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.
For this reason, it is important for patients to be treated at a medical center that can offer many different treatments and a health care team that may involve medical oncologists, radiation oncologists, surgeons and specialists in pulmonary (lung) medicine.
The following is a general overview of treatment for stage IIIA NSCLC. Treatment may consist of surgery, radiation, chemotherapy, targeted therapy, or a combination of these treatment techniques. Combining two or more of these treatment techniques--called multi-modality care--has become an important approach for increasing a patient's chance of cure and prolonging survival.
In some cases, participation in a clinical trial utilizing new, innovative therapies may provide the most promising treatment. Treatments that may be available through clinical trials are discussed in the section titled Strategies to Improve Treatment.
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.
A combination of therapies has become the standard approach to treating patients with stage IIIA NSCLC.1 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.2
Chemotherapy and radiation therapy: Treating patients with both chemotherapy and radiation therapy is a standard treatment for patients with stage III NSCLC.3 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.4 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).
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 an 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
The development of more effective cancer treatments requires that new and innovative therapies be evaluated with cancer patients. Clinical trials are studies that evaluate the effectiveness of new drugs or treatment strategies. Future progress in the treatment of stage IIIA 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 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 stage IIIA NSCLC include the following:
- Strategies to Improve Chemotherapy
- Chemotherapy prior to chemoradiation
- Additional chemotherapy after chemoradiation
- Strategies to Improve Radiation Therapy
- Conformal radiation
- Prophylactic brain radiation
- Targeted Therapy
- Managing Side Effects
- Other Novel Approaches to Treatment
- Radiofrequency ablation
- Gene Therapy
Clinical trials are ongoing to determine the optimal combination and sequence of surgery, radiation, and chemotherapy in the treatment of stage IIIA NSCLC. In particular, researchers continue to evaluate whether it is beneficial to administer additional chemotherapy before or after chemoradiation.
Chemotherapy prior to chemoradiation: A course of chemotherapy delivered prior to chemoradiation—sometimes called “induction” chemotherapy—is still being evaluated in clinical trials. Induction chemotherapy that includes the drug Gemzar has been shown to produce promising outcomes. Patients with inoperable stage IIIA or IIIB NSCLC survived 23 months, on average, when treated with Gemzar-based chemotherapy followed by chemoradiation. Nearly three quarters of the patients experienced at least a partial reduction in their cancer following treatment. Nearly half of the patients survived two years or more after treatment.7
Additional chemotherapy after chemoradiation: Administering additional chemotherapy after chemoradiation may produce better outcomes than induction chemotherapy before chemoradiation. In a clinical trial that directly compared these two techniques showed that patients who were treated with chemoradiation first experienced longer survival—approximately 16 months on average, compared to 13 months for patients treated with chemotherapy followed by chemoradiation. However, side effects from treatment side effects of treatment—including inflammation of the throat—were more common among patients who were treated with chemoradiation first.8
Brachytherapy: Brachytherapy involves the placement of small radioactive objects—called “seeds”—in or near the cancer. The seeds may be placed during surgery and will emit radioactivity for limited duration of time. Brachytherapy is used in the treatment of various types of cancers.
Results from a clinical trial suggest that brachytherapy may improve survival of patients with inoperable lung cancer. In this trial, 35 patients underwent surgery to partially remove their cancer and had brachytherapy seeds placed into the site of cancer at the time of surgery. Approximately 88% of the patients survived one year or more and three quarters of the patients had their cancer controlled at the site where the seeds were implanted. One year after the procedure there were no serious side effects.9
Conformal radiation therapy: By using a special computer and CT scan, radiation therapy can be delivered more precisely to the cancer in the lungs. This technique is called 3-dimensional conformal radiation therapy. Precise delivery of radiation therapy directly to the cancer may spare healthy tissue from the side effects of radiation and can allow for higher doses of radiation to be administered, killing more cancer cells.
In a clinical trial involving patients with stage III NSCLC, conformal radiation administered with chemotherapy produced anti-cancer responses in 75% of the patients. Nearly one quarter of the patients had a complete disappearance of their cancer and half had a partial disappearance. Half of the patients survived one year or more and one quarter survived two years or more. On average, patients survived one year.10
Prophylactic brain radiation: Researchers have found that the most common site for cancer to spread in patients with stage IIIA NSCLC is the brain.11 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.12
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.
Conventional cancer treatments, such as chemotherapy and radiation therapy, cannot distinguish between cancer cells and healthy cells. Consequently, healthy cells are commonly damaged in the process of treating the cancer, which results in side effects. Chemotherapy damages rapidly dividing cells, a hallmark trait of cancer cells. In the process, healthy cells that are also rapidly dividing, such as blood cells and the cells lining the mouth and GI tract are also damaged. Radiation therapy kills some healthy cells that are in the path of the radiation or near the cancer being treated. Newer radiation therapy techniques can reduce, but not eliminate this damage. Treatment-related damage to healthy cells leads to complications of treatment, or side effects. These side effects may be severe, reducing a patient’s quality of life, compromising their ability to receive their full, prescribed treatment, and sometimes, limiting their chance for an optimal outcome from treatment.
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 unresectable (not able to be surgically removed), locally advanced, recurrent or metastatic non-squamous, non-small cell lung cancer. The combination of Avastin with paclitaxel and carboplatin has been shown to improve survival compared to chemotherapy alone.13
Tarceva® (erlotinib): Tarceva is a type of targeted therapy that inhibits growth of the cancer cell by binding to a portion of the epidermal growth factor receptor (EGFR), a protein located on the surface of many cancer cells, including NSCLC. Tarceva has been shown to improve survival and quality of life in patients with recurrent NSCLC and is FDA-approved for the treatment of these patients.14 Research is ongoing to determine if Tarceva may benefit patients with earlier stage disease.
