are considered (78). Certain classes of antihypertensive medications are preferred depending on the anticancer regimen used. For example, for VEGFI-induced hypertension, ACE-I/ARB, dihydropyridine calcium channel blocker (CCB), and/or thiazide/thiazide-like diuretic are first-line agents (78, 79).

The European Society of Medical Oncology (ESMO) 2020 guidelines suggest that patients receiving cardiotoxic anticancer therapies, e.g., anthracyclines and/or trastuzumab, are considered to have stage A HF and thus should be treated with ACE-I/ARB and/or beta blockers (e.g., carvedilol or nebivolol) to protect against cardiotoxicity (80). The 2022 ACC/AHA/HFSA guidelines recommend that patients with type 2 DM and history of ASCVD or high ASCVD risk receive SGLT2 inhibitors to prevent hospitalization for HF (81). Stage B HF patients with LVEF < 40% should be managed with ACE-I/ARB and beta blocker (81).

Hyperlipidemia is another highly prevalent CV risk factor among lung cancer patients (11). Similar to hypertension, the current recommendations for lipid screening and management are extrapolated from the general population due to lack of specific data in cancer patients. The 2018 ACC/AHA guidelines recommend routinely screening patients between the ages of 40-75 and consider it reasonable to screen patients aged 20-39 every 4 to 6 years. There are currently no guidelines to direct the timing of screening in patients with a history of cancer or those actively receiving cancer treatment. Initial steps for the management of hyperlipidemia include dietary and lifestyle changes (75). Statins are the cornerstone of pharmacotherapy management for dyslipidemia. Statin initiation is currently recommended in primary prevention for patients with an LDL-C ≥190 mg/dL, patients between 40 and 75 years of age with DM, and patients between 40 and 75 years of age and 10-year ASCVD risk ≥20% (75). High-intensity statin therapy is indicated for secondary prevention of ASCVD. Non-statin therapies, such as ezetimibe or proprotein convertase subtilisin/kexin type 9 serine protease (PCSK9) inhibitors, should be started in patients with established ASCVD on maximally tolerated statin therapy with an LDL-C ≥70 mg/dL (82). There is evidence that hyperlipidemia contributes to inflammation in cancer patients. ESMO 2020 guidelines recommend that patients be continued on treatment for hyperlipidemia while receiving chemotherapy and to consider initiation of statin in patients with concomitant CAD (80).

For patients with lung cancer who will receive cardiotoxic anticancer therapies, a multidisciplinary collaboration among cardiology, oncology, radiation oncology, PCP, and pharmacology is essential to minimize CV toxicity while allowing cancer treatment to proceed without interruption (65, 70, 80). For most lung cancer patients, it is recommended to perform a baseline CV risk assessment and evaluation, which includes physical examination, BP measurement, ECG, lipid panel and hemoglobin A1c (HbA1c), and smoking status assessment. Since patients with cancer undergo serial blood draws, lipid profile and HbA1c can be easily added for screening and monitoring. As discussed above, modifiable CV risk factors should be optimally controlled prior to initiation of anticancer therapy (65, 70, 80). Patients with lung cancer undergo non-gated chest CT scans for cancer staging and surveillance. Incidental detection of coronary artery calcification is prevalent and can be helpful in providing CAD risk stratification and guiding prevention strategies (83). BP measurements that are routinely performed at oncology visits should be assessed and followed for the screening and monitoring of hypertension (84). In addition, established CVD should be managed according to relevant ACC/AHA and ESC guidelines before, during, and after antineoplastic therapy (65, 70, 80).

For patients with lung cancer receiving ICI, strategies for outpatient monitoring of ICI myocarditis are not well-defined. Most cardio-oncology programs use a symptom-based approach and do not routinely check biomarkers and echocardiogram (echo) on all patients receiving ICI because of the relatively low incidence (0.04% to 1.14%) of ICI myocarditis (85, 86). Lee Chuy et al. monitored ECG and troponin levels in all patients treated with combination ICI therapy (87). Among 76 consecutive patients, no overt or subclinical myocarditis was detected (87). However, it is generally recommended to check a baseline ECG and measure biomarkers (BNP and cardiac troponin (cTn)) prior to ICI therapy initiation (70). Baseline echo can be considered in high-risk patients before starting ICI. Risk factors for developing ICI cardiotoxicity include treatment with dual ICI (e.g., anti–CTLA-4 plus anti–PD-1) or ICI in combination with another cardiotoxic agent, noncardiac immune-related adverse events, and prior history of CVD. Currently, there are international efforts to better understand the risk factors and the full clinical spectrum of ICI myocarditis (88). It is recommended to repeat CV assessment every 6-12 months in high-risk patients who require long-term ICI treatment (70).

