Medically reviewed by C.H. Weaver M.D. updated 7/2019
In general treatment for non-small cell lung (NSCLC) may require surgery, radiation, and/or systemic therapy with chemotherapy, immunotherapy or precision cancer medicines. The specific treatment for each person is individualized and is based on the stage of the cancer and its genomic profile.(1,2,3)
For patients with NSCLC have cancer that is limited to the chest surgical resection is not only an important therapeutic modality, but in many cases, the most effective method of controlling the disease. Patients with stages I-II localized cancer without spread to lymph nodes are considered to have early stage lung cancer and are almost always treated with a thoracotomy, which is a surgical procedure to open the chest and remove cancerous lung tissue. This surgical procedure is performed under general anesthesia. Some individuals with stage IIIA NSCLC can be treated with surgery as well however surgery for stage IIIB and IV disease is ineffective because the lung cancer has already spread.(1,2,3)
Radiation therapy uses high-powered energy beams, such as X-rays or protons, to kill cancer cells. Radiation therapy may be used alone or with chemotherapy before surgery to shrink a tumor or after surgery to kill any remaining cancer cells.(1-6)
Systemic Therapy: Precision Cancer Medicine, Chemotherapy
Systemic therapy is any treatment directed at destroying cancer cells throughout the body. Many patients with NSCLC already have small amounts of cancer that have spread outside the lungs that cannot be treated with surgery or radiation. These cancer cells cannot be detected with any of the currently available tests and are referred to as micrometastases. The presence of micrometastases causes NSCLC recurrence following local treatment with surgery and/or radiation therapy alone. An effective systemic treatment is needed to cleanse the body of micrometastases in order to improve a patient’s duration of survival and potential for cure.
Systemic therapies commonly used in the treatment of NSCLC include:
Precision Cancer Medicines
The purpose of precision cancer medicine is to define the genomic alterations in the cancers DNA that are driving that specific cancer. Precision cancer medicine utilizes molecular diagnostic testing, including DNA sequencing, to identify cancer-driving abnormalities in a cancer’s genome. Once a genetic abnormality is identified, a specific targeted therapy can be designed to attack a specific mutation or other cancer-related change in the DNA programming of the cancer cells. Precision cancer medicine uses targeted drugs and immunotherapies engineered to directly attack the cancer cells with specific abnormalities, leaving normal cells largely unharmed.
Large-scale screening for epidermal growth factor receptor (EGFR) PD-1, ROS1, ALK, RET, BRAF, MET, TRK and other mutations in lung cancer is feasible and allows for customization of treatment leading to improved outcomes.(7-16)
Chemotherapy uses medications that can be taken orally as a pill or are injected into a vein to kill cancer cells. In some situations chemotherapy is combined with radiation therapy or other precision cancer medicines to achieve the best results.
Treatment of Non Small Cell Lung Cancer by Stage
Stage II: The cancer has not spread to the lymph nodes but is larger than 5 centimeters or involves structures near the lung such as the chest wall or diaphragm. NSCLC is also considered to be Stage II if it measures 7 centimeters or less and involves the lymph nodes within the lung or near the bronchus.
Stage IIIA: The cancer involves lymph nodes in the space between the lungs (mediastinum) or near where the windpipe divides; is large or extensive but the only lymph node involvement is within the lung or near the bronchus; or there is no lymph node involvement but the cancer extends to other organs or tissues such as the heart, great vessels, trachea, or other lobes of the lung.
Stage IIIB: The cancer involves lymph nodes on the opposite side of the chest or above the collar bone, or is extensive (involves organs such as the heart or trachea) and also involves lymph nodes in the center of the chest (mediastinum) or near where the windpipe divides.
Radiation therapy uses high-powered energy beams, such as X-rays or protons, to kill cancer cells. Radiation therapy may be used as part of an overall strategy to treat stage III disease, treat single metastases, or control the cancer in individuals unable to undergo surgery systemic chemotherapy treatment.
