Tobacco use is the primary risk factor for lung cancer. It accounts for 90% cases in men and 70% in women. Other environmental exposure risk factors include radon, asbestos, and occupational exposure such as arsenic, bis-chloromethyl ether, hexavalent chromium, mustard gas, nickel, and polycyclic aromatic hydrocarbon.
In the United States, lung cancer is the second most common cancer following breast cancer in women and prostate cancer in men, not including skin cancer. Lung cancers comprise about 14% of all new cancers. About 220,000 new lung cancers are diagnosed each year with about 155,000 deaths estimated. Lung cancer is the number one cancer killer in both men and women. The number of deaths due to lung cancer surpasses the deaths attributable to prostate, breast, and colon cancers combined. Over the past several decades, the incidence of lung cancer has been declining in men, but just only recently in women.
Non-small lung carcinoma (NSCLC) accounts for approximately 80% to 90% of all lung cancers. Small-cell lung carcinoma (SCLC) makes up the remainder. Three major histologic types of NSCLC are adenocarcinoma, squamous cell carcinoma, and large cell carcinoma. Adenocarcinoma is the most common type of NSCLC. It accounts for 50% of cases and has a high propensity to metastasize. Bronchoalveolar carcinoma is a subtype of adenocarcinoma which can present as a solitary nodule or multifocal disease. Typically, it is not associated with smoking. Squamous cell carcinoma and large cell carcinoma comprise 35% and 15%, respectively.
Thyroid transcription factor (TTF)-1 helps to distinguish if a tumor is a lung primary. Increasingly, molecular diagnostic studies are being performed to determine the presence of certain gene alterations in the tumor such as EGFR mutations, ALK gene rearrangements, ROS1 rearrangements, and PD-L1 expression. There is increasing evidence to show that such tumors with these specific gene mutations or alterations can respond to targeted therapies.
Most patients present with symptoms of dyspnea, cough, hemoptysis, chest pain, and weight loss. They may also present with a change in mental status, clubbing, post-obstructive pneumonia, pleural effusion, hoarseness due to recurrent laryngeal nerve involvement, and superior vena cava syndrome (SVC). Some patients present with superior sulcus tumor with Pancoast syndrome exhibiting symptoms of shoulder pain, brachial plexopathy, and Horner syndrome (ptosis, meiosis, and ipsilateral anhidrosis). Poor prognostic factors include an advanced stage, weight loss (more than 10% body weight over past six months), Karnofsky Performance Status (KPS less than 90), pleural effusion, age older than 70 years, use of chemotherapy, and nodal stage.
Workup for suspected lung cancer begins with a good history and physical examination with attention to performance status, weight loss, and tobacco history. Imaging includes computerized or computed tomography (CT) of the chest, abdomen, and pelvis, magnetic resonance imaging (MRI) of the brain, and positron emission tomography-computed tomography (PET-CT). Lab work includes a complete blood count (CBC), comprehensive metabolic panel (CMP), and liver function test (LFT). Pulmonary function testing is needed for pre-surgical evaluation. Tissue diagnosis and staging are crucial to helping guide treatment recommendations. Diagnosis can be obtained through bronchoscopy for central lung tumors. Biopsy via endobronchial ultrasound (EBUS) or mediastinoscopy is performed for suspected hilar or mediastinal nodes. CT-guided needle biopsy is performed for peripheral lung tumors. Other times, diagnosis is obtained from surgical resection. 
The stage at presentation typically breaks down to the following: stage I 10%, stage II 20%, stage III 30%, and stage IV 40%. Unfortunately, the majority of patients present with advanced stage or metastatic disease. Most common sites of distant metastases are bone, adrenal glands, and brain. Survival depends on the stage at presentation, response to treatment, and physical tolerance to therapy. In general, five-year survival for stage IA/IB is 40% to 70%, stage IIA/IIB is 30% to 55%, stage IIIA/IIIB 5% to 25%, and stage IV is 1% to 13%.
Surgery is typically recommended for early-stage NSCLC (Stage I-II). Surgery consists of lobectomy and lymph node sampling or dissection and occasionally, pneumonectomy or wedge resection. Depending on surgical findings, some patients may require adjuvant chemotherapy or radiation therapy. For T1 tumor, the local control is 94% for lobectomy and 82% for wedge resection. Therefore, if possible, lobectomy is preferred. The five-year overall survival for resected T1N0 and T2N0 tumors are 80% and 68%, respectively.
Some patients are not surgical candidates due to high operative risk from a poor cardiopulmonary function, comorbid conditions, or advanced age. Others refuse surgery. In these cases, definitive radiation therapy is given. For stage I, medically inoperable patients, stereotactic body radiation therapy (SBRT), also known as stereotactic ablative body radiation (SABR), has emerged as a safe and effective alternative option to surgery. SBRT or SABR involve giving a high dose of radiation therapy with precision to lung tumors. This technique maximizes tumor cell kill of the target while minimizing radiation-related injury to normal critical structures. Patient immobilization system along with image guidance is required for accurate patient positioning and tumor localization before the delivery of each treatment. SBRT is delivered in three to five sessions over one to two weeks. Studies have shown that three-year local tumor control is 85% to 95% and three-year overall survival is 55% to 91%. For Stage II inoperable patients, definitive conventional radiation therapy has been offered, although the results are not comparable to surgery. If patient physical fitness allows, three-dimensional conformal radiation therapy is given in standard fractionation over six to seven weeks with concurrent chemotherapy.
