Overview

Stage IIIA non-small cell lung cancer (NSCLC) is a single cancer mass that is not invading any adjacent organs, but has spread to nearby lymph nodes in the chest.

Stage IIIA cancers are further subdivided into N1 and N2 subgroups. N1 cancers involve lymph nodes farther away from the heart and are easier to remove with surgery. N2 cancers involve lymph nodes that may be difficult to remove with surgery because they are located in the part of the chest cavity that is between the lungs and contains the heart.

Because stage IIIA cancers have spread to nearby lymph nodes, it is also possible that some cancer cells have spread to other locations in the body. These small amounts of cancer cannot be detected with any of the currently available tests. However, their presence often results in cancer recurrence after surgery or radiation therapy alone.

Administration of chemotherapy after surgery, referred to as adjuvant therapy improves survival for patients with NSCLC when compared to treatment with surgery alone and is now considered standard of care.1, 2 Efforts are underway to evaluate new precision or targeted therapies to further improve the outcome of individuals with early stage IIIA lung cancer.

The following is a general overview of treatment for Stage IIIA NSCLC. Treatment may consist of surgery, radiation, chemotherapy, precision medicine, or a combination of these treatment techniques. 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.

Multi-modality Treatment

A combination of therapies has become the standard approach to treating patients with stage IIIA NSCLC.3 Typically, patients are treated with a local therapy to eliminate cancer cells in the chest and a systemic therapy that circulates throughout the body and can kill cancer cells that may have spread to distant locations in the body. Local therapies include surgery and radiation and systemic therapy consists of chemotherapy.

The combination of chemotherapy and radiation appears to produce better outcomes than chemotherapy plus surgery.4

Surgery

Role of surgery in the treatment of stage IIIA NSCLC: Since stage IIIA NSCLC has spread extensively to lymph nodes that are deep in the center of the chest cavity, it is often difficult to remove with surgery. Administering systemic therapy and/or radiation therapy prior to surgery is one approach that doctors may use to shrink the cancer and increase the chance that it may be removed with surgery. However, patients are more susceptible to complications of surgery after systemic treatment.5 Therefore, the risks and benefits of surgery must be carefully weighed for each individual.

Researchers have reported that select patients with stage IIIA NSCLC may benefit from surgery following chemoradiation. However, patients who are candidates for a pneumonectomy—which is surgery to remove an entire lung—have a higher risk of complications from surgery and the researchers suggest that they may benefit from foregoing radiation therapy before surgery.6

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.

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.

Radiation Therapy

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. 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 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.7, 8

Prophylactic brain radiation: Researchers have found that the most common site for cancer to spread in patients with stage IIIA NSCLC is the brain.9 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.10

Chemotherapy and radiation therapy: Treating patients with both chemotherapy and radiation therapy is a standard treatment for patients with stage III NSCLC.11 However, the way in which these treatments are administered appears to make a difference. Researchers have reported that administering the two treatments together, or concurrently—a technique called chemoradiation—appears to improve outcomes compared to administering the treatments sequentially, or one following the other.12 While chemoradiation does appear to improve survival, this approach is also accompanied with increased side effects.
The chemotherapy drugs Taxotere® (docetaxel) and Gemzar® (gemcitabine) are approved by the FDA for the treatment of patients with stage III NSCLC and are commonly administered in combination with a platinum-based chemotherapy drug, such as Platinol® (cisplatin).

Chemotherapy

It is important to realize that patients with Stage IIIA NSCLC may already have small amounts of cancer that have spread outside the lung and cannot be detected with any of the currently available tests. Undetectable areas of cancer are referred to as micrometastases. The presence of micrometastases causes the cancer recurrences that follow treatment with surgery or radiation alone.

Adjuvant chemotherapy-treatment with chemotherapy after surgery is considered standard treatment for stage IIIA NSCLC: A National Cancer Institute of Canada clinical trial showed that adjuvant chemotherapy increased the number of patients who lived 5 years or more from 54% to 69%,1 and US researchers have demonstrated that adjuvant chemotherapy increased the number of patients who survived 3 years or more from 69% to 82%.13

Neoadjuvant chemotherapy: Neoadjuvant therapy is chemotherapy that is delivered before surgery with the goal of providing immediate treatment and reducing the size of the cancer for easier resection. A meta-analysis that included data from 15 eligible randomized controlled trials involving a total of 2,385 patients has revealed that neoadjuvant chemotherapy reduces the time to cancer recurrence and improves overall survival. Patients should discuss the potential risks and benefits of receiving chemotherapy prior to surgery with their treating physician.14