Some patients with NSCLC are not able to undergo the surgery to remove their cancer. Advanced age and other medical conditions such as heart disease and diminished lung capacity make it more difficult for these patients to withstand surgery. Studies have demonstrated that patients with stages IIIA NSCLC who are not able to, or do not wish to undergo surgery may be treated with radiation therapy alone. Results indicated that radiation therapy alone produced an average survival time of over 30 and 34 months, respectively.(2,4)
Prophylactic brain radiation: Researchers have found that the most common site for cancer to spread in patients is the brain. These patients may benefit from radiation treatment to the brain during their initial therapy, which is called prophylactic treatment. Results of a clinical trial indicate that prophylactic brain radiation reduced the rate of cancer recurrence in the brain from 30% to 8% and the overall chance of relapse in the brain from 54% to 13%. Researchers reported that patients who received prophylactic brain radiation did not experience impaired attention or visual memory after treatment.(2,5,6)
The role of surgery in the management of lung cancer consists of obtaining a biopsy to make a correct diagnosis, determining the correct stage of the cancer in order to ensure optimal treatment and treating the cancer by surgical removal in selected situations. The decision to treat lung cancer surgically depends on the type of lung cancer, as well as several prognostic factors. Surgery is a common form of treatment for non-small cell lung cancer (NSCLC), whereas, it is not as commonly used with small cell lung cancer (SCLC).(1,2)
Types of Surgical Procedures for Diagnosing Lung Cancer
In order to accurately diagnose a lung cancer, a biopsy, or small piece of tissue, must be obtained and examined under a microscope. Because of the use of computed tomography (CT) screening, the detection of small abnormal areas in the lung that may or may not be cancer has become more common. There are several procedures that can be used to perform a biopsy.
CT Guided Fine Needle Aspiration Biopsy: CT guided fine needle aspiration biopsy is the most common way to evaluate possible cancers. A CT scan takes a very detailed picture of a patient’s suspected cancer, allowing the insertion of a thin needle to remove a sample of the tissue. This gives doctors the most information without resorting to a more invasive surgery (thoracotomy) and direct biopsy.
Thoracotomy: During a thoracotomy, a surgeon makes a large incision in a patient’s chest in order to directly access the mass and directly remove part or all of the suspicious area. In some patients with a peripheral lung mass and no evidence of mediastinal or systemic cancer, a wedge resection of the lesion is sometimes performed and diagnosis made on a frozen-section of tissue. If lung cancer is confirmed, a formal cancer resection is then performed.
Endoscopic Ultrasound Guided Fine Needle Aspiration Biopsy: The mediastinum is the area behind the breast bone and consists of blood vessels, lymph nodes and other structures. Because lung cancer frequently spreads to lymph nodes in the mediastinum, biopsies to this area are often necessary. An endoscopic ultrasound guided fine needle aspiration biopsy is often used to evaluate the mediastinum. This technique is performed in order to avoid the more invasive procedures of mediastinoscopy or thoracotomy. Using this technique, more invasive methods of diagnosis can be avoided in approximately 50% of patients. An ultrasound machine is used to take pictures of the mediastinum, allowing a small biopsy needle to be directly inserted into the suspicious area without making an incision in the chest.
Cervical Mediastinoscopy: Mediastinoscopy is another diagnostic procedure used to determine whether mediastinal lymph nodes contain cancer. This procedure is used in cases where endoscopic ultrasound guided fine needle aspiration biopsy is not indicated or was not successful. Medianstinoscopy requires general anesthesia, a small anterior neck incision and insertion of an endoscope, which is a thin, lighted tube. A complete procedure includes extensive sampling of lymph nodes in the upper and lower mediastinum.
Bronchoscopy: During a bronchoscopy, a physician inserts a bronchoscope (thin, lighted tube) through the nose or mouth into the trachea (windpipe) and bronchi (air passages that lead to the lung). Through this tube, the surgeon can examine the inside of the trachea, bronchi and lung and collect cells or small tissue samples.
Thorascopy: During this procedure, an endoscope called a thorascope is inserted through a small incision in the chest wall. Thorascopy is a limited surgical procedure that allows the lining of the chest wall and the lungs to be examined and biopsied to determine if cancer is present.
