Stages of Lung Cancer
Stages of Lung Cancer
Stage I – IIIA Non-Small Cell Lung Cancer
Overview
Stage I-IIIA non-small cell lung cancers (NSCLC) are considered surgically resectable and treated with a combination of surgery and systemic therapy consisting of chemotherapy, immunotherapy and/or precision cancer medicines. Stage I is a cancer that is located in only one lung and has not spread to the adjacent lymph nodes or outside the chest – surgical removal of the cancer results in over 60% of patients surviving without evidence of cancer recurrence within 5 years of treatment. Stage II cancers are located in one lung and may involve lymph nodes on the same side of the chest that do not include lymph nodes in the mediastinum.
Systemic chemotherapy improves survival for patients with stage I – IIIA NSCLC when compared to treatment with surgery alone and is now considered standard of care. Efforts are underway to evaluate newer precision cancer medicines that target cancer causing mutations to further improve the outcome of individuals with early stage NSCLC. The precision cancer medicine Tagrisso improves the outcomes of EGFR mutated NSCLC and patients should ensure NGS-biomarker testing is performed to identify treatable cancer driving mutations.1,2,9,10
The following is a general overview of treatment for stage I-III surgically resectable NSCLC. The information on this website is intended to help educate patients about their treatment options and to facilitate a mutual or shared decision-making process with their treating cancer physician.
Treatments
Surgery
For patients with NSCLC 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-IIIA localized cancer are considered to have early stage disease and are almost always treated with surgery. The following are the types of surgical procedures that may be performed.
Thoracotomy: Thoracotomy is a surgical procedure to open the chest and remove cancerous lung tissue. This surgical procedure is performed under general anesthesia.
Surgical removal of the cancer may be accomplished by removing the entire lung (pneumonectomy), a lobe of the lung (lobectomy) or even a small segment of the lung (segmentectomy). In general, the less lung that is removed, the greater the preservation of lung function and the lower the risk of major side effects from the surgery. On the other hand, if too little lung is removed, there is an increased chance of a local cancer recurrence. Currently, most physicians recommend a lobectomy. A patient’s general overall condition, age and location of the cancer are other factors that may influence the type of surgery performed and the side effects associated with the surgery. Prior to surgery, patients should carefully discuss the risks and benefits of removing the cancer with their surgeon.
When surgery is conducted in patients with early-stage NSCLC, physicians often remove nearby lymph nodes and send them to the laboratory to determine if they contain cancer cells. The number of lymph nodes removed is often based on physician preference. Results from a recent study conducted by researchers in New York indicate that patients with a larger number of sampled lymph nodes may be more accurately staged and receive more appropriate therapy, ultimately leading to improved overall and cancer-free survival. These researchers suggest that 6 or more lymph nodes should be surgically removed and evaluated in all patients with NSCLC undergoing surgery to remove cancer.3
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.
Systemic therapy: precision cancer medicine, chemotherapy, and immunotherapy
Systemic therapy is any treatment directed at destroying cancer cells throughout the body. Some patients with early stage cancer already have small amounts of cancer that have spread outside the lungs. These cancer cells cannot be treated with surgery alone and require systemic treatment to decrease the chance of cancer recurrence. Systemic therapy can be administered after (adjuvant) or before surgery (neoadjuvant).
- Chemotherapy: Chemotherapy is any treatment involving the use of drugs to kill cancer cells. Cancer chemotherapy may consist of single drugs or combinations of drugs. Adjuvant chemotherapy decreases cancer recurrences and prolongs survival.1,6 Chemotherapy drugs however cannot tell the difference between a cancer cell and a healthy cell. Therefore, chemotherapy often affects the body’s normal tissues and organs, which can result in complications or side effects. In order to more specifically target the cancer and avoid unwanted side effects researchers are increasingly using precision cancer medicines that target specific cancer causing mutations.
- Precision Cancer Medicines: Through genomic-biomarker testing performed on a biopsy of the cancer or from a blood sample doctors are increasingly able to define the genomic alterations in a cancers DNA that is driving the growth of a specific cancer. Once a genetic abnormality is identified, a precision medicine can be designed to target 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.9,10,11,12,13,14
- EGFR positive NSCLC: Approximately 10-15% of NSCLC patients in the US and Europe, and 30-40% of patients in Asia have epidermal growth factor receptor – mutated (EGFRm) NSCLC. These patients are particularly sensitive to treatment with precision cancer medicines known as EGFR-tyrosine kinase inhibitors (TKIs) which block the cell-signaling pathways that drive the growth of EGFR expressing lung cancer cells. Tagrisso (osimertinib) is a third-generation, irreversible EGFR-TKI designed to inhibit both EGFR-sensitizing and EGFR T790M-resistance mutations, with clinical activity against CNS metastases.13,14
- Immunotherapy: Precision immunotherapy treatment of cancer 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. 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 cancer.15
Neoadjuvant therapy is any systemic treatment that is delivered before surgery with the goal of providing immediate treatment and reducing the size of the cancer for easier resection. Neoadjuvant chemotherapy reduces the time to cancer recurrence and improves overall survival in patients with NSCLC.7 Neoadjuvant immunotherapy also appears effective. The CheckMate -816 clinical trial demonstrated benefit with an immune checkpoint inhibitor in combination with chemotherapy as a neoadjuvant treatment in select patients with resectable NSCLC.15 Patients should discuss the pros and cons of neoadjuvant compared to adjuvant systemic therapy with their physician.
