Medically reviewed by Dr. C.H. Weaver M.D. Medical Editor 4/2022
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 therapy improves survival for patients with stage I - IIIA NSCLC when compared to treatment with surgery alone and considered the standard of care. Currently research efforts are underway to better personalize treatment using precision cancer medicines and immunotherapy that target specific cancer causing mutations to further improve the outcome of individuals with early stage NSCLC. Studies show that specific specific precision medicines and immunotherapy is superior to chemotherapy so all 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 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.
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.
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 all factors that may influence the type of surgery performed and the side effects associated with the surgery.
Systemic Therapy: Precision Cancer Medicine, Chemotherapy, and Immunotherapy
Systemic therapy is any treatment directed at destroying cancer cells throughout the body. Most NSCLC patients with early stage cancer already have small amounts of cancer that have spread outside the lungs. These cancer cells cannot be treated effectively with surgery alone and their eradication requires systemic treatment to decrease the chance of cancer recurrence. Systemic therapy can be administered after (adjuvant) or before (neoadjuvant) surgery.
The use of a cisplatin-based chemotherapy for approximately 4 cycles, given as adjuvant therapy after complete resection of either stage II-III NSCLC or select stage I patients has been the recommended standard of care for more than a decade.1,6 The use of this approach is associated with approximately a 5% absolute improvement in overall survival compared to treatment with surgery alone.
Chemotherapy drugs 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.
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. In the Phase III ADAURA clinical trial Tagrisso treatment for up to three years was compared to placebo as adjuvant therapy in patients with Stage IB, II and IIIA EGFRm NSCLC following complete cancer resection and found to delay cancer progression leading to FDA approval.
Immunotherapy in Individuals without cancer driving mutations:
Precision immunotherapy treatment of cancer has also progressed considerably over the past few decades and has now become a standard treatment. PD-1 and PD-L1 are proteins that inhibit certain types of immune responses, allowing cancer cells to evade detection and attack by certain immune cells in the body. Checkpoint inhibitor immunotherapy drugs can block the PD-1 and PD-L1 pathway and 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 cancer cells. A diagnostic test to measure the level of PD-L1 is available.
The combination of chemotherapy with a checkpoint inhibitor improves overall survival for patients with advanced NSCLC and recent studies suggest similar benefit when used in earlier stage disease. Both adjuvant Tecentriq (atezolizumab), and neoadjuvant Opdivo checkpoint inhibitors used in combination with chemotherapy appear superior to chemotherapy alone in the management of early stage NSCLC but studies have not demonstrated neoadjuvant therapy produces similar or superior survival rates to adjuvant therapy.19,20
FDA Approves Adjuvant Tecentriq for early-stage NSCLC
The IMPower 010 clinical trial evaluated 1005 patients with completely resected NSCLC that was pathologically staged as IB (≥4 cm)-IIIA NSCLC were treated with either 16 cycles of Tecentriq every 21 days or best supportive care following completion of four 21-day cycles of cisplatin-based adjuvant chemotherapy. Tecentriq was found to delay cancer progression and reduction the risk of disease recurrence or death by 34%. The median duration of survival with the addition of Tecentriq was greater than the 35.3 months attained with surgery and platinum based chemotherapy. The greatest magnitude of benefit was observed in patients with PD-L1 ≥50%.18,19
The Phase 3 KEYNOTE-091 trial investigating anti-PD-1 immunotherapy treatment with Keytruda (pembrolizumab) as adjuvant treatment following surgical resection regardless of PD-L1 expression also appears to delay cancer recurrence but overall survival benefit has not yet been reported. The KEYNOTE-091 trial evaluated compared Keytruda to placebo for the adjuvant treatment of patients with stage IB-IIIA NSCLC following surgical resection (lobectomy or pneumonectomy) with or without adjuvant chemotherapy in 1,177 patients.
