Lung Cancer

Introduction

Lung cancer is the second most common malignancy in males and females, surpassed in incidence only by prostate and breast cancer, respectively. Moreover, it is the most common cause of cancer death in all genders, in part because it is diagnosed at more advanced stages and in part because management is less successful than breast and prostate cancer. In the US, mortality from lung cancer represents about thirty percent of all cancer-related deaths.

Lung cancer is divided into two main types, non-small cell (NSCLC) and small cell (SCLC). This histological classification scheme has significant implications in terms of the origin, natural history, and management of these tumors, as outlined below.

Epidemiology and Etiology

Incidence of over 230,000 estimated cases in 2024, with a trend of decreasing incidence in men but increasing incidence in women secondary to changes in smoking behaviors. No known racial predilection exists. Mortality of greater than 125,000 deaths predicted in the United States in 2024 [1].

Etiology of most lung cancers is related to chronic cellular damage and DNA mutations from exposure to carcinogens such as cigarette smoke (the cause of 87% of cases), radon gas, ionizing radiation, asbestos, and industrial chemicals [2]. As smoking among males has decreased in the United States, so too has the rate of smoking-related lung cancer. However, the rates for females have increased in the same time period, likely owing to the delayed popularity of smoking in women compared to men.

• High yield: Patients with exposure to asbestos are more likely to develop carcinomas of the lung than mesothelioma, an aggressive cancer of the pleural lining of the lungs.

Hereditary links or molecular genetic defects have not been well established.

• High yield: Li Fraumeni syndrome is a rare genetic disorder defined by a mutation in the TP53 gene. Patients with Li Fraumeni syndrome have a lifetime lung cancer risk of 22% [3].

Risk factors include exposure to carcinogens, as mentioned above, especially tobacco smoke, which shows a direct link between dose and cancer risk and acts synergistically with other carcinogens to increase risk; history of interstitial lung disease; history of tuberculosis.

Screening in Asymptomatic, High-Risk Population

The United States Preventative Services Task Force (USPSTF) defines high-risk adults as aged 50-80 who have a 20-pack year smoking history and are current smokers or have quit smoking within the last 15 years [4, 5].

Routine screening with annual low-dose CT scan of high-risk adults has been shown in several clinical trials to decrease the relative reduction in lung cancer specific mortality by approximately 20%. However, adherence to screening recommendations remains low at between 20-50% [6-9].

Clinical Presentation, Work Up and Diagnosis

History: About 90% of patients are symptomatic at diagnosis [10].

• Local disease: cough (45-75% of patients), hemoptysis (15-30%), dyspnea (30-50%), sputum production (most often associated with bronchoalveolar cell carcinoma), chest pain (20-40% of patients; often dull and intermittent for early stage disease, severe and constant for locally advanced disease), shoulder and arm pain (Pancoast tumors), Horner syndrome, hoarseness (High yield: from compression of the recurrent laryngeal nerve), wheezing, dysphagia, superior vena cava (SVC) syndrome [11, 12].
• Metastatic disease: weight loss, bone/back pain, fatigue, weakness, headaches, seizures, back pain, paraplegia.
• Paraneoplastic syndromes (10-20%): hypercalcemia, hyponatremia, anemia, weight loss, digital clubbing, Eaton-Lambert, myasthenia syndrome, peripheral neuropathy, hypercortisol effects.

Physical exam: Abnormal lung and/or cardiac auscultation is possible. Signs of SVC compression may be present and include facial or upper extremity swelling, dilated neck veins, plethora, and a prominent venous pattern on the chest. Signs of metastatic disease include neurological abnormalities, bone pain to percussion, weakness, cachexia.

• Most common sites of metastasis include brain, bone, liver, adrenals (high yield: unique site of metastasis for lung cancer), skin.

Lab studies: Variable CBC and chemistry panel; LFTs; hyponatremia from paraneoplastic vasopressin-like factors or hypercalcemia from PTH-like substance; pulmonary function tests; no specific tumor markers routinely used.

Radiologic studies: CT scan of the chest and upper abdomen, including the liver and adrenal glands; PET scans have improved sensitivity and specificity over CT scans for identifying lymph node involvement and metastatic disease; bone scan +/- brain MRI if symptoms or disease stage warrant [13].

