About 218,000 new cases of lung cancer were reported in 2016 and more than 148,000 people died from this disease, according to the CDC.1

More individuals die from lung cancer each year than from breast, colon, and prostate cancer combined.2 Cigarette smoking is the biggest risk factor for developing lung cancer, as it is responsible for 80% to 90% of lung cancer deaths.3 The 2 main types of lung cancer are non–small cell lung cancer (NSCLC) and small cell lung cancer.4 The majority of lung cancer cases are NSCLC, however, representing about 80% to 85% of cases.4 Additionally, NSCLC has 3 main subtypes: adenocarcinoma, large cell carcinoma, and squamous cell carcinoma (see Figure 14). For patients with localized NSCLC, the overall 5-year survival rate is about 60%. For regional NSCLC, the 5-year survival rate is about 33%. If the cancer has spread to distant sites of the body (metastatic lung disease), the 5-year survival rate precipitously declines to just 6%. However, with the advent of earlier interventions and newer, more effective therapies, these survival percentages are improving.5

The choice of first-line agents used initially in patients with NSCLC depends on multiple factors (see Figure 14). The expression of programmed cell death ligand 1 (PD-L1) greatly influences therapy decisions.6 In patients with a low PD-L1 expression of less than 50% and no other genetic mutations, pembrolizumab, an immunotherapy agent, in combination with carboplatin and pemetrexed, are the preferred therapy options.5 In patients with a high PD-L1 expression, pembrolizumab monotherapy can be used in the absence of rapidly progressing disease. For instance, in rapidly progressive disease, pembrolizumab with chemotherapy is preferred.6

First-line agents depend on a variety of genetic test results that could display certain mutations, according to the most recent National Comprehensive Cancer Network NCSLC guidelines.7

Mutations are biomarkers and act as predictive and prognostic markers for therapy efficacy. For example, the firstline agents in patients with a known epidermal growth factor receptor mutation prior to starting any chemotherapy are afatinib, erlotinib, or gefitinib. Additionally, the presence or absence of PD-L1, anaplastic lymphoma kinase, B-raf proto-oncogene, and c-ros oncogene 1 are all examined to establish initial therapy.7

New types of treatment options are being tested in clinical trials, which include chemoprevention and other investigational options.

Chemoprevention
Despite advances in lung cancer treatment, including biologic therapy and targeted treatment, survival rates have not dramatically improved, primarily because by the
time most patients present with symptoms, the disease has metastasized to an advanced stage. Chemoprevention involves using dietary or pharmacologic agents to prevent or slow the growth of cancer, and it is classified as either primary, secondary, or tertiary chemoprevention, depending on the target population8 (see Figure 29).





Although antioxidants and vitamins have not been successful as agents for primary chemoprevention, incidental observations regarding the use of inhaled corticosteroids and low-dose aspirin have shown more promising results. In a cohort study of 10,474 US veterans diagnosed with chronic obstructive lung disease and no history of lung cancer, there was a dose-dependent decrease in lung cancer associated with the use of inhaled corticosteroids.10 Additional randomized controlled trials with extended follow-up periods are warranted to further validate these findings. In a retrospective cohort study of nearly 13 million individuals in the Korean National Health Institute, low-dose aspirin (less than 100 mg) was associated with a reduced risk of lung cancer, which was even more apparent in participants 65 years and older and those diagnosed with diabetes.11

Secondary and tertiary chemoprevention, such as oral iloprost and celecoxib, displayed promising results in phase II trials,12,13 but the end points used were not validated, and future larger trials are necessary to confirm supportive data.

Screening
Early detection confers better treatment outcomes in most malignancies and NSCLC is no exception.

Low-dose chest computed tomography screening is recommended for patients aged 55 to 77 years, who are asymptomatic smokers and former smokers who have smoked for 30 pack-years or more and either continue to smoke or have quit within the past 15 years. Asymptomatic is defined as the absence of symptoms suggesting the presence of lung cancer.14

Investigational Options
A promising alternative to chemotherapy and pembrolizumab in patients with low or unknown PD-L1 expression is the immunotherapy combination of nivolumab plus ipilimumab. In the CheckMate-227 trial, the results indicated superior survival outcomes over chemotherapy alone.15 Durvalumab and tremelimumab were also studied in a phase 3 trial, MYSTIC, versus chemotherapy alone.





Although preliminary results did not show improved outcomes, post hoc exploratory analysis displayed improved outcomes in patients with a higher tumor mutational burden.16

Radiosensitizers, substances that work to enhance the effect of radiation on tumors without increasing the effect on normal tissue, are being investigated in patients with NSCLC.17 Vicenin-2, a substance that has been reported to possess a wide variety of pharmacologcal activities, has been proven effective in lowering cancer cell survival while promoting expression of proapoptotic genes, making it an effective radiosensitizing agent.18

Conclusion
Although there have been numerous advancements in the treatment of NSCLC, early detection, public education, and smoking cessation are the most important cornerstones of preventing the disease and improving patient survival outcomes. Additional research and targeted therapy will continue to improve survival, but tobacco
avoidance and early intervention are the key areas of opportunity for combating this lethal malignancy.
 