Radiation therapy
Some patients with lung cancer 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. For these patients, staging of their cancer may be relatively precise using newer scanning techniques, including positron emission tomography (PET) and they are often offered radiation therapy as treatment for their cancer.
Two studies have demonstrated that patients with early stage NSCLC who are not able to, or do not wish to undergo surgery may be treated with radiation therapy alone. One of these was an extensive review of the literature since the mid-1980’s and the other was a recently conducted clinical trial that evaluated the use of radiation administered twice-daily for approximately 5 weeks. Results indicated that radiation therapy alone produced an average survival time of over 30 and 34 months, respectively.4,5
Treatment follow-up
Although patients with NSCLC have a relatively high rate of long-term survival following treatment some patients are still at risk for developing a cancer recurrence, and others may still develop another lung cancer if lifestyle or other factors that increase their risk of developing cancer have not been changed. Researchers have been evaluating different screening methods and schedules for these patients in order to detect recurrent or second cancers early, when they are most treatable.
Researchers from the City of Hope National Medical Center recently determined that annual CT scans and chest x-rays three times per year may detect early second cancers in patients with previously treated NSCLC who appeared to be cured.8
References
1 The International Adjuvant Lung Trial Collaborative Group. Cisplatin-based adjuvant chemotherapy in patients with completely resected Non-Small Cell Lung Cancer. New England Journal of Medicine. 2004;350:351-360.
2 Kato H, Ichinose Y, Ohta M, et al. A randomized trial of adjuvant chemotherapy with uracil-tegafur for adenocarcinoma of the lung. New England Journal of Medicine. 2004;350(17):1713-21.
3 Gajra A, Newman N, Gamble G, et al. Effect of number of lymph nodes sampled on outcome in patients with Stage II non-small-cell lung cancer. Journal of Clinical Oncology 2003;21:1029-1034.
4 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, Physics2002;54:119.
5 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, Physics2002;54:119.
6 Strauss GM, Herndon J, Maddaus MA, et al. Randomized clinical trial of adjuvant chemotherapy with paclitaxel and carboplatin following resection in Stage IB non-small cell lung cancer: Report of Cancer and Leukemia Group B (CALGB) Protocol 9633. Journal of Clinical Oncology. 2004;22:Suppl 14S: Abstract #7019.
7 NSCLC Meta-analysis Collaborative Group. Preoperative chemotherapy for non-small cell lung cancer: a systematic review and meta-analysis of individual participant data. The Lancet. Published early online February 25, 2014. doi:10.1016/S0140-6736(13)62159-5
8 Lamong J, Kakuda J, Smith D, et al. Systematic postoperative radiologic follow-up in patients with non-small cell lung cancer for detecting second primary lung cancer in stage IA. Archives of Surgery2002;137:935-939.
9 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.
10 OSI Pharmaceuticals. FDA Approves Tarceva as a Maintenance Therapy for Advanced Non-small Cell Lung Cancer. Available at: investor.osip.com/releasedetail.cfm?ReleaseID=460783. Accessed April 19, 2010.
11 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.
12 Kwak EL, Bang Y-J, Camidge DR et al. Anaplastic lymphoma kinase inhibition in non-small-cell lung cancer. New England Journal of Medicine. 2010;363:1693-1703.
13 Randomized controlled phase III trial of adjuvant chemoimmunotherapy to lung cancer patients: Results of malignant effusions. Presented at: IASLC 2019 World Conference on Lung Cancer hosted by the International Association for the Study of Lung Cancer; September 7-10, 2019; Barcelona, Spain. Abstract P1.04-08.
14 Tagrisso – First Precision Medicine Approved for Treatment of Early Stage NSCLC
15 Opdivo (nivolumab) Plus Chemotherapy Shows Statistically Significant Improvement in Pathologic Complete Response as Neoadjuvant Treatment of Resectable Non-Small Cell Lung Cancer in Phase 3 CheckMate-816 Trial [news release]. Princeton, NJ. Published October 7, 2020. Accessed October 7, 2020.
Stage IIIB Non-Small Cell Lung Cancer
Overview
A stage IIIB non-small cell lung cancer (NSCLC) 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.
Although some patients with Stage IIIB NSCLC have cancer that has spread to only a single other site that can be treated with surgery or radiation therapy, systemic therapy with chemotherapy or targeted therapy is the mainstay of treatment for most patients with Stage IIIB NSCLC. Targeted therapies (which may be used in combination with chemotherapy) are also playing an increasing role in the treatment of selected patients with NSCLC.