Diagnostic studies: Sputum cytology; CT-guided needle aspiration; bronchoscopy; mediastinoscopy; video-assisted thoracoscopic surgery; thoracotomy.

Staging: Both a clinical and a pathologic assessment together are critical; distinction between clinical stage and pathologic stage should be considered when evaluating reports of survival outcomes.

• Surgical staging of the mediastinum is considered standard if accurate evaluation of the nodal status is needed to determine therapy.
• NSCLC: The 8^th edition of the AJCC’s NSCLC staging system, which employs TNM staging, was adopted in 2017 by the American Joint Committee on Cancer and the International Association for the Study of Lung Cancer (IASLC).  This system follows a typical TNM staging system ranging from stage 0 through IV, and mortality decreases with each increase in stage [14].
• SCLC: As occult or overt metastatic disease is usually present at diagnosis, survival is generally not affected by small differences in the amount of locoregional tumor involvement. A simple 2-stage system of limited vs. extensive disease, developed by the Veterans Administration Lung Cancer Study Group, is commonly used. In this paradigm, limited stage is considered disease that can be safely encompassed in a single radiation portal whereas extensive stage cannot.

Natural Course and Pathology

Non-Small Cell Lung Cancers (NSCLC) (85% of all lung cancers) [15]

• Squamous cell carcinoma
  • 25-30% of total lung cancer cases
  • Two-thirds have anatomically central origin near the bronchi, thus often diagnosed on sputum cytology
  • Grow relatively slowly; often grow large before symptoms occur
  • Cavitation due to central necrosis seen on imaging
  • Clinical pearl: Patient tends to be an older male smoker.
• Adenocarcinoma
  • 30-40% of total lung cancer cases
  • Clinical pearl: Most common lung cancer in women, nonsmokers, and former smokers
  • Two-thirds originate peripherally in pulmonary tree, thus more commonly found as an asymptomatic solitary peripheral nodule
  • More commonly metastasize to brain and other distant sites compared to other non-small cell cancers
  • Bronchioloalveolar subtype incidence is rising and is often diffuse/multicentric with prominent mucin production
• Large cell carcinoma
  • 10-15% of total lung cancer cases
  • Commonly large, peripheral lesions
  • High propensity to metastasize to regional lymph nodes and distant sites

Small Cell Lung Cancers (SCLC) (15-20% of all lung cancers)

• It occurs almost exclusively in smokers
• Commonly grow centrally in bronchi, submucosal locations
• Often very aggressive tumors with rapid growth, early metastasis
• Up to 70% are widely disseminated at diagnosis to bone, liver, brain, and/or lung [16,17]
• High yield: SCLC is a neuroendocrine tumor, so cancerous cells will appear as small, round, blue cells on histology
• Frequently associated with paraneoplastic syndromes (especially SIADH, hypercortisolism)

Other Lung Cancers

• Carcinoid tumors, bronchial gland carcinomas, and metastatic disease from another primary site, such as colon cancer

Treatment

Early-stage NSCLC

• Surgery with lobectomy and lymph node dissection for all subtypes, with 50%- 5-year survival rates in Stage I patients, and 30% 5-year survival rates in Stage II patients [18, 19, 20].
  • A recent study published in NEJM comparing the efficacy of sub-lobar resection vs lobar resection of stage IA NSCLC patients with peripherally located tumors found that a sub-lobar resection was non-inferior to lobar resection with a 5-year overall survival of 63.6% and 64.1%, respectively. These results suggest that for patients with small, peripheral tumors, a sub-lobar resection may be an alternative surgical approach to lobectomy [21].
  • Alternative procedures: pneumonectomy (higher perioperative mortality compared with lobectomy); wedge or segmental resection (3 to 5 times higher incidence of local recurrence, lower survival) [13,22].
• Stereotactic body radiation therapy (SBRT) is an alternative to surgery for patients who decline or are not surgical candidates with Stage I or II disease. SBRT has been found to have similar survival as surgical resection. Five-year overall survival was 87% and 84% for radiation vs. surgery, respectively [23].
• Post-operative radiotherapy (PORT) may be used for positive surgical margins, but this approach is falling out of favor.
• Chemotherapy may be used as an adjuvant treatment in patients with larger tumors (typically > 4 cm) since many patients treated with surgery alone subsequently develop regional or distant metastases [22]. Additionally, neoadjuvant chemotherapy has been shown to improve disease-free survival when compared to patients treated with surgery alone [24].
  • Chemotherapy agents commonly used in the adjuvant setting include cisplatin/pemetrexed, cisplatin/gemcitabine or cisplatin/docetaxel [25]. 
• More recently, immunotherapy and other targeted agents have also been approved for use in the adjuvant setting. 
  • Atezolizumab, an anti PD-L1 monoclonal antibody, may be used after adjuvant chemotherapy and showed an improvement in disease free survival, with the greatest benefit seen in patients with PDL1 high expressing tumors [26].
  • Osimertinib and Alectinib are targeted therapies for patients with EGFR+ and ALK+ tumors, respectively [27,28].