For patients presenting with a clinical suspicion for ICI myocarditis, prompt initiation of workup, which includes ECG, troponin, BNP, CRP, echo, cardiac MRI, and consideration of endomyocardial biopsy, is important (80, 89). The presence of concomitant noncardiac immune-related adverse events, such as myositis or nephritis, in addition to cardiac symptoms raises the clinical suspicion of ICI myocarditis. While pursuing the diagnostic workup, it is generally recommended to start steroids (1000 mg IV methylprednisolone daily for 3 days) (89). In a case series of clinically suspected ICI myocarditis (n= 126), those patients who received corticosteroids within 24 hours of presentation regardless of dose showed the best outcome, while those who received corticosteroids after 72 hours showed the worst outcome (90). Additionally, high-dose corticosteroid administration was associated with a 73% lower risk of major adverse cardiac events (90). If the diagnostic workup reveals definite or probable myocarditis, steroids should be continued and tapered over at least 4-6 weeks depending on clinical and biomarker response (89).

Before starting VEGFI therapy, patients with lung cancer should be informed about the risk of developing new-onset or worsening hypertension so that they can participate in BP monitoring. BP measurement must be obtained in all patients at baseline and every subsequent clinical visit (54, 70, 78). This is necessary not only to detect an exaggerated hypertensive response with VEGFI, but also to identify patients with preexisting hypertension who could benefit from early BP management (54, 70, 78). In addition, regular home BP monitoring (HBPM) during the first cycle, after each increase of VEGFI dose, and every 2-3 weeks thereafter is recommended (70). In patients treated with VEGFI at elevated risk of QTc prolongation (e.g., vandetanib, sorafenib, and sunitinib), ECG should be performed monthly during the first 3 months and every 3-6 months thereafter (70). Baseline echo is recommended in high- and very high-risk patients treated with VEGFI to rule out underlying cardiomyopathy. Serial follow-up echos should be considered in moderate- and high-risk patients (70). The role of cardiac biomarkers in VEGFI cardiotoxicity detection is currently not well-defined.

Similar to other anticancer regimens above, lung cancer patients receiving ALK or EGFR inhibitor should undergo baseline CV risk assessment (70). Because osimertinib has the potential to cause clinical HF or asymptomatic LV dysfunction, baseline echo is recommended in all patients before starting osimertinib (70). Serial echo imaging every 3 months can be considered during therapy. For early detection of the hypertensive side effect, HBPM should be considered for patients treated with brigatinib, crizotinib, or lorlatinib (70). Since ALK inhibitor therapy is associated with QT prolongation and conduction disease, ECG should be considered 4 weeks after starting therapy and every 3-6 months during treatment (70). Guidelines for the prevention and monitoring of anthracycline induced cardiotoxicity have been extensively reviewed elsewhere in previous literature. Table 5 summarizes the key recommendations for the surveillance of cardiotoxicity during treatment for lung cancer.

In patients with lung cancer, concomitant CV comorbidities are exceedingly common due to overlapping risk factors: smoking, hypertension, DM, advanced age, and obesity. Coexistent CVD portends poor overall and oncologic prognosis in patients with lung cancer. This review highlights the complex interrelationship between CVD and lung cancer. Furthermore, many of the anticancer regimens used for the treatment of NSCLC and SCLC can potentially cause adverse CV effects. To improve the overall survival of lung cancer patients, it is critical to understand the cardiotoxicities associated with modern treatment regimens. More data are needed on how to prevent, surveil, and treat CV adverse effects due to novel anticancer therapies. A multidisciplinary collaboration among cardiology, oncology, radiation oncology, PCP, and pharmacology is critical to minimize CV toxicity while allowing cancer treatment to proceed without interruption.

MDJ: Writing – original draft, Writing – review & editing. AC: Writing – original draft, Writing – review & editing. TG: Writing – original draft, Writing – review & editing. MK: Supervision, Writing – review & editing. AK: Conceptualization, Supervision, Writing – review & editing.