Stage IIIB NSCLC has not historically been considered curable, but advances in treatment including the development of new chemotherapy drugs and targeted therapies are prolonging survival and reducing cancer symptoms well beyond what was expected just a few years ago. Some patients with stage 3B NSCLC can now expect to survive beyond 5 years and have a good quality of life.
Treatments
The following is a general overview of treatment for stage IIIB NSCLC. Cancer treatment may consist of chemotherapy, targeted therapy, or a combination of these treatment techniques. Combining two or more of these treatment techniques has become an important approach for prolonging survival and increasing a patient’s chance for cure.
Circumstances unique to each patient’s situation influence which treatment or treatments are utilized. The potential benefits of multi-modality care, participation in a clinical trial, or standard treatment must be carefully balanced with the potential risks. The information on this website is intended to help educate patients about their treatment options and to facilitate a mutual or shared decision-making process with their treating cancer physician.
Currently, no one “best” treatment has been established for individuals with stage IIIB NSCLC. Treatment depends upon the size and location of the cancer, lymph node involvement, and whether surgery has already been performed. Treatment options may include surgery, radiation therapy, and chemotherapy alone or in combination. Chemotherapy and radiation may be administered concurrently or sequentially and surgery can be performed before or after. Its important for individuals with stage 3B NSCLC to be evaluated by a multi-speciality team so that they best overall strategy can be determined.
Chemotherapy for stage IIIB NSCLC
Chemotherapy uses drugs that kill rapidly dividing cells, a hallmark of cancer. Cancer chemotherapy may consist of single drugs or combinations of drugs. It can be administered through a vein, injected into a body cavity, or delivered orally in the form of a pill.
Chemotherapy is different from surgery or radiation therapy in that the cancer-fighting drugs circulate in the blood to parts of the body where the cancer may have spread; it thus can kill or eliminate cancers cells at sites great distances from the original cancer. As a result, chemotherapy is considered a systemic treatment.
Patients with advanced NSCLC are treated with chemotherapy to alleviate the symptoms of their disease and prolong their duration of survival. Most treatments involve a combination (regimen) of two chemotherapy drugs. The most commonly used regimens include either cisplatin or carboplatin; combined with one of several other drugs approved for the treatment of NSCLC; Alimta® (pemetrexed), Taxol® (paclitaxel), Taxotere® (docetaxel), Gemzar® (gemcitabine), Camptosar® (irinotecan), or Navelbine® (vinorelbine).1
Targeted therapy for stage IIIB NSCLC
A targeted therapy is one that is designed to treat only the cancer cells and minimize damage to normal, healthy cells. Cancer treatments that “target” cancer cells may offer the advantage of reduced treatment-related side effects and improved outcomes. Targeted therapies are playing an increasing role in the treatment of NSCLC.
Avastin® (bevacizumab): Avastin®is a type of targeted therapy that slows or stops the growth of blood vessels that deliver blood to the cancer, effectively starving the cancer of the oxygen and nutrients it requires to survive and grow. Avastin®, in combination with the chemotherapy drugs paclitaxel and carboplatin, is FDA-approved for the treatment of advanced, non-squamous NSCLC.2
EGFR: Mutations in the epidermal growth factor receptor (EGFR) gene may affect how NSCLC responds to certain drugs. EGFR contributes to the growth of several types of cancer, and drugs that block the activity of EGFR can slow cancer growth. One EGFR-targeted drug that has been shown to benefit selected patients with NSCLC is Tarceva® (erlotinib). Tarceva® is currently approved for the treatment of advanced NSCLC and as maintenance therapy after chemotherapy.3,4
EGFR mutations are most common in people of Asian ethnicity, women, never-smokers, and those with a type of lung cancer known as adenocarcinoma. Researchers have reported that EFGR positive individuals treated with Tarceva® plus chemotherapy have delayed time to cancer progression and improved survival compared to those treated with chemotherapy alone.4
XalkoriTM (crizotinib): Up to 7% of NSCLC’s have an abnormal version of the ALK gene that contributes to the growth and development of cancer. XalkoriTM is an oral medication that blocks certain proteins, including the protein produced by this abnormal gene. For advanced NSCLC that test positive for the ALK gene mutation, XalkoriTM has produced very promising rates of response and appears to have some activity treating cancer that has spread to the brain.5,6 A recent clinical trial involving 343 NSCLC patients with overactive ALK reported the results of individuals treated with XalkoriTM or a standard chemotherapy regimen using pemetrexed, and either carboplatin or cisplatin. On average, individuals treated with XalkoriTM, experienced control of their cancer for almost 11 months compared to only 7 months for those receiving the chemotherapy treatment regimen. XalkoriTM treated patients also experienced a greater reduction in symptoms related to their cancer and improved quality of life.