Ethyol® (amifostine): Ethyol is a drug that protects some organs from the side effects of radiation therapy, which can make treatment more tolerable and allow for the maximal dose to be administered. Ethyol is approved by the Food and Drug Administration for use with Platinol and clinical trials are evaluating the use of Ethyol with other chemotherapy drugs.
The addition of Ethyol to radiochemotherapy has been shown to reduce side effects in the treatment of patients with advanced NSCLC. A direct comparison of treatment with and without Ethyol showed that patients who received Ethyol experienced significantly less inflammation of the esophagus and lung-related side effects. Ethyol did not compromise the effectiveness of treatment.15
Radiofrequency ablation (RFA): RFA is a type of treatment that utilizes high temperatures to kill cancer cells. The procedure typically involves a small probe that the doctor guides into or near the cancer with the help of an imaging device, such as computed tomography (CT) scan. Heat is emitted from the probe and kills the cancer cells. RFA is often used for tumors in the liver and is associated with low risks of side effects.
Researchers have evaluated RFA in the treatment of patients with NSCLC and it appears to be an effective and promising treatment approach for patients with NSCLC who are not eligible for surgery. Patients with cancer that was 3.5 cm or smaller in diameter who were treated with RFA survived16 months, on average.16
Cryosurgery: Lung cancer that is located inside the bronchial tubes—the passages that deliver air to the lungs—may obstruct the airway. Symptoms of airway obstruction include shortness of breath, cough, and coughing up blood.
In such cases, a technique called cryosurgery may be helpful in alleviating symptoms and improve quality of life. Cryosurgery uses extreme cold to freeze and kill abnormal cells. Cryosurgery’s benefits include fewer side effects than other treatments, lower cost and a shorter recovery period.
Evaluation of data from 329 patients with obstructive lung cancer that underwent cryosurgery revealed that shortness of breath, cough, and coughing up blood were significantly improved after treatment. Two treatments with cryosurgery appears to produce better outcomes than one; patients who underwent cryosurgery twice survived 15 months versus 8.3 months for patients that underwent only one cryosurgery procedure.17
Gene therapy: Gene therapy is a new field of research that involves inserting a functional copy of a gene into a cell to replace an abnormal or malfunctioning gene. Advexin is a gene therapy that uses the virus that causes the common cold to transport a functional p53 gene into cancer cells. The p53 gene is known as the “cell-suicide” gene because it causes the cell to die if the cell becomes abnormal, as in cancer cells. However, p53 is inactive in many cancers.
Results of a clinical trial have shown that the addition of Advexin® (INGN 201) to radiation therapy appears to improve anti-cancer responses in patients with inoperable NSCLC. Patients in this trial had cancer that had not spread to distant sites, but were not eligible to undergo surgery or the combination of chemotherapy and radiation therapy. These patients received injections of Advexin over one month and underwent radiation therapy for 6 weeks. Three months following treatment, over 60% of patients had a partial or complete disappearance of their initial cancer as indicated by scans and biopsies. Side effects were not increased compared to expected side effects with radiation therapy alone.18
1 Robinson LA, Wagner H, Ruckdeschel JC, et al. Treatment of Stage IIIA Non-small Cell Lung Cancer. Chest. 2003;123:202S-220S.
2 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.
3 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.
4 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.
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 Lee DH, Han J-Y, Cho KH et al. Phase II Study of Induction Chemotherapy with Gemcitabine and Vinorelbine Followed By Concurrent Chemoradiotherapy With Oral Etoposide and Cisplatin in Patients with Inoperable Stage III non-small-cell lung cancer. International Journal of Radiation Oncology, Biology, Physics. 2005;63:1037-1044.
8 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.
9 Mutyala S, et al. Toxicity of permanent I-125 interstitial planar seed brachytherapy for close or positive margins for thoracic malignancies. Proceedings from the 47th annual meeting of the American Society of Therapeutic Radiation Oncology. Presented October 19, 2005. Denver, Colorado.
10 Lee SW, Choi EK, Lee JS, et al. Phase II study of three-dimensional conformal radiotherapy and concurrent mitomycin-C, vinblastine, and cisplatin chemotherapy for Stage III locally advanced, unresectable, non-small-cell lung cancer. International Journal of Radiation Oncology Biology Physics. 2003;56(4):996-1004.
11 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.
12 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.
13 Sandler A, Gray R, Perry MC et al. Paclitaxel-carboplatin Alone or with Bevacizumab for Non-small Cell Lung Cancer. New England Journal of Medicine. 2006;355:2542-50.
14 Shepherd F, Pereira J, Ciuleanu T, et al. Erlotinib in Previously Treated Non–Small-Cell Lung Cancer. The New England Journal of Medicine. 2005; 353:123-132.
15 Antonadou D, Throuvalas N, Petridis A, et al. Effect of amifostine on toxicities associated with radiochemotherapy in patients with locally advanced non-small cell lung cancer. International Journal of Radiation Oncology Biology Physics. 2003;57:402-408.
16 Ambrogi M, Lencioni R, Fontanini G, et al. Percutaneous radiofrequency ablation of primary NSCLC. Proceedings from the 11th World Conference on Lung Cancer, Barcelona, Spain. 2005; Abstract #Pr1.
17 Asmakopoulos G, Beeson J, Evans J, et al. Cryosurgery for Malignant Endobrachial Tumors. Chest; 127: 2007-2014.
18 Swisher S, Roth J, Komaki R, et al. Induction of p53-regulated genes and tumor regression in lung cancer patients after intratumoral delivery of adenoviral p53 (INGN 201) and radiation therapy. Clinical Cancer Research. 2003;9:93-101.