Jerry A. Barbee Jr, PharmD, BCPS, CPh, and Glenn Schulman, PharmD, MS, BCPS, BCACP, BCG BCIDP, are clinical pharmacists in Pensacola, Florida.

Carys Davies is a PharmD candidate at the Universityof Florida in Gainesville.



REFERENCES
  1. Leading cancer cases and deaths, male and female, 2016. CDC website. gis.cdc.gov/Cancer/USCS/DataViz.html. Accessed January 5, 2020.
  2. Key statistics for lung cancer. American Cancer Society website. cancer.org/cancer/lung-cancer/about/key-statistics.html. Updated January 8, 2020. Accessed February 11, 2020.
  3. What are the risk factors for lung cancer? CDC website. cdc.gov/cancer/lung/basic_info/risk_factors.htm. Updated September 18, 2019. Accessed January 5, 2020.
  4. Non-small cell lung cancer treatment (PDQ)-patient version. National Cancer Institute website. cancer.gov/types/lung/patient/non-small-cell-lung-treatment-pdq. Updated October 6, 2019. Accessed January 5, 2020.
  5. Lung cancer - non-small cell: statistics. Cancer.Net website. cancer.net/cancer-types/lung-cancer-non-small-cell/statistics. Published January 2019. Accessed January 5, 2020.
  6. Management of advanced non-small cell lung cancer lacking a driver mutation: immunotherapy. UpToDate website. uptodate.com/contents/management-of-advanced-non-small-cell-lung-cancer-lacking-a-driver-mutation-immunotherapy. Accessed January 5, 2020.
  7. Non-small cell lung cancer. National Comprehensive Cancer Network Clinical Practice Guidelines in Oncology website. nccn.org/professionals/physician_gls/pdf/nscl.pdf. Accessed January 5, 2020.
  8. New M, Keith R. Early detection and chemoprevention of lung cancer. F1000Research website. ncbi.nlm.nih.gov/pmc/articles/PMC5770990/. Published January 16, 2018. Accessed January 5, 2020.
  9. Keith RL, Miller YE. Chemoprevention of lung cancer. UpToDate website. uptodate.com/contents/chemoprevention-of-lung-cancer. Updated April 10, 2019. Accessed January 5, 2020.
  10. Parimon T, Chien JW, Bryson CL, McDonell MB, Udris EM, Au DH. Inhaled corticosteroids and risk of lung cancer among patients with chronic obstructive pulmonarydisease. Am J Respir Crit Care Med. 2007;175(7):712-719.
  11. Ye S, Lee M, Lee D, Ha EH, Chun EM. Association of long-term use of lowdose aspirin as chemoprevention with risk of lung cancer. JAMA Netw Open. 2019;2(3):e190185. doi:10.1001/jamanetworkopen.2019.0185.
  12. Keith RL, Blatchford PJ, Kittelson J, et al. Oral iloprost improves endobronchial dysplasia in former smokers. Cancer Prev Res (Phila). 2011;4(6):793-802. doi:10.1158/1940-6207.CAPR-11-0057.
  13. Kim ES, Hong WK, Lee JJ, et al. Biological activity of celecoxib in the bronchial epithelium of current and former smokers. Cancer Prev Res (Phila). 2010;3(2):148-159. doi:10.1158/1940-6207.CAPR-09-0233.
  14. Mazzone PJ, Silvestri GA, Patel S, et al. Screening for lung cancer: CHEST guideline and expert panel report. Chest. 2018;153(4):954-985. doi: 10.1016/j.chest.2018.01.016.
  15. Hellmann MD, Paz-Ares L, Bernabe Caro R, et al. Nivolumab plus ipilimumab in advanced non–small-cell lung cancer. N Engl J Med. 2019;381(21):2020-2031. doi:10.1056/NEJMoa1910231.
  16. Peters S, Cho BC, Reinmuth N, et al. Tumor mutational burden (TMB) as a biomarker of survival in metastatic non-small cell lung cancer (mNSCLC): blood and tissue TMB analysis from MYSTIC, a phase III study of first-line durvalumab ± tremelimumab vs chemotherapy. Cancer Res. 2019;79(13). doi: 10.1158/1538-7445.AM2019-CT074.
  17. Van Belle S. Do radiosensitizers enhance the treatment of patients with NSCLC? The need for better models and alternative methods of treatment. Chest. 1996;109(5suppl):115S-118S.
  18. Baruah TJ, Kma L. Vicenin-2 acts as a radiosensitizer of the non-small cell lung cancer by lowering Akt expression. Biofactors. 2019;45(2):200-210. doi: 10.1002/biof.1472.