Small cell lung cancer is not typically treated with surgery because the disease is usually widespread at the time of diagnosis. Once a diagnosis of SCLC is made and the amount of disease is characterized as either limited or extensive, patients typically receive treatment with systemic therapy and possibly radiotherapy. However, good results from surgery alone have been reported in a small subgroup of patients that have a small primary cancer and no lymph node involvement. Sometimes surgery is used in conjunction with chemotherapy and/or radiation therapy, but the contribution of surgery to overall outcome is not clear in this setting.(2)
Approximately 45% of all patients with NSCLC have cancer that is limited to the chest. For these patients, surgical resection is not only an important therapeutic modality, but in many cases, the most effective method of controlling the disease. Patients with stages I-II localized cancer without spread to lymph nodes are considered to have early stage lung cancer and are almost always treated with surgery.
Patients with stage III NSCLC may be treated with either neoadjuvant chemotherapy followed by surgery or combined treatment with chemotherapy and radiation therapy.(2) The following are the types of surgical procedures that may be performed in patients with stage I-III NSCLC. For patients with stage IV disease, surgery is usually not indicated.
Thoracotomy: Thoracotomy is a surgical procedure to open the chest and remove cancerous lung tissue. This surgical procedure is performed under general anesthesia.
During a thoracotomy the surgeon may remove part or all of a lung. There are two operations to remove a small part of the lung. A wedge resection removes a very small part of the lung and segmentectomy removes a slightly larger part of lung based on anatomical segments. These types of operation are used when the cancer has been diagnosed early and is only in one very small area. A lobectomy is the removal of one lobe of the lung and is the most frequent operation performed for early stage NSCLC. A pneumonectomy is the removal of the entire lung. This procedure is performed when the cancer is found to involve more than one lobe. Pneumonectomy is associated with more than twice the mortality rate of lobectomy, as well as more long-term pulmonary side effects.
Video-Assisted Thorascopic Surgery (VATS): This is a form of minimally invasive surgery that utilizes a television camera. The advantages of the camera-aided procedures are that smaller incisions can be used and there is no need to cut through a rib, which is necessary for conventional thoracotomy. This results in quicker, less intrusive surgery, with a much smaller scar. However, using these new procedures requires significant skill and a great deal of training. There is less, or at least different, visibility with VATS. If a serious problem arises, VATS can be converted to an open or traditional procedure, creating a small additional risk.
Chest Tube Thoracostomy: This is a procedure performed to drain fluid, blood or air from the space around the lungs (pleural space).
Precision Cancer Medicine - Not all cancer cells are alike
Lung cancers may differ from one another based on what genes have mutations. Precision cancer medicine utilizes molecular diagnostic testing, including DNA sequencing, to identify cancer-driving abnormalities in a cancer’s genome. This “genomic testing” is performed on a biopsy sample of the cancer and sometimes with a "blood biopsy"
Once a genetic abnormality is identified that is driving the growth of the lung cancer, a specific precision cancer medicine or targeted therapy can be developed to attack that specific mutation or other cancer-related change in the DNA programming of the cancer cells.
Precision cancer medicine uses targeted drugs and immunotherapies engineered to directly attack the specific genetic mutation that is driving the lung cancers growth. Precision cancer medicines can be used both instead of and in addition to chemotherapy to improve treatment outcomes.
Lung Cancer Biomarkers & Medicines to Target Them
Testing an individual’s lung cancer for specific biomarkers and genomic alterations allow doctors to identify cancer driving genetic mutations and offer the most personalized treatment approach utilizing precision medicines. Individuals with lung cancer should undergo genomic testing to determine whether newer precision cancer medicines are a treatment option.(2,6,7)
- NSCLC: EGFR, MET, ALK, TRK, RET, BRAF, ROS1 mutations can be treated with a specific precision cancer medicine.
- Squamous and non-squamous NSCLC with high levels of PD-L1 can benefit from treatment with immunotherapy.