The FDA has approved Opdivo immunotherapy plus platinum-doublet chemotherapy for adult patients with resectable NSCLC in the neoadjuvant setting.1 Systemic treatment administered before surgery with the goal of providing immediate treatment and reducing the size of the cancer for easier resection is referred to as "neoadjuvant" therapy. The CheckMate-816 clinical trial found that neoadjuvant Opdivo in combination with chemotherapy increases the number of patients with complete disappearance of their cancer from 2.2% to the 24% without negatively impacting a patients ability to undergo timely surgery.17 Opdivo plus chemotherapy improved average survival without recurrence to 32 months compared with 21 months for treatment with chemotherapy alone.17,19-24
It is currently unknown if neoadjuvant therapy is better than adjuvant therapy and patients should discuss the pros and cons of neoadjuvant compared to adjuvant systemic therapy with their physician.
Stage IIIA and B NSCLC
Historically the standard treatment for patients with surgically unresectable stage IIIA NSCLC was a treatment combination of platinum-based chemotherapy and radiation producing a 5 year survival rate of around 15%.23,24
Based on encouraging results in stage IIIB NSCLC researchers evaluated a combination of targeted radiation therapy with immunotherapy in the PACIFIC clinical trial for individuals unable or unwilling to undergo surgery.
The Phase 3 Pacific clinical trial determined that the addition of Immunotherapy with Imfinzi (durvalumab) in patients with unresectable stage III NSCLC further improved patient survival. In the trial patients were initially treated with 2 or more cycles of platinum based chemoradiotherapy25 and those with stable disease then received additional treatment with Imfinzi immunotherapy. 26 Average survival duration was improved from 29 to 48 months with the addition of Imfinzi and the estimated 5-year survival rate increased to 43%.
Checkpoint Inhibitors + Avastin for Recurrent Ovarian Cancer
Anit-angiogenic - immunotherapy combination represents new treatment option for recurrent ovarian cancer.
The survival benefit for patients with unresectable stage III NSCLC harboring EGFR or ALK mutations with Durvalumab is unclear and further studies with target therapy is currently undergoing for this subgroup of patients.
Some patients with lung cancer are not able to undergo 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
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
Strategies to Improve NSCLC Treatment
Currently, there are several areas of active exploration aimed at improving the treatment of stage I - IIIA NSCLC which are mainly available in clinical trials. All individuals should undergoing genomic biomarker testing to see if their cancer has a "targetable" cancer driving mutation that can be treated with a precision cancer medicine.
Neoadjuvant vs Adjuvant Therapy: Both adjuvant chemotherapy and immunotherapy have been shown to improve survival. Neoadjuvant therapy has been shown to reduce the amount of cancer remaining before surgery is performed. Neoadjuvant and adjuvant therapy have not been directly compared and it remains unclear if one approach is superior to the other. Neoadjuvant therapy can be helpful in shrinking difficult to resect cancers.
The CheckMate-816 clinical trial compared Opdivo immunotherapy plus chemotherapy to chemotherapy alone as neoadjuvant treatment in patients with resectable NSCLC. In the trial 358 patients were treated with platinum chemotherapy every three weeks with or without Opvido followed by surgery. Significantly more patients treated with Opdivo plus chemotherapy before surgery showed no evidence of cancer cells in their resected tissue compared to those treated with chemotherapy alone.
Precision Cancer Medicines
A targeted or precision therapy is one that is designed to treat only the cancer cells and minimize damage to normal, healthy cells. Precision cancer medicines that “target” cancer cells offer the advantage of reduced treatment-related side effects and improved outcomes and have become standard treatment for more advanced NSCLC. Therapies directed at mutations in the epidermal growth factor receptor (EGFR) and the ALK gene have improved outcomes in the treatment of advanced NSCLC and are now being evaluated in stage I-IIIA disease.
- A clinical trial in 1000 early-stage lung cancer patients compared Keytruda immunotherapy to placebo and found that Keytruda reduced the risk of cancer recurrence or death by 24%. Data will be submitted to the FDA.