Treatment Follow-Up

Patients with NSCLC are still at risk for developing a cancer recurrence due to micrometastases. Also, patients who have been treated for NSCLC 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 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. These researchers evaluated 124 patients previously treated with surgery alone. Follow-up included an annual CT scan of the chest with interval chest x-rays every 4 months for 2 years and every 6 months for 3 additional years. During this time, 14 patients were found to have developed a second cancer and received further surgery. The average diameter of cancers detected by CT smaller than those detected by x-ray, 14 millimeters compared to 26.5 millimeters.15

Strategies to Improve Non Small Cell Lung Cancer Treatment

The development of more effective treatment for NSCLC requires that new and innovative therapies be evaluated with cancer patients. Future progress in treatment 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 NSCLC include some of the following:

New chemotherapy regimens: Current clinical trials are focusing on combining chemotherapy drugs known to be active in advanced NSCLC, such as Gemzar®, Taxotere®, paclitaxel, Paraplatin®, and Platinol® into treatment regimens with newer cancer killing drugs in order to further improve survival duration and decrease side effects in both the adjuvant and neoadjuvant setting.

Precision Medicine or Targeted Therapy: A targeted or precision 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 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.

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.

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.16

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.16,17

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.  Xalkori is an oral medication that blocks certain proteins, including the protein produced by this abnormal gene. For advanced NSCLC’s that test positive for the ALK gene mutation, Xalkori has produced very promising rates of response and appears to have some activity treating cancer that has spread to the brain.18,19

Angiogenesis inhibitors: A growing area of cancer research involves the inhibition of angiogenesis. Cancer cells require food, oxygen and proteins in order to grow and spread. These essential nutrients are transported to the cancer cells by blood vessels. Angiogenesis is the process of creating new blood vessels necessary to transport “food” to the cancer cells. Two of several key proteins that are necessary for the process of angiogenesis are called vascular endothelial growth factor (VEGF) and matrix metalloproteinases (MMPs). VEGF causes endothelial cells (cells comprising the innermost layer of blood vessels) to replicate and migrate from existing blood vessels to the cancer. Endothelial cells secrete MMPs, which create an opening in existing tissues surrounding the cancer, allowing the endothelial cells to move near the cancer and form new blood vessels to “feed” the cancer. Researchers have been evaluating targeted treatments hinder or reduce the effects of VEGF and thus, slow cancer progression.

Bevacizumab (Avastin) is an angiogenesis inhibitor still being evaluated in clinical trials. It produces its anti-angiogenic effects by binding to VEGF and inhibiting or reducing the growth of new blood vessels necessary to promote cancer cell growth. The addition of (Avastin) to standard chemotherapy treatment is being evaluated in patients with NSCLC.20

Cryotherapy: Cryotherapy is a new treatment procedure that is still in investigative stages for various cancers. 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.21

Image-guided radiation therapy (IGRT): IGRT involves a 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 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 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.22

References for Non Small Cell Lung Cancer


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 Robinson LA, Wagner H, Ruckdeschel JC, et al. Treatment of Stage IIIA Non-small Cell Lung Cancer.Chest. 2003;123:202S-220S.

4 van Meerbeeck J, et al. A Randomised Trial of Radical Surgery Versus Thoracic Radiotherapy After Response to Induction Chemotherapy in Patients With Histo-/Cytologically Proven Irresectable Stage IIIA-N2 NSCLC (EORTC 08941). Abstract Pr5. Proceedings from the 11th World Conference on Lung Cancer. July 2005.

5 Concurrent cisplatin/etoposide plus chest radiotherapy followed by surgery for stages IIIA (N2) and IIIB non-small-cell lung cancer: mature results of Southwest Oncology Group phase II study 8805. Albain KS, Rusch VW, Crowley JJ, et al. Journal of Clinical Oncology. 1995;13:1880-1892.

6 Cerfolio RJ, Bryant AS, Spencer SA, et al. Pulmonary resection after high-dose and low-dose chest irradiation. Annals of Thoracic Surgery. 2005;80(4):1224-30.

7 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.

8 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.

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.

10 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.

11 van Meerbeeck J, et al. A Randomised Trial of Radical Surgery Versus Thoracic Radiotherapy After Response to Induction Chemotherapy in Patients With Histo-/Cytologically Proven Irresectable Stage IIIA-N2 NSCLC (EORTC 08941). Abstract Pr5. Proceedings from the 11th World Conference on Lung Cancer. July 2005.

12 Belani CP, Choy H, Bonomi P et al. Combined chemotherapy regimens of paclitaxel and carboplatin for locally advanced non-small-cell lung cancer: a randomized phase II locally advanced multi-modality protocol.Journal of Clinical Oncology. 2005;23:5883-5891.

13 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.

14 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

15 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.

16 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.

17 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.

18 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.

19 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.

20 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.

21 Deygas N, Froudarakis M, Ozenne G, and Vergnon JM. Cryotherapy in Early Superficial Bronchogenic Carcinoma. Chest. 2001;120:26-31.

22 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.

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