PD-1 Checkpoint Inhibitors
Checkpoint inhibitors are a novel precision cancer immunotherapy that helps to restore the body’s immune system in fighting cancer by releasing checkpoints that cancer uses to shut down the immune system. PD-1 and PD -L1 are proteins that inhibit certain types of immune responses, allowing cancer cells to evade an attack by the body’s immune cells. Checkpoint inhibitor drugs that block the PD-1 pathway enhance the ability of the immune system to fight cancer. By blocking the binding of the PD-L1 ligand these drugs restore an immune cells’ ability to recognize and fight the lung cancer cells.
Overall two thirds of lung cancer patients have some expression of PD-1, and one third are “high expressers” meaning over 50% of the tested tumor expresses PD-1. A diagnostic test to measure the level of PD-L1 is available and checkpoint inhibitors are effective in the management of many lung cancers.(9,10)
Keytruda® (pembrolizumab) was the first checkpoint inhibitor to have received FDA approval in the U.S for the treatment of NSCLC and Keytruda® improves survival rates among patients with certain lung cancers.(8)
- Keytruda® (pembrolizumab)
- Opdivo (nivolumab)
- Imfinzi (durvalumab)
- Tecentriq® (atezolizumab)
Epidermal growth factor receptor (EGFR): The EGFR pathway is a normal biologic pathway found in healthy cells. It is involved in regular cellular division and growth. However, certain mutations within the EGFR gene can lead to an overactive EGFR pathway, leading to the development and/or spread of cancer. These cancers are referred to as EGFR-positive, and there are several FDA-approved medications know as tyrosine kinase inhibitors (TKI) that block the activity of EGFR and slow cancer growth for EGFR-positive cancers. EGFR mutations are most common in individuals who never smoked, woman, people of Asian ethnicity, and those with a type of lung cancer known as adenocarcinoma.(11,12) There are several FDA approved TKI inhibitors and others in development.
- Tagrisso (Osimertinib)
- Tarceva (Erlotinib)
- Erbitux (Cetuximab)
- Iressa (Gefitinib)
- Gilotrif (Afatinib)
- Vectibix (Panutumamab)
ALK+ Lung Cancer: Approximately 5% of all NSCLC have an identified mutation referred to as the anaplastic lymphoma kinase (ALK) mutation. The ALK mutation is responsible for initiating and promoting cancer growth. Individuals with ALK+ lung cancer tend to be non-smokers or former light smokers; younger, and are a type of NSCLC referred to as adenocarcinoma (based upon the cells affected); and respond worse to standard chemotherapy regimens than patients who do not have the ALK mutation.(13,14) There are several FDA approved medications that target ALK and others in development.
- Zykadia® (ceritinib)
- Alecensa (alectinib)
- Alunbrig (brigatinib)
- Xalkori (crizotinib)
- Alunbrig (brigatinib)
ROS-1+ Lung Cancer: The ROS-1 mutation is an uncommon mutation found in only 1% of individuals with NSCLC. Research has indicated that the ROS-1 mutation plays a role in the development and progression of some lung cancers, and patient characteristics are similar to those who have ALK+ NSCLC and can be targeted with Xalkori.(14)
BRAF & MEK Kinase Inhibitors: The BRAF and MEK genes are known to play a role in cell growth, and mutations of these genes are common in several types of cancer. Lung cancers may carry the BRAF mutation known as V600E. This mutation produces an abnormal version of the BRAF kinase that stimulates cancer growth. Another mutation known as V600K may also be present. BRAF and MEK inhibitors are precision cancer medicines that block the activity of the V600E and V600K mutations respectively.(16)
- Zelboraf®(vemurafenib) BRAF V600E kinase inhibitor
- Tafinlar®(dabrafenib) BRAF V600E kinase inhibitor
- Mekinist®(trametinib) MEK V600 kinase inhibitor
- Cotellic® (cobimetinib) MEK V600 kinase inhibitor
A combination of a BRAF and a MEK inhibitor appears to decrease the emergence of disease resistance that occurs in patients treated with a BRAF mutation. The combination of Taflinar plus Mekinist has been evaluated and FDA approved.(16)
RET + Lung Cancer: Genetic alternations in the RET ( rearranged during transfection) receptor tyrosine kinase are present in 1-2% of NSCLC's and drive their development and growth.(17)
TRK + Lung Cancer: Tropomyosin receptor kinases (TRK) fusions are rare chromosomal abnormalities that occur when one of the NTRK genes (NTRK1, NTRK2, NTRK3) becomes abnormally connected to another, unrelated gene (e.g. ETV6, LMNA, TPM3). This abnormality results in uncontrolled TRK signaling that can lead to cancer. (18,19)
- Vitrakvi (larotrectinib)
Immunologic Therapy or Immuno-oncology
Immunotherapy treatment of NSCLC has also progressed considerably over the past few decades and has now become a standard treatment. The immune system is a network of cells, tissues, and biologic substances that defend the body against viruses, bacteria, and cancer. Doctors have been trying for years to find ways to harness an individual’s immune system to fight cancer.