Maintenance therapy
Maintenance therapy refers to treatment that is given after initial treatment but before cancer progression. It is a relatively new approach to lung cancer treatment. Drugs that have been approved for maintenance therapy in selected patients include Alimta® (pemetrexed) and Tarceva®. For patients who are candidates for maintenance therapy, the approach has been shown to delay cancer progression and improve overall survival.7, 8
Treatment of elderly patients
Many NSCLC cases occur in people over the age of 70, but there is limited information about how best to treat older patients. As a result of the limited information and concern that elderly patients will not be able to tolerate aggressive treatment, older patients may be treated with single-agent chemotherapy rather than the combination chemotherapy that is commonly used in younger patients. Studies have suggested, however, that although combination chemotherapy increases side effects, it also improves survival among elderly patients.9
Managing bone complications
NSCLC cells commonly spread to the bone, causing bone metastases. Bone metastases may cause pain, bone loss, increased risk of fractures, and a life-threatening condition characterized by a high level of calcium in the blood, called hypercalcemia.
Preventing or delaying these skeletal-related events (SREs) can preserve quality of life and reduce healthcare costs. Bisphosphonate drugs such as Zometa® (zoledronic acid) and a newer type of bone drug, Xgeva® (denosumab) can be used to reduce the risk of complications from bone metastases. Xgeva® is a drug that targets a protein known as the RANK ligand. This protein regulates the activity of osteoclasts (cells that break down bone). Xgeva® is approved for the prevention of bone complications such as fracture in patients with bone metastases from solid (not blood-related) cancers.
Xgeva® has been directly compared to Zometa® for the treatment of bone metastases in 702 with NSCLC and 109 with small-cell lung cancer (SCLC). Xgeva® is associated with a decrease in SREs and improved overall survival when directly compared with Zometa.10
Managing brain metastases
When NSCLC spreads to the brain, it can symptoms such as headaches and seizures. Depending on the number, size, and location of the tumors in the brain, treatment may involve radiation therapy and/or surgery to remove the tumor.
Managing pleural effusion
In some patients with advanced NSCLC, fluid collects in the space around the lungs. This is called pleural effusion. The fluid can compress the lung and make it difficult to breath. If a patient is experiencing symptoms due to pleural effusion, the fluid may be drained using a catheter.
Strategies to improve non small cell lung cancer treatment
The development of more effective treatment for advanced NCSLC requires that new and innovative therapies be evaluated with cancer patients. Future progress in the treatment of NSCLC will result from the continued evaluation of new treatments in clinical trials.
Patients may gain access to better treatments by participating in a clinical trial. Participation in a clinical trial also contributes to the cancer community’s understanding of optimal cancer care and may lead to better standard treatments. Patients who are interested in participating in a clinical trial should discuss the risks and benefits of clinical trials with their physician.
Areas of active investigation aimed at improving the treatment of lung cancer include some of the following:
New Drugs in Development: More-targeted and more-individualized treatments for NSCLC has recently became a reality. Results from studies evaluating ALK-inhibitors continued to show promise and initial studies exploring immunomodulatory approaches using anti-PD-1 antibodies demonstrated high response rates and slowed cancer progression in previously untreated stage IV NSCLC. The optimal approach to using these and other novel drugs has not been established and researchers continue to evaluate different ways of combining these drugs with each other and with other therapies in order to further improve outcomes.
The Lung-MAP Trial for Squamous Cell Carcinoma: In Lung-MAP (Lung-MAP.org), researchers with several public institutions, including the National Cancer Institute (NCI), are working with pharmaceutical companies to study treatment for advanced squamous cell lung cancer. Though only a fraction (about a quarter) of all lung cancer diagnoses as squamous cell, it’s an important area of research, as there are few treatment options for these patients.
Lung-MAP will evaluate several investigational treatments and match patients with the therapy most likely to benefit them. Participants will undergo genomic profiling—a type of testing that provides information about all the genes in an organism, including variation, gene expression, and the way genes interact with each other and the environment. The drugs studied in Lung-MAP are designed to target genomic alterations involved in the growth of cancer, and researchers will use genomic profiling to match patients with the therapy designed to target the particular genomic alterations that their cancer expresses.
This more comprehensive approach marks a change in the typical clinical trial model for targeted therapies, in which separate studies for the same disease focus on particular genomic abnormalities and treatments. Potential participants are tested for that genomic biomarker (a molecule that is a sign of a normal or abnormal process or of a condition or disease), and only individuals who test positive are enrolled in the study. As a result, many patients are left out of each trial and—with multiple, separate trials—overall progress in treatment development is made less efficient.
In Lung-MAP, however, everyone who’s tested will be eligible for a therapy. And several treatments for advanced squamous cell lung cancer will be evaluated under one protocol in an effort to accelerate safe drug development.
X-396 is a novel ALK inhibitor that is well tolerated and has antitumor activity in patients with ALK positive NSCLC. X-396 is being developed for the treatment of solid tumors where ALK is deregulated. X-396 has been validated in potency and selectivity assays indicating that it is more selective and up to 10 times more potent than competitive ALK inhibitors.