- ALCHEMIST- the Adjuvant Lung Cancer Enrichment Marker Identification and Sequencing Trials – represents three integrated, precision medicine trials that are designed to identify people with early-stage lung cancer who have tumors that harbor EGFR and ALK gene alterations and evaluate whether drug treatments targeted against those molecular changes can lead to improved survival compared to current standard of care therapy alone.
- Epidermal growth factor receptor (EGFR): Mutations in the 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. 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 Tagrisso or Tarceva® plus chemotherapy have delayed time to cancer progression and improved survival compared to those treated with placebo or chemotherapy alone respectively.9,10,16
- Anaplastic lymphoma kinase (ALK) gene: Up to 7% of NSCLC’s have an abnormal version of the ALK gene that contributes to the growth and development of cancer. Lung cancers with this abnormality typically occur in non-smokers. The abnormal gene contributes to the growth and development of cancer cells. Medicines have been developed that target the ALK gene mutation and produced very promising rates of response in more advanced cancers.11,12
Cryotherapy: Cryotherapy is a technique that kills cancer cells by freezing them with sub-zero temperatures. During this procedure, hollow steel probes are placed inside and surrounding the cancer. Liquid nitrogen is then circulated through the probes, freezing the cancer cells and creating a ball of ice that surrounds the cancer. Once an adequate ice ball is formed, heated nitrogen is circulated through the probes. This process is then repeated.
Researchers from France conducted a clinical trial evaluating cryotherapy for the treatment of early stage lung cancer. Cryotherapy was performed through a rigid bronchoscope (a lighted tube that is placed into the bronchi). In this trial, 35 patients with early stage lung cancer received cryotherapy, 20% of whom had multiple locations of early stage lung cancer. One year following treatment, 91% of patients had a complete disappearance of cancer. Four years following treatment, only 10 patients experienced a local cancer recurrence. The treatment was well tolerated by these patients.15
Image-guided radiation therapy (IGRT): IGRT involves a computed tomography (CT) scanner and computer modeling to accurately determine the size and depth of the cancer. In addition, this technique determines the measurement of the cancer through all stages of respiration and can direct the radiation more precisely while the patient is breathing normally. Researchers from Japan recently concluded that IGRT appears to be an effective and well tolerated radiation technique for patients with inoperable stage I NSCLC with poor lung function. A distinct advantage of IGRT is that patients do not have to hold their breath during the treatment, which is necessary for standard radiation therapy. This is important because many patients with lung cancer have poor lung function and are not able to hold their breath during treatment.
Of the 21 patients with stage I NSCLC involved in this clinical trial, 5 experienced a complete disappearance of detectable cancer, 11 patients experienced at least a 50% reduction in the volume of their cancer, and one patient had progressive disease following therapy. Approximately two years following therapy, only 5 patients had experienced a cancer recurrence. The treatment was well tolerated with no major side effects reported. Further clinical trials will are necessary to determine the role of IGRT in the clinical setting and demonstrate whether chemotherapy prior to or following radiation therapy may further improve long-term outcomes.16
Gut Microbiome: The NEOSTAR clinical trial tested the administration of Opdivo with or without Yervoy (ipilimumab), prior to surgery in 44 patients with with operable stage IA to IIIA NSCLC between June 2017 and November 2018. Overall, 41 patients completed the planned three doses of therapy prior to surgery. Eight of 21 treated patients (38%) achieved a pathological complete response following Opdivo-Yervoy compared to only 10%, treated with Yervoy alone.
The researchers analyzed the gut microbiome and found that pathologic response to combination therapy was associated with the presence of certain fecal microbes that also have been correlated with immunotherapy response in melanoma and other cancers.18
- 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.
- 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.
- 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.
- 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.
- 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.
- 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.
- 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
- 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.
- 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.
- 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.
