Interventional Chest/Diagnostic Procedures

Update: 8th ed IASLC lung cancer staging guidelines

The new 8th edition guidelines on the staging of non-small cell lung cancer sponsored by the International Association for the Study of Lung Cancer (IASLC), and developed jointly by the American Joint Committee on Cancer and the Union Internationale Contre le Cancer were enacted January 1, 2017, and provide a methodologically rigorous update to staging nomenclature (Detterbeck et al. Chest. 2017;151[1]:193). The new guidelines were developed using a database comprising 94,708 patients in 16 countries, integrating clinical, pathologic, and survival data with multivariate analysis to establish prognostically significant staging subgroups.

In the new guidelines, tumor size has been divided into 1-cm increments for T classifications with new subcategories of T1a <1 cm, T1b 1-2 cm, and T1c 2-3 cm (Rami-Porta et al. J Thorac Oncol. 2015;10[7]:990). Furthermore, T2 has been broadened to include main bronchus tumors causing lobar or whole lung atelectasis extending to the hilum. Tumors with diaphragmatic involvement have been reclassified as T4. Guidance on heterogeneous nodules has also been provided, with emphasis on measurement of the solid component (based on imaging) or depth of invasion (on pathology) to determine T classification.

The N classification remains unchanged from the 7th edition. Exploratory analysis suggested prognostic significance to the number of involved N1/N2 lymph nodes; however, this requires detailed pathologic assessment and was not adopted as a staging criterion (Asamura et al. J Thorac Oncol. 2015;10[12]:1675).

Classification of metastatic disease has been modified from M1a/M1b to M1a for thoracic metastasis, M1b for single/oligometastatic extrathoracic metastasis, and the new category M1c for multiple/disseminated metastases. M1c involvement now denotes stage IVb disease, with lower survival compared to IVa disease (0% vs 10% 5-year survival (Goldstraw et al. J Thorac Oncol. 2015;11[1]:39). Application in broader cohorts, including patients undergoing bronchoscopic staging, will be needed to further validate the new guidelines.

Vivek Murthy, MD

Fellow-in-Training MemberSteering Committee

Pulmonary Physiology, Function, and Rehabilitation

6-minute walk test

The 6-minute walk test (6MWT) is a widely used measure of functional status and exercise capacity. Though it does not diagnose specific etiologies of impairment, the 6MWT provides an assessment of the overall integrated physiologic responses to exercise (Am J Respir Crit Care Med. 2002;166[1]:111). The test is a self-paced, submaximal study. Patients are instructed to “walk as far as possible for 6 minutes” with this distance (6MWD) measured as the primary outcome. 6MWD is associated with clinical outcomes in many cardiopulmonary disorders and is reliable, valid, and responsive to treatment. Normative equations provide predicted and lower limit of normal values (Singh et al. Eur Respir J. 2014;44[6]:1447). In addition to patient comorbidities, several important factors impact 6MWD interpretation. Standardization of the testing course, patient instructions, encouragement, technician assistance, walking aids, and supplemental oxygen use are important in reducing testing variability (Holland et al. Eur Respir J. 2014;44[6]:1428). A significant learning effect exists during the first several walks. An improvement of about 26 m (range 24-29 m) has been reported in patients with COPD, with the majority improving during the second test despite a short time interval lapse. Assessing for longitudinal change in serial testing is based on the minimal clinically important difference (MCID). This represents the difference in 6MWD that is perceived as important to the patient or leads to change in management. Techniques to develop these estimates are based upon statistical analysis of study sample data (distribution-based) or changes in a different, but related, clinical variable that is used as a reference (anchor-based). While minor differences in MCID are reported based on specific disease processes, a European Respiratory Society/American Thoracic Society review based on data from patients with COPD, ILD, and PAH found a MCID value of about 30 m (range 25-33 m) for adults with chronic respiratory disease, independent of specific disease, which is only slightly larger than the short term variability (Puente-Maestu et al. Eur Respir J. 2016;47[2]:429). Knowledge of these factors can assist in proper interpretation of the 6MWT.

Lana Alghothani, MD

NetWork Member

Nitin Bhatt, MD

Steering Committee Member

Pulmonary Vascular Disease

Methamphetamine-associated pulmonary hypertension (MAPAH): “tip of the iceberg”

Pulmonary hypertension (PH) is a devastating condition with serious morbidity and mortality. The Evian Classification and more recent revisions (J Am Coll Cardiol. 2013;62(25 Suppl ):D34) reclassified PH into five subgroups based upon etio-pathogenesis. Group I PH (pulmonary arterial hypertension, PAH) represents a growing list of entities, with Drugs & Toxins (Group 1.3) as a separate subgroup. This subgroup was first recognized following the discovery of an association between PH and the ingestion of the anorexigen aminorex (Gurtner HP. Schweiz Med Wochenschr. 1985;115[24]:818).

Methamphetamine (ME) as a potential etiology for PAH was first reported in 1993 (Schaiberger et al. Chest. 1993;104[2]:614). More recently, Chin et al suggested an association between stimulant use and PAH in 28.9% of their patients diagnosed with idiopathic PAH (Chest. 2006;130[6]:1657). The growing body of evidence linking ME to PAH resulted in upgrading of ME from “Possible” to “Likely” in the latest revision of the PH classification.

