Thoracic imaging

Lung cancer

Lung cancer is the leading cause of cancer deaths in men and women worldwide with a 5-year survival of only around 20% ( ). Cigarette smoking is the single most common risk factor for the development of lung cancer, but air quality, residential radon, and occupational exposures such as asbestos rank among the other major factors ( ; ). In areas with more stringent cigarette use policies, the incidence has been decreasing, particularly in men ( ). However, areas of poorer air quality and increases in women smokers over the last century have resulted in a higher prevalence of lung cancer in women, overtaking breast cancer mortality in the last decade. While tobacco cigarette smoking has been decreasing in developed countries, the legalization of marijuana smoking and vaping may maintain high incidences of lung cancer in the future in those countries ( ; ).

Because early lung cancer is largely asymptomatic, by the time symptoms arise, the tumor will have already become locally advanced or metastatic and 80% of patients are being diagnosed at these stages. This is a major reason for the poor 5-year survival. Indeed, patients with stage I resected lung cancer have a much better 5-year survival of around 80% ( ). With the more generalized use of CT scans, more lung cancers are now being found incidentally and survival following resection of these incidentally found cancers stage-matched to those found due to symptoms is higher, suggesting some differences in biology ( ). Because survival is so strongly linked to stage, there is a strong basis for the development of lung screening programs in people at high risk. The National Lung Screening Trial utilized low-dose CT scans of the chest, in comparison to chest radiograohy, to screen for lung cancer in more than 50,000 participants ( ). There were 247 deaths from lung cancer per 100,000 person-years in the low-dose CT group and 309 deaths per 100,000 person-years in the chest X-ray group, representing a relative reduction in mortality from lung cancer with low-dose CT screening of 20% ( ).

With the identification of a lung nodule suspicious for lung cancer, a tissue diagnosis needs to be established. CT scans of the chest, abdomen, and pelvis allow for an initial staging and also for selecting a method for biopsy. Widely metastatic disease may allow for tissue diagnosis from thoracentesis of a malignant pleural effusion, bedside fine needle aspiration of supraclavicular lymph nodes, or ultrasound-guided liver biopsy, as examples. If distant metastatic disease is not identified, tissue sampling of mediastinal or hilar lymph nodes can be achieved by endobronchial ultrasound-guided fine-needle aspiration ( ). If the tumor appears confined to the lung, CT-guided lung biopsy or radial endobronchial ultrasound-guided biopsy, if close to an airway, can be used. The diagnosis of lung cancer can be made on cytologic or histopathologic samples, but histopathologic samples are preferable to a cytologic specimen as it provides extraarchitectural information and usually yields more tissue for immunohistochemical and genetic analysis of the tumor ( ). As endobronchial ultrasound-guided aspiration can only generate cytological specimens, advances in immunocytochemistry are improving the diagnostic yield of these specimens ( ). Among lung cancers, the major first distinction is between small-cell (SCLC) and non–small-cell (NSCLC) histologies due to the marked difference in the clinical course. SCLC is a high-grade neuroendocrine tumor that occurs almost exclusively in smokers and is characterized by rapid growth and early development of metastases ( ). These tumors are also frequently associated with paraneoplastic syndromes such as syndrome of inappropriate antidiuretic hormone secretion, Cushing syndrome, Lambert–Eaton syndrome, encephalomyelitis, and sensory neuropathy syndromes ( ). The NSCLC group includes adenocarcinoma, squamous cell carcinoma, and large cell carcinoma. Because these tumors generally follow a similar clinical course, they are grouped together despite different histologies.

The clinical stage needs to be established next. Lung cancer follows the primary tumor, regional lymph node, distant metastasis (TNM) standard of staging according to the eighth edition of TNM (AJCC-UICC) ( ). Unlike many other cancers, the prevalence of lung cancer and the presence of an international database of patients and their outcomes means that stage classifications are data-driven. The International Association for the Study of Lung Cancer used 94,708 lung cancer patients and their outcomes for stage groupings ( ).