Locally Advanced NSCLC

• For patients with unresectable disease, concurrent chemoradiation [29-33] followed by consolidative durvalumab (an anti-PD-L1 monoclonal antibody) is the standard of care. Compared to placebo, consolidative durvalumab extended median survival from 5.6 to 16.8 months. Front line durvalumab is currently being evaluated for advanced stage NSCLC patients.
• In patients with resectable disease, an emerging paradigm is the use of peri-operative chemoimmunotherapy (neoadjuvant immunotherapy agents include nivolumab, pembrolizumab, and durvalumab) followed by surgical resection. Optimal patient selection for this paradigm, however, is currently unknown [34-36].
  • Historically, neoadjuvant chemoradiation was considered for patients with potentially resectable disease, but with the rise of perioperative regimens, this treatment approach is falling out of favor.
  • A notable exception is patients with superior sulcus tumors. The standard of care for these tumors is induction chemoradiation followed by surgical resection and consolidative chemotherapy.
• Chemotherapy regimens commonly used in concurrent chemoradiation for unresectable disease include carboplatin/pemetrexed, cisplatin/pemetrexed, and paclitaxel/carboplatin [25].

Metastatic NSCLC

• Systemic therapy is the standard of care for patients with advanced lung cancer. Common agents include pembrolizumab/carboplatin/pemetrexed [25].
• Palliative radiation or chemotherapy for distant metastases, can improve patient quality of life, but survival rates remain very poor (5-year survival rates of < 5%) [37].
• Targeted Therapies/Biologic Therapies, classes of medications that have been specifically designed to function at precise molecular pathways and receptors, are used in the treatment of late-stage NSCLC. Such therapies, which are often given in conjunction with standard chemotherapeutic agents, include farnesyl transferase inhibitors, signal transduction inhibitors (including the tyrosine kinase inhibitor, erlotinib [Tarceva] and ROS 1 inhibitors loratinib and Repotrectinib), antiangiogenic agents (sunitinib, sorafenib, bevacizumab), and monoclonal antibodies (including trastuzumab [Herceptin]) [25].
  • Limited stage SCLC (M0)
    • Chemotherapy and local radiation given concurrently can achieve a 14% reduction in the mortality rate when compared to chemotherapy alone [38].
      • Chemotherapeutic regimens often include cisplatin or carboplatin and etoposide.
      • Radiation therapy given twice daily has been shown to significantly increase survival when compared to standard daily regiments [39].
    • Prophylactic cranial irradiation remains controversial but can decrease the risk of brain metastasis by 50% and result in a 5.4% increase in the rate of survival at three years [40].
  • Extensive stage SCLC (M1)
    • The combination of cisplatin or carboplatin with etoposide is the standard of care in the United States for the treatment of extensive SCLC disease.
    • Emerging treatment strategies include the use of targeted therapies such as PARP inhibitors and immunotherapies.
    • Several phase III clinical trials have shown benefit of adding immunotherapies, such as durvalumab and atezolizumab, to chemotherapy regimens [41, 42].
    • Palliative radiation or chemotherapy for local and distant symptoms are employed to improve patient quality of life [43].