The role of radiation for the management of early stage lung cancer is limited. It is only considered in patients not deemed surgical candidates or who have numerous co-morbidities. Radiation therapy also for early-stage lung cancer has poor 5-year survival. Several types of radiation delivery techniques have been used to treat early-stage lung cancer in non-surgical patients. To date, stereotactic body radiotherapy appears to have the highest survival compared to other techniques, with 3-year survival approaching 55%. Other studies have shown that radiation therapy does lower the recurrence rate but not the overall survival. The role of adjuvant radiation therapy after surgical resection of the primary lung cancer remains questionable. Radiation therapy has been shown to reduce local recurrence but not overall survival rates. At present, radiation therapy is reserved for patients with positive margins after resection.
TNM Staging (AJCC, 8th Edition)
Primary Tumor (T)
Tx: Primary tumor cannot be assessed or tumor proven by the presence of malignant cells in sputum or bronchial washings but not visualized by imaging or bronchoscopy
T0: No evidence of a primary tumor
Tis: Carcinoma in situ - tumor measuring 3 cm or less, no invasive component
T1: Tumor measuring 3 cm or less in greatest dimension, surrounded by lung or visceral pleura without bronchoscopic evidence of invasion more proximal than the lobar bronchus (i.e. not in the main bronchus)
T1mi: Minimally invasive adenocarcinoma, tumor has an invasive component measuring 5 mm or less
T1a: Tumor ≤1 cm in greatest dimension, superficial spreading tumor in central airways (spreading tumor of any size but confined to the tracheal or bronchial wall)
T1b: Tumor >1 cm but ≤2 cm in greatest dimension
T1c: Tumor >2 cm but ≤3 cm in greatest dimension
T2: Tumor >3 cm but ≤5 cm or tumor with any of the following features: involves the main bronchus regardless of distance from the carina but without the involvement of the carina,
invades visceral pleura, associated with atelectasis or obstructive pneumonitis that extends to the hilar region, involving part or all of the lung
T2a: Tumor >3 cm but ≤4 cm in greatest dimension
T2b: Tumor >4 cm but ≤5 cm in greatest dimension
T3: Tumor >5 cm but ≤7 cm in greatest dimension or associated with separate tumor nodule(s) in the same lobe as the primary tumor or directly invades any of the following: parietal pleura, chest wall (including superior sulcus tumors), phrenic nerve, parietal pericardium, or separate tumor nodule(s) in the same lobe as the primary
T4: Tumor >7 cm in greatest dimension or any tumor invading one or more of the following: diaphragm, mediastinum, heart, great vessels, trachea, recurrent laryngeal nerve, esophagus, vertebral body, or carina; separate tumor nodule(s) in a different ipsilateral lobe than that of the primary tumor
Regional Lymph Nodes (N)
Nx: Regional lymph nodes cannot be assessed
N0: No regional lymph node metastasis
N1: Ipsilateral peribronchial and/or ipsilateral hilar nodes and intrapulmonary nodes, including involvement by direct extension
N2: Ipsilateral mediastinal and/or subcarinal nodes
N3: Supraclavicular/scalene nodes and/or contralateral mediastinal/hilar nodes
Distant Metastases (M)
M0: No distant metastasis
M1: Distant metastasis present
M1a: Separate tumor nodule(s) in a contralateral lobe; tumor with pleural or pericardial nodule(s) or malignant pleural or pericardial effusions
M1b: Single extrathoracic metastasis, involving a single organ or a single distant (nonregional) node
a single extrathoracic metastasis has a better survival and different treatment choices, reason why it has now been staged separately
M1c: Multiple extrathoracic metastases in one or more organs
Stage 0: Tis, N0, M0
Stage IA1: T1mi/T1a, N0, M0
Stage IA2: T1b, N0, M0
Stage IA3: T1c, N0, M0
Stage IB: T2a, N0, M0
Stage IIA: T2b, N0, M0
Stage IIB: T1/T2, N1, M0 or T3, N0, M0
Stage IIIA: T1/T2, N2, M0 or T3/T4, N1, M0 or T4, N0, M0
Stage IIIB: T1/T2, N3, M0 or T3/T4, N2, M0
Stage IIIC: T3/T4, N3, M0
Stage IVA: any T, any N with M1a/M1b
Stage IVB: any T, any N with M1c
It is important to appreciate that the definitive treatment for early lung cancer is surgery. Radiation is only considered in early cases when the patient is not deemed a surgical candidate. Overall, radiation therapy alone for managing early lung cancer has been disappointing. Over the past two decades, several newer modalities of delivering radiation have been developed with improved survival at three years. Trials are now comparing surgery versus radiation therapy for early lung cancer. The best way to manage lung cancer is to try and prevent it. The public should be educated on the harms of smoking; cessation of this social habit would lead to a drastic reduction of not only lung cancer but many other disorders like a peripheral vascular disease, COPD, atherosclerosis and so on. (Level V)
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