Clinical staging is largely imaging-based. CT scans are usually already available once a tissue diagnosis is made and are helpful for both T-staging of the primary, based on size and location, and M-staging for distant disease. In most cases, N-staging can also be identified by bulky enlarged mediastinal or hilar lymph nodes, but microscopic involvement greatly affects staging, and invasive mediastinal staging of lymph nodes by cervical mediastinoscopy or endobronchial ultrasound is needed for confirmation ( ). In most centers, an ¹⁸ F-fluorodeoxyglucose (FDG) PET/CT scan is routinely performed as it has been shown to be more accurate in the detection of mediastinal nodal disease and can detect occult metastatic disease not identified by CT ( ). Some argue therefore that routine invasive mediastinal staging precludes the need for PET/CT; however, studies have shown the impact of PET/CT in changing clinical care and current guidelines for the workup of lung cancer include PET/CT ( ; ; ).

Because brain metastases may be hyper- or hypo-metabolic, FDG-PET is less useful for the identification of brain metastases. Therefore, gadolinium-enhanced MRI of the brain is preferred in stage III and IV patients ( ). While TNM staging exists and remains recommended for the staging of SCLC, due to the cancer's rapid dissemination potential, a treatment-based staging system is often utilized clinically. In this system, SCLC is separated into “limited stage” disease which means that the cancer is on one side of the chest and can be treated with a single radiation field, and “extensive stage” which means the cancer has spread beyond limited stage ( ). This system helps separate patients treated with chemoradiotherapy from those treated with chemotherapy but does not separate out the rare early stage patients from the much more common locally advanced disease.

SCLC tumors are very responsive to chemotherapy. The very rare patient without nodal or distant metastases can undergo surgery followed by adjuvant chemotherapy and consideration of prophylactic cranial irradiation (PCI). Because this population is so rare, there are few randomized controlled trials comparing surgical to nonsurgical approaches and comparing outcomes with and without PCI ( ). For the more common situations of limited-stage SCLC, chemoradiotherapy is the established first line of treatment ( ). PCI has been shown to decrease the risk of symptomatic brain metastases in this population and increase overall survival ( ). In patients with extensive stage disease, chemotherapy alone using a platinum agent with etoposide is the standard of care. Radiation is reserved for palliation and PCI is not obviously beneficial in this setting ( ). For NSCLC patients, surgery is the mainstay of treatment in stage I and II disease. Lobectomy, resection of a single lobe of the lung with formal division of the pulmonary artery, bronchus, and pulmonary vein of that lobe, is the standard operation ( ). However, with the advent of CT and the development of lung cancer screening programs, smaller tumors are being detected more frequently. As many have favorable histology, sublobar resection may yet be adequate and preserve lung parenchyma. A review of SEER and NCDB database data demonstrated a survival benefit with lobectomy ( ; ; ; ; ). Adjuvant or neoadjuvant chemotherapy is offered to stage II disease and in selected stage IB patients with high-risk features ( ). For stage III disease, the mainstay of therapy is concurrent chemoradiation ( ). Patients with single nodal station, microscopically positive disease may benefit from surgery afterward, but patient selection is critical ( ). Stage IV disease is treated with systemic therapy and targeted palliative treatments.

Around 20 years ago, the molecular pathways which drove NSCLC malignancy began to be elucidated ( ). Certain recurrently mutated genes in molecular signaling pathways were identified such as in the epidermal growth factor receptor (EGFR) gene, the anaplastic lymphoma kinase (ALK) gene, or c-ROS oncogene one gene, among many others ( ). These mutations are known as “driver mutations” which indicate that they are important in converting a noncancerous cell to a malignant one and that the resulting malignant cell relies on this mutated cell signaling for continued survival. Consequently, these mutations are desirable therapeutic targets, and therapies that aim to disrupt these pathways are known as “targeted therapies.” While tumors will ultimately develop escape mutations that render treatment ineffective, in general, tumors with a targetable mutation have better prognoses ( ).