Recent gene sequencing data showed carboxylesterase-1, an enzyme that protects against ME-mediated pulmonary vascular injury, may be downregulated in patients with methamphetamine-associated PAH (MAPAH) (Perez et al. Am J Respir Crit Care Med. 193;2016:A2912). Furthermore, amphetamines promote mitochondrial dysfunction and DNA damage in pulmonary hypertension (Chen PI. JCI Insight. 2017;2[2]:e90427). Importantly, Barnett et al demonstrated a poorer prognosis in MAPAH compared with individuals with idiopathic PAH, but they are less likely to be treated with infused prostanoid therapies (Circulation. 2012;126:A13817).

Amphetamine-type stimulants have become the second most widely used class of illicit drugs worldwide (United Nations Office on Drugs & Crime. World Drug Report 2012). An estimated 4.7 million Americans (2.1% of the US population) have tried MA at some time in their lives (J Psychoactive Drugs. 2000;32[2]:137). The true incidence and prevalence of MAPAH remains unknown. One can surmise that with the widespread use of ME, we are only witnessing the “tip of the iceberg.”

Vijay Balasubramanian, MD, FCCP

Steering Committee Member

Franck Rahaghi, MD, FCCP

NetWork Member

Thoracic Oncology

Immunotherapy for lung cancer

The management of non-small cell lung cancer has traditionally focused on surgical resection of early and limited stage tumors and radiation and cytotoxic chemotherapy for patients with advanced disease. Recent progress in the management of patients with metastatic lung cancer treatment has concentrated on the precise histologic diagnosis and the characterization of molecular drivers of malignant progression. Distinguishing small cell from non-small cell carcinomas, as well as differentiating adenocarcinoma from squamous cell carcinomas, enables clinicians to more effectively tailor appropriate chemotherapy. The identification of molecular mutations in EGFR (epidermal growth factor receptor) or fusions in ELM4-ALK translocations as drivers of the malignant process has facilitated tumor regression by targeting the molecular pathways with small molecular inhibitors (tyrosine-kinase inhibitors) or synthetic antibodies. Unfortunately, not all lung cancers carry activating mutations, and those that do may develop resistance to this molecular-targeted approach and show tumor progression.

Immunotherapy, an anticancer therapeutic approach that activates the host immune system to target the tumor, has historically been either a broad spectrum management utilizing immune cytokine modifiers to augment host immune activity or a directed adaptive recruitment and stimulation of host lymphocytes to attack targeted tumor cells. More recently, immunotherapy has taken a targeted molecular approach to modify immune checkpoint inhibitory pathways, the “brakes” of the immune system that tumor cells have manipulated to evade immune surveillance. Cancer cells may be attacked by activated T cells through the MHC complex and T cell receptor pathways. However, cancer cells that express a checkpoint ligand can deactivate T cells through its checkpoint pathway. Cancer cells may evade immune recognition by signaling inhibitory checkpoint receptor pathways, such as PD-1/PDL-1, or CTLA-4 receptors. Blocking the checkpoint inhibition may reactivate the immune response and enhance host immune recognition and killing of tumor cells. Infusions containing FDA-approved nivolumab (Opdivo) and pembrolizumab (Keytruda) block the PD-1 receptor checkpoint, whereas atezolizumab (Tecentriq) blocks PD-L1, the ligand that binds PD-1. These immune therapeutic approaches have been successfully utilized in a variety of solid tumors, including lung cancer and malignant melanomas. Impressive clinical results of prolonged tumor regression have been demonstrated in second-line immunotherapy with improvements over chemotherapy; newer immunotherapy trials have demonstrated efficacy in the first-line setting for metastatic disease. Tumors with high PDL-1 expression and high mutational load predict improved immunotherapy outcomes. As expected, blocking checkpoint immune inhibition may lead to autoimmune-like conditions of pneumonitis, hepatitis, colitis, and dermatitis. Tumor tissue markers predictive of a therapeutic immune response are in the research phase. Immunotherapy against lung cancer adds to the therapeutic armamentarium of cancer management and provides an exciting new research arena into the biology and immunology of lung cancer.

Arnold M. Schwartz, MD, PhD, FCCP

Steering Committee Member

References

Cousin-Frankel J. Breakthrough of the year 2013: cancer immunotherapy. Science . 2013;342[6165]:1432.

Sharma P, et al. The future of immune checkpoint therapy. Science . 2015;348[6230]:56.

Garon EB, et al. Pembrolizumab for the treatment of non-small cell lung cancer. N Engl J Med . 2015;372[21]:2018.

Brahmer J, et al. Nivolumab versus docetaxel in advanced squamous cell non-small cell lung cancer. N Engl J Med . 2015;373[2]:123.

Reck M, et al. Pembrolizumab versus chemotherapy for PDL-1 positive non-small cell cancer. N Engl J Med . 2016;375[19]:1823. Herbst RS, et al. Pembrolizumab versus docetaxel for previously treated PDL-1- positive advanced non-small cell lung cancer. Lancet . 2016;387[10027]:1540.

Networks: NSCLC staging, MAPAH, cough in teen athletes