- 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.
- 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.
- 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.
- Deygas N, Froudarakis M, Ozenne G, and Vergnon JM. Cryotherapy in Early Superficial Bronchogenic Carcinoma. Chest. 2001;120:26-31.
- Fukumoto S, Shirato H, Shimzu S, et al. Small-volume image-guided radiotherapy using hypofractionated, coplanar, and noncoplanar multiple fields for patients with inoperable Stage II non-small cell lung carcinomas. Cancer. 2002;95:1546-1553.
- Tagrisso – First Precision Medicine Approved for Treatment of Early Stage NSCLC
- 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.
FDA approves atezolizumab as adjuvant treatment for non-small cell lung cancer. News release. October 15, 2021. Accessed October 15, 2021. https://bit.ly/3lHUgv
Wakelee HA, Altorki NK, Zhou C, et al. IMpower010: primary results of a phase III global study of atezolizumab versus best supportive care after adjuvant chemotherapy in resected stage IB-IIIA non-small cell lung cancer (NSCLC). J Clin Oncol. 2021;39(suppl 15):8500. doi:10.1200/JCO.2021.39.15_suppl.8500.
US Food and Drug Administration approves Opdivo (nivolumab) with chemotherapy as neoadjuvant treatment for certain adult patients with resectable non-small cell lung cancer. News release. Bristol Myers Squibb; March 4, 2022. Accessed March 4, 2022. https://bit.ly/3sG3zQA
Spicer J, Wang C, Tanaka F, et al. Surgical outcomes from the phase 3 CheckMate 816 trial: nivolumab (NIVO) + platinum-doublet chemotherapy (chemo) vs chemo alone as neoadjuvant treatment for patients with resectable non-small cell lung cancer (NSCLC). J Clin Oncol. 2021;39(suppl 15):8503. doi:10.1200/JCO.2021.39.15_suppl.8503
Neoadjuvant Opdivo (nivolumab) plus chemotherapy significantly improves pathologic complete response in patients with resectable non-small cell lung cancer in phase 3 CheckMate -816 trial. News release. Bristol Myers Squibb; April 10, 2021. Accessed February 28, 2022. https://bit.ly/3HrBxw7
Yoon SM, Shaikh T, Hallman M. Therapeutic management options for stage III non-small cell lung cancer. World J Clin Oncol 2017;8:1-20
Ahn JS, Ahn YC, Kim JH, et al. Multinational randomized phase III trial with or without consolidation chemotherapy using docetaxel and cisplatin after concurrent chemoradiation in inoperable stage III non-small-cell lung cancer: KCSG-LU05-04. J Clin Oncol 2015;33:2660-2666.
Antonia SJ, Villegas A, Daniel D, Vicente D, Murakami S, Hui R, Yokoi T, Chiappori A, Lee KH, de Wit M, Cho BC, Bourhaba M, Quantin X, Tokito T, Mekhail T, Planchard D, Kim YC, Karapetis CS, Hiret S, Ostoros G, Kubota K, Gray JE, Paz-Ares L, de Castro Carpeño J, Wadsworth C, Melillo G, Jiang H, Huang Y, Dennis PA, Özgüroğlu M; PACIFIC Investigators. Durvalumab after chemotherapy and stage III non-small cell lung cancer. N Engl J Med. 2017 Nov 16;377(20):1919-1929.
Paz-Ares L, Spira A, Raben D, Planchard D, Cho BC, Özgüroğlu M, Daniel D, Villegas A, Vicente D, Hui R, Murakami S, Spigel D, Senan S, Langer CJ, Perez BA, Boothman AM, Broadhurst H, Wadsworth C, Dennis PA, Antonia SJ, Faivre-Finn C. Outcomes with durvalumab by tumour PD-L1 expression in unresectable, stage III non-small-cell lung cancer in the PACIFIC trial. Ann Oncol. 2020 Jun;31(6):798-806.