The immune system recognizes cancer cells as foreign and can eliminate them or keep them in check—up to a point. Cancer cells are very good at finding ways to avoid immune destruction however, so the goal of immunotherapy is to help the immune system eliminate cancer cells by either activating the immune system directly or inhibiting the mechanisms of suppression of the immune system.
Recent promising clinical results have generated an explosion of interest and research in the field of immuno-oncology. Researchers are mainly focused on two promising types of immunotherapy. One type creates a new, individualized treatment for each patient by removing some of the person’s immune cells, altering them genetically to kill cancer, and then infusing them back into the bloodstream. This procedure has been pioneered mainly in the treatment of leukemia or lymphoma.
The second type of immunotherapy is a group of drugs that do not have to be tailored to each patient; these are called checkpoint inhibitors. These drugs block a mechanism, called a checkpoint, that cancer uses to shut down the immune system. These drugs have been approved by the US Food and Drug Administration (FDA) to treat several types of cancer, including NSCLC.(8,9)
Checkpoint inhibitors work on killer T-cells—the white blood cells that are often described as the soldiers of the immune system. T-cells have built-in brakes, or checkpoints, to turn them off and keep them from attacking normal tissue, which could result in autoimmune diseases. One checkpoint stops T-cells from multiplying; another weakens them and shortens their life span.
Several checkpoint inhibitors have already been approved for treatment of patients with more-advanced NSCLC, based on clinical trials showing they were superior to chemotherapy. Keytruda has shown prolonged survival and an increased time to cancer recurrence compared with standard chemotherapy in patients with newly diagnosed advanced NSCLC whose tumors expressed high levels of PD-L1. Patients had to have PD-L1 expression greater than 50 percent to participate in the trial.(8)
This is in contrast to the checkpoint inhibitor Opdivo, which, in another clinical trial in newly diagnosed patients, did not improve outcomes for PD-L1–positive NSCLC when compared with chemotherapy.vThis came as a bit of a surprise to many in the oncology community, but the results may be explained by the fact that the Opdivo trial did not require participants’ cancers to have as high a level of PD-L1 expression.(9)
Researchers suspect that checkpoint inhibitors might work better if they are combined with treatments that kill tumor cells because debris from dead cancer cells may help the immune system recognize its target. Studies are under way to test checkpoint inhibitors in combination with chemotherapy. But it is a delicate balance to adjust the timing and doses because in addition to killing cancer cells, chemotherapy treatments can knock out the immune system just when it is needed most.
One significant side effect of checkpoint inhibitors will require further research: in addition to causing lung inflammation, checkpoint inhibitors can lead to autoimmune disease, including colitis and rheumatoid arthritis, which result from an attack on other tissues by the revved-up immune system.
More-detailed and in-depth results of the recent clinical trials evaluating checkpoint inhibitors will is forth coming, and this will provide better guidance regarding their optimal use in the treatment of NSCLC. Importantly, there are also ongoing clinical trials evaluating these and other novel targeted and immunotherapies for the management of NSCLC; patients should discuss the potential role of these trials with their treating physician.
- American Cancer Society. Cancer Facts & Figures 2017.
- Jeremic B, Calssen J, Bamberg M. Radiotherapy alone in technically operable, medically inoperable, early-stage (I/II) non-small-cell lung cancer. International Journal of Radiation Oncology, Biology, Physics 2002;54:119.
