Stage I non small cell lung cancer (NSCLC) is located in only one lung and has not spread to the adjacent lymph nodes or outside the chest. The mainstay of treatment for patients diagnosed with a stage I NSCLC has been surgical removal of