The interim results of one study have demonstrated that among 11 ALK positive patients evaluable for response 6 patients had a partial response (55%) and 2 had stable disease (18%). Of the three patients with progressive disease, and acquired resistance to Xalkori® anti-cancer activity was also observed.11
EGFR: Mutations in the epidermal growth factor receptor (EGFR) gene may affect how NSCLC responds to certain drugs. EGFR contributes to the growth of several types of cancer, and drugs that block the activity of EGFR can slow cancer growth. One EGFR targeted drug that is currently approved for the treatment of advanced NSCLC and as maintenance therapy after chemotherapy is Tarceva®.3, 4
Erbitux® (cetuximab) is another targeted therapy that has produced promising results in selected patients with NSCLC.12
Ganetespib is an investigational drug that targets a protein known as heat shock protein (Hsp) 90. Hsp90 is necessary for the function of several other proteins that are known to play an important role in lung cancer. In a Phase II clinical trial, second-line treatment with a combination of chemotherapy and the investigational drug ganetespib improved overall survival among patients with advanced lung adenocarcinoma.13
CyramzaTM (ramucirumab) is a targeted therapy that inhibits the growth of new blood vessels in tumors and, therefore, slows tumor growth. When combined with Taxotere®, CyramzaTM has been shown to extend overall survival and delay time to cancer progression14
Nintedanib is an angiokinase inhibitor that when combined with Taxotere® improves progression-free and overall survival in patients with NSCLC-adenocarcinoma.15
References
1 Chemotherapy for non small cell lung cancer: http://www.cancer.net/research-and-advocacy/asco-care-and-treatment-recommendations-patients/chemotherapy-stage-IIIB-non-small-cell-lung-cancer
2 Second Phase III Study of Avastin Plus Chemotherapy Shows Improved Progression-Free Survival in First-Line Non-Squamous, Non-Small Cell Lung Cancer. Available at:http://www.gene.com/gene/news/press-releases/display.do?method=detail&id=10727.
3 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.
4 Cappuzo F, Ciuleanu T, Stelmakh L, et al. Erlotinib as maintenance treatment in advanced non-small-cell lung cancer: A multi-center, randomized, placebo-controlled phase 3 study. The Lancet Oncology. Published early online May 20, 2010.
5 Solomon, B., et al. (2014). First-Line Crizotinib versus Chemotherapy in ALK-Positive Lung Cancer New England Journal of Medicine, 371 (23), 2167-2177 DOI.
6 Kwak EL, Bang Y-J, Camidge DR et al. Anaplastic lymphoma kinase inhibition in non-small-cell lung cancer. New England Journal of Medicine. 2010;363:1693-1703.
7 Ciuleanu T, Brodowicz T, Zielinski C et al. Maintenance pemetrexed plus best supportive care versus placebo plus best supportive care for non-small-cell lung cancer: a randomised, double-blind, phase 3 study. Lancet. 2009;374:1432-40
8 Cappuzzo F, Ciuleanu T, Stelmakh L et al. Erlotinib as maintenance treatment in advanced non-small-cell lung cancer: a multicentre, randomised, placebo-controlled phase 3 study. Lancet Oncology. 2010;11:521-529.
9 Quoix E, Zalcman G, Oster J-P et al. Carboplatin and weekly paclitaxel doublet chemotherapy compared with monotherapy in elderly patients with advanced non-small-cell lung cancer: IFCT-0501 randomised, phase 3 trial. The Lancet. Early online publication August 9, 2011.
10 Scagliotti GV, Hirsh V, Siena S, et al. Overall survival improvement in patients with lung cancer and bone metastases treated with denosumab versus zoledronic acid: Subgroup analysis from a randomized phase 3 study. Journal of Thoracic Oncology. 2012; 7(12): 1823-1829.
11 Horn L, Infante J, Blumenshcein G, et al. A phase I trial of X-396, a novel ALK inhibitor, in patients with advanced solid tumors. J Clin Oncol 32:5s, 2014 (suppl; abstr 8030^)
12 Pirker R, Pereira JR, Szczesna A et al. Cetuximab plus chemotherapy in patients with advanced non-small-cell lung cancer (FLEX): an open-label randomised phase III trial. Lancet. 2009;373:1525-1531.
13 Ramalingam SS, Goss GD, Andric ZG et al. A randomized study of ganetespib, a heat shock protein 90 inhibitor, in combination with docetaxel versus docetaxel alone for second-line therapy of lung adenocarcinoma (GALAXY-1). Presented at the 49th Annual Meeting of the American Society of Clinical Oncology. May 31-June 4, 2013; Chicago, IL. Abstract CRA8007.
14 Perol M, et al. REVEL: A randomized, double-blind, phase III study of docetaxel and ramucirumab versus docetaxel and placebo in the second-line treatment of stage IIIB non-small cell lung cancer following disease progression after one prior platinum-based therapy. ASCO 2014; Abstract LBA8006.
15 Reck M, Kaiser R, Mellemgaard A, et al: Docetaxel plus nintedanib versus docetaxel plus placebo in patients with previously treated non-small-cell lung cancer (LUME-Lung 1): a phase 3, double-blind, randomised controlled trial. The Lancet Oncology. 2014; 15(2): 143-155.