Targeted therapies now exist for a variety of NSCLC mutations. EGFR mutation is observed in ∼15% of lung adenocarcinomas in the US but is markedly higher in the Asian population ( ). In advanced NSCLC with EGFR mutations, EGFR tyrosine kinase inhibitors (TKI) targeting these mutations are more effective than conventional chemotherapy and are considered the front-line treatment ( ; ). Multiple generations of EGFR TKIs have now been developed ( ). Other mutations include ALK rearrangements which are present in ∼4% of NSCLC adenocarcinomas and can be targeted by ALK TKIs ( ). In 1–2% of patients, ROS1 rearrangements can act as a driver oncogene when translocated with other genes such as the CD74 gene. ROS1/MET inhibitor crizotinib and ROS1/TRK inhibitor entrectinib are used in the front-line setting for these mutations ( ). MET amplifications independent of ROS1 can also be treated with crizotinib.

As targeted therapies evolve, testing for these mutations must evolve along with them ( ; ).

Novel methods of detecting lung cancer are now actively being developed. One promising method is the “liquid biopsy” which obviates the need for tumor biopsies ( ). Tumor cells shed compounds into the blood which can then be detected, demonstrating the existence of the tumor. Currently, circulating tumor DNA (ctDNA), that is, DNA from dying tumor cells shed into the blood, and circulating tumor cells, that is, tumor cells shed into the blood are the most promising candidates ( ). Because NSCLC mutations are so well defined, ctDNA can be identified on the basis of those mutations ( ). Tests for ctDNA containing EGFR mutations have been developed. There is considerable expectation that these tests will allow for tumor detection, evolution tracking, and recurrence in the future.

Though many driver mutations have been identified in NSCLC, many tumors will still lack known mutations. In this setting, conventional chemotherapy has remained the sole choice of therapy until recently. Immune checkpoint inhibitors are a recent class of drug which targets the physiologic brake of immune activation. Common examples include programmed cell death protein 1 (PD-1) or programmed cell death ligand 1 (PD-L1) inhibitors ( ). When PD-L1 interacts with PD-1, it inhibits T effector cells and promotes the conversion of T effector cells to T regulatory cells. Therefore, by expressing PD-L1, tumors can escape host immune surveillance. PD-1 and PD-L1 inhibitors, therefore, act to break this mechanism of immune escape. In advanced NSCLC, PD-L1 expression by the tumor is tested by immunohistochemistry. Pembrolizumab is currently approved for the front-line treatment of patients with EGFR/ALK wild-type NSCLC with PD-L1 expression >50%. In the KEYNOTE-024 trial, where these patients were randomized to single-agent pembrolizumab versus platinum chemotherapy, both progression-free survival (10.3 vs. 6 months) and medial overall survival (26.3 vs. 13.4 months) were markedly better with immunotherapy ( ). In patients with low PD-L1 expression, PD-1 or PD-L1 blockade has still demonstrated benefit over chemotherapy. The CheckMate-227 trial showed that nivolumab and ipilimumab allowed longer overall survival compared to chemotherapy (17.1 vs. 13.9 months) ( ). Multiple trials continue to define how immunotherapy will best be used to treat NSCLC. Indeed, trials attempting neoadjuvant immunotherapy may redefine how resectable NSCLC will be treated in the future ( ).

In summary, lung cancer is currently the most common cause of cancer mortality in men and women around the world. NSCLC is treated based on the stage at presentation, with early disease treated primarily with surgery and locally advanced disease treated with chemoradiation. Advanced disease is treated palliatively with systemic therapy and palliative treatments. Immunotherapy has led to a paradigm shift in the treatment of NSCLC and neoadjuvant in the future. In contrast, SCLC is much more aggressive than NSCLC and systemic chemotherapy is the mainstay of treatment and radiation added for limited-stage disease.