- Stuschke M, Eberhardt W, Pottgen C, Stamatis G, Wilke H, Stuben G, Stoblen F, Wilhelm HH, Menker H, Teschler H, Muller RD, Budach V, Seeber S, Sack H. Prophylactic cranial irradiation in locally advanced non-small-cell lung cancer after multimodality treatment: long-term follow-up and investigations of late neuropsychologic effects. Journal of Clinical Oncology. 1999 Sep;17(9):2700-9.
- Mamon H, Yeap B, Jänne P, et al. High Risk of Brain Metastases in Surgically Staged IIIA Non–Small-Cell Lung Cancer Patients Treated With Surgery, Chemotherapy, and Radiation. Journal of Clinical Oncology. 2005; 23: 1530-1537.
- Rosell R, Moran T, Queralt C, et al. Screening for epidermal growth factor receptor mutations in lung cancer. New England Journal of Medicine. [early online publication]. August 19, 2009.
- Quest Diagnostics Press Release. Quest Diagnostics Introduces Dako’s PD-L1 Complementary Diagnostic Test to Support Bristol-Myers Squibb’s OPDIVO® Anti-PD-1 Therapy for Non-squamous Non-small Cell Lung Cancer. The new Quest test service is based on the first FDA-approved complementary diagnostic. Available online at: . Accessed November 8, 2015.
- Keytruda (pembrolizumab) demonstrates superior progression-free and overall survival compared to chemotherapy as first line treatment in patients with advanced non-small cell lung cancer. [Press release.] http://www.mercknewsroom.com/news-release/oncology-newsroom/mercks-keytruda%C2%A0pembrolizumab-demonstrates-superior-progression-free- Accessed June 21, 2016.
- Borghaei H, Paz-Ares L, Horn L, et al. Nivolumab versus Docetaxel in Advanced Nonsquamous Non–Small-Cell Lung Cancer. New England Journal of Medicine. 2015; 373:1627-1639.
- OSI Pharmaceuticals. FDA Approves Tarceva as a Maintenance Therapy for Advanced Non-small Cell Lung Cancer. Available at: http://investor.osip.com/releasedetail.cfm?ReleaseID=460783. Accessed April 19, 2010.
- Zhou C, Wu Y-L, Chen G et al. Erlotinib versus chemotherapy as first-line treatment for patients with advanced EGFR mutation-positive non-small-cell lung cancer (OPTIMAL, CTONG-0802): A multicentre, open-label, randomized, phase 3 study. Lancet Oncology. Early online publication July 22, 2011.
- Shaw AT, Kim DW, Mehra R, et al: Ceritinib in ALK-rearranged non–small-cell lung cancer. New England Journal of Medicine. 2014; 370: 1189-1197.
- Leighl NB, Rekhtman N, Biermann WA, et al. Molecular testing for selection of patients with lung cancer for epidermal growth factor receptor and anaplastic lymphoma kinase tyrosine kinase inhibitors: American Society of Clinical Oncology endorsement of the College of American Pathologists/International Association for the Study of Lung Cancer/Association for Molecular Pathology Guideline. Journal of Clinical Oncology. 2014;32(32):3673-79. Available at: <a href="http://jco.ascopubs.org/content/32/32/3673.">http://jco.ascopubs.org/content/32/32/3673.</a> Accessed September 30, 2016.
- United States Food and Drug Administration (FDA). FDA expands use of Xalkori to treat rare form of advanced non-small cell lung cancer. Available at: http://www.fda.gov/NewsEvents/Newsroom/PressAnnouncements/ucm490329.htm. Accessed March 11, 2016.
- <a href="https://www.fda.gov/Drugs/InformationOnDrugs/ApprovedDrugs/ucm564331.htm?source=govdelivery&utm\_medium=email&utm\_source=govdelivery">https://www.fda.gov/Drugs/InformationOnDrugs/ApprovedDrugs/ucm564331.htm?source=govdelivery&utm_medium=email&utm_source=govdelivery</a>
- Gainor JF, et al. Abstract 9008. Presented at: ASCO Annual Meeting; May 31-June 4, 2019; Chicago.