Stage IV Non-Small Cell Lung Cancer
Overview
Stage IV non-small cell lung cancer (NSCLC) is found in both lungs, in the fluid that surrounds the lungs or heart, or has spread to other parts of the body such as the liver, brain, or bones.
Although some patients with Stage IV NSCLC have cancer that has spread to only a single other site that can be treated with surgery or radiation therapy, systemic therapy with chemotherapy or targeted therapy is the mainstay of treatment for most patients with Stage IV NSCLC. Targeted therapies (which may be used in combination with chemotherapy) are also playing an increasing role in the treatment of selected patients with NSCLC.
Stage IV NSCLC is usually not considered curable, but newer treatments are prolonging survival and reducing cancer symptoms well beyond what was expected just a few years ago.
Treatments
The following is a general overview of treatment for stage IV NSCLC. Cancer treatment may consist of chemotherapy, targeted therapy, or a combination of these treatment techniques. Combining two or more of these treatment techniques has become an important approach for prolonging survival and increasing a patient’s chance for cure.
Circumstances unique to each patient’s situation influence which treatment or treatments are utilized. The potential benefits of multi-modality care, participation in a clinical trial, or standard treatment must be carefully balanced with the potential risks. The information on this website is intended to help educate patients about their treatment options and to facilitate a mutual or shared decision-making process with their treating cancer physician.
Chemotherapy for stage IV NSCLC
Chemotherapy uses drugs that kill rapidly dividing cells, a hallmark of cancer. Cancer chemotherapy may consist of single drugs or combinations of drugs. It can be administered through a vein, injected into a body cavity, or delivered orally in the form of a pill.
Chemotherapy is different from surgery or radiation therapy in that the cancer-fighting drugs circulate in the blood to parts of the body where the cancer may have spread; it thus can kill or eliminate cancers cells at sites great distances from the original cancer. As a result, chemotherapy is considered a systemic treatment.
Patients with advanced NSCLC are treated with chemotherapy to alleviate the symptoms of their disease and prolong their duration of survival. Most treatments involve a combination (regimen) of two chemotherapy drugs. The most commonly used regimens include either cisplatin or carboplatin; combined with one of several other drugs approved for the treatment of NSCLC; Alimta® (pemetrexed), Taxol® (paclitaxel), Taxotere® (docetaxel), Gemzar® (gemcitabine), Camptosar® (irinotecan), or Navelbine® (vinorelbine).1
Targeted therapy for stage IV NSCLC
A targeted therapy is one that is designed to treat only the cancer cells and minimize damage to normal, healthy cells. Cancer treatments that “target” cancer cells may offer the advantage of reduced treatment-related side effects and improved outcomes. Targeted therapies are playing an increasing role in the treatment of NSCLC.
Avastin® (bevacizumab): Avastin®is a type of targeted therapy that slows or stops the growth of blood vessels that deliver blood to the cancer, effectively starving the cancer of the oxygen and nutrients it requires to survive and grow. Avastin®, in combination with the chemotherapy drugs paclitaxel and carboplatin, is FDA-approved for the treatment of advanced, non-squamous NSCLC.2
EGFR: Mutations in the epidermal growth factor receptor (EGFR) gene may affect how NSCLC responds to certain drugs. EGFR contributes to the growth of several types of cancer, and drugs that block the activity of EGFR can slow cancer growth. One EGFR-targeted drug that has been shown to benefit selected patients with NSCLC is Tarceva® (erlotinib). Tarceva® is currently approved for the treatment of advanced NSCLC and as maintenance therapy after chemotherapy.3,4
EGFR mutations are most common in people of Asian ethnicity, women, never-smokers, and those with a type of lung cancer known as adenocarcinoma. Researchers have reported that EFGR positive individuals treated with Tarceva® plus chemotherapy have delayed time to cancer progression and improved survival compared to those treated with chemotherapy alone.4
Xalkori (crizotinib): Up to 7% of NSCLC’s have an abnormal version of the ALK gene that contributes to the growth and development of cancer. XalkoriTM is an oral medication that blocks certain proteins, including the protein produced by this abnormal gene. For advanced NSCLC that test positive for the ALK gene mutation, XalkoriTM has produced very promising rates of response and appears to have some activity treating cancer that has spread to the brain.5,6 A recent clinical trial involving 343 NSCLC patients with overactive ALK reported the results of individuals treated with XalkoriTM or a standard chemotherapy regimen using pemetrexed, and either carboplatin or cisplatin. On average, individuals treated with XalkoriTM, experienced control of their cancer for almost 11 months compared to only 7 months for those receiving the chemotherapy treatment regimen. Xalkori treated patients also experienced a greater reduction in symptoms related to their cancer and improved quality of life.
Maintenance therapy
Maintenance therapy refers to treatment that is given after initial treatment but before cancer progression. It is a relatively new approach to lung cancer treatment. Drugs that have been approved for maintenance therapy in selected patients include Alimta® (pemetrexed) and Tarceva®. For patients who are candidates for maintenance therapy, the approach has been shown to delay cancer progression and improve overall survival.7, 8
Treatment of elderly patients
Many NSCLC cases occur in people over the age of 70, but there is limited information about how best to treat older patients. As a result of the limited information and concern that elderly patients will not be able to tolerate aggressive treatment, older patients may be treated with single-agent chemotherapy rather than the combination chemotherapy that is commonly used in younger patients. Studies have suggested, however, that although combination chemotherapy increases side effects, it also improves survival among elderly patients.9
Managing bone complications
NSCLC cells commonly spread to the bone, causing bone metastases. Bone metastases may cause pain, bone loss, increased risk of fractures, and a life-threatening condition characterized by a high level of calcium in the blood, called hypercalcemia.
Preventing or delaying these skeletal-related events (SREs) can preserve quality of life and reduce healthcare costs. Bisphosphonate drugs such as Zometa® (zoledronic acid) and a newer type of bone drug, Xgeva® (denosumab) can be used to reduce the risk of complications from bone metastases. Xgeva® is a drug that targets a protein known as the RANK ligand. This protein regulates the activity of osteoclasts (cells that break down bone). Xgeva® is approved for the prevention of bone complications such as fracture in patients with bone metastases from solid (not blood-related) cancers.
Xgeva® has been directly compared to Zometa® for the treatment of bone metastases in 702 with NSCLC and 109 with small-cell lung cancer (SCLC). Xgeva® is associated with a decrease in SREs and improved overall survival when directly compared with Zometa.10
Managing brain metastases
When NSCLC spreads to the brain, it can symptoms such as headaches and seizures. Depending on the number, size, and location of the tumors in the brain, treatment may involve radiation therapy and/or surgery to remove the tumor.
Managing pleural effusion
In some patients with advanced NSCLC, fluid collects in the space around the lungs. This is called pleural effusion. The fluid can compress the lung and make it difficult to breath. If a patient is experiencing symptoms due to pleural effusion, the fluid may be drained using a catheter.
Strategies to improve non small cell lung cancer treatment
The development of more effective treatment for advanced NCSLC requires that new and innovative therapies be evaluated with cancer patients. Future progress in the treatment of NSCLC will result from the continued evaluation of new treatments in clinical trials.
Patients may gain access to better treatments by participating in a clinical trial. Participation in a clinical trial also contributes to the cancer community’s understanding of optimal cancer care and may lead to better standard treatments. Patients who are interested in participating in a clinical trial should discuss the risks and benefits of clinical trials with their physician.
Areas of active investigation aimed at improving the treatment of lung cancer include some of the following:
New Drugs in Development: More-targeted and more-individualized treatments for NSCLC has recently became a reality. Results from studies evaluating ALK-inhibitors continued to show promise and initial studies exploring immunomodulatory approaches using anti-PD-1 antibodies demonstrated high response rates and slowed cancer progression in previously untreated stage IV NSCLC. The optimal approach to using these and other novel drugs has not been established and researchers continue to evaluate different ways of combining these drugs with each other and with other therapies in order to further improve outcomes.
The Lung-MAP Trial for Squamous Cell Carcinoma
In Lung-MAP (Lung-MAP.org), researchers with several public institutions, including the National Cancer Institute (NCI), are working with pharmaceutical companies to study treatment for advanced squamous cell lung cancer. Though only a fraction (about a quarter) of all lung cancer diagnoses as squamous cell, it’s an important area of research, as there are few treatment options for these patients.
Lung-MAP will evaluate several investigational treatments and match patients with the therapy most likely to benefit them. Participants will undergo genomic profiling—a type of testing that provides information about all the genes in an organism, including variation, gene expression, and the way genes interact with each other and the environment. The drugs studied in Lung-MAP are designed to target genomic alterations involved in the growth of cancer, and researchers will use genomic profiling to match patients with the therapy designed to target the particular genomic alterations that their cancer expresses.
This more comprehensive approach marks a change in the typical clinical trial model for targeted therapies, in which separate studies for the same disease focus on particular genomic abnormalities and treatments. Potential participants are tested for that genomic biomarker (a molecule that is a sign of a normal or abnormal process or of a condition or disease), and only individuals who test positive are enrolled in the study. As a result, many patients are left out of each trial and—with multiple, separate trials—overall progress in treatment development is made less efficient.
In Lung-MAP, however, everyone who’s tested will be eligible for a therapy. And several treatments for advanced squamous cell lung cancer will be evaluated under one protocol in an effort to accelerate safe drug development.
X-396 iis a novel ALK inhibitor that is well tolerated and has antitumor activity in patients with ALK positive NSCLC. X-396 is being developed for the treatment of solid tumors where ALK is deregulated. X-396 has been validated in potency and selectivity assays indicating that it is more selective and up to 10 times more potent than competitive ALK inhibitors.
The interim results of one study have demonstrated that among 11 ALK positive patients evaluable for response 6 patients had a partial response (55%) and 2 had stable disease (18%). Of the three patients with progressive disease, and acquired resistance to Xalkori® anti-cancer activity was also observed.11
EGFR: Mutations in the epidermal growth factor receptor (EGFR) gene may affect how NSCLC responds to certain drugs. EGFR contributes to the growth of several types of cancer, and drugs that block the activity of EGFR can slow cancer growth. One EGFR targeted drug that is currently approved for the treatment of advanced NSCLC and as maintenance therapy after chemotherapy is Tarceva®.3, 4
Erbitux® (cetuximab) is another targeted therapy that has produced promising results in selected patients with NSCLC.12
Ganetespib is an investigational drug that targets a protein known as heat shock protein (Hsp) 90. Hsp90 is necessary for the function of several other proteins that are known to play an important role in lung cancer. In a Phase II clinical trial, second-line treatment with a combination of chemotherapy and the investigational drug ganetespib improved overall survival among patients with advanced lung adenocarcinoma.13
CyramzaTM (ramucirumab) is a targeted therapy that inhibits the growth of new blood vessels in tumors and, therefore, slows tumor growth. When combined with Taxotere®, CyramzaTM has been shown to extend overall survival and delay time to cancer progression14
Nintedanib is an angiokinase inhibitor that when combined with Taxotere® improves progression-free and overall survival in patients with NSCLC-adenocarcinoma.15
References
1 Chemotherapy for non small cell lung cancer: http://www.cancer.net/research-and-advocacy/asco-care-and-treatment-recommendations-patients/chemotherapy-stage-iv-non-small-cell-lung-cancer
2 Second Phase III Study of Avastin Plus Chemotherapy Shows Improved Progression-Free Survival in First-Line Non-Squamous, Non-Small Cell Lung Cancer. Available at:http://www.gene.com/gene/news/press-releases/display.do?method=detail&id=10727.
3 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.
4 Cappuzo F, Ciuleanu T, Stelmakh L, et al. Erlotinib as maintenance treatment in advanced non-small-cell lung cancer: A multi-center, randomized, placebo-controlled phase 3 study. The Lancet Oncology. Published early online May 20, 2010.
5 Solomon, B., et al. (2014). First-Line Crizotinib versus Chemotherapy in ALK-Positive Lung Cancer New England Journal of Medicine, 371 (23), 2167-2177 DOI
6 Kwak EL, Bang Y-J, Camidge DR et al. Anaplastic lymphoma kinase inhibition in non-small-cell lung cancer. New England Journal of Medicine. 2010;363:1693-1703.
7 Ciuleanu T, Brodowicz T, Zielinski C et al. Maintenance pemetrexed plus best supportive care versus placebo plus best supportive care for non-small-cell lung cancer: a randomised, double-blind, phase 3 study. Lancet. 2009;374:1432-40
8 Cappuzzo F, Ciuleanu T, Stelmakh L et al. Erlotinib as maintenance treatment in advanced non-small-cell lung cancer: a multicentre, randomised, placebo-controlled phase 3 study. Lancet Oncology. 2010;11:521-529.
9 Quoix E, Zalcman G, Oster J-P et al. Carboplatin and weekly paclitaxel doublet chemotherapy compared with monotherapy in elderly patients with advanced non-small-cell lung cancer: IFCT-0501 randomised, phase 3 trial. The Lancet. Early online publication August 9, 2011.
10 Scagliotti GV, Hirsh V, Siena S, et al. Overall survival improvement in patients with lung cancer and bone metastases treated with denosumab versus zoledronic acid: Subgroup analysis from a randomized phase 3 study. Journal of Thoracic Oncology. 2012; 7(12): 1823-1829.
11 Horn L, Infante J, Blumenshcein G, et al. A phase I trial of X-396, a novel ALK inhibitor, in patients with advanced solid tumors. J Clin Oncol 32:5s, 2014 (suppl; abstr 8030^)
12 Pirker R, Pereira JR, Szczesna A et al. Cetuximab plus chemotherapy in patients with advanced non-small-cell lung cancer (FLEX): an open-label randomised phase III trial. Lancet. 2009;373:1525-1531.
13 Ramalingam SS, Goss GD, Andric ZG et al. A randomized study of ganetespib, a heat shock protein 90 inhibitor, in combination with docetaxel versus docetaxel alone for second-line therapy of lung adenocarcinoma (GALAXY-1). Presented at the 49th Annual Meeting of the American Society of Clinical Oncology. May 31-June 4, 2013; Chicago, IL. Abstract CRA8007.
14 Perol M, et al. REVEL: A randomized, double-blind, phase III study of docetaxel and ramucirumab versus docetaxel and placebo in the second-line treatment of stage IV non-small cell lung cancer following disease progression after one prior platinum-based therapy. ASCO 2014; Abstract LBA8006.
15 Reck M, Kaiser R, Mellemgaard A, et al: Docetaxel plus nintedanib versus docetaxel plus placebo in patients with previously treated non-small-cell lung cancer (LUME-Lung 1): a phase 3, double-blind, randomised controlled trial. The Lancet Oncology. 2014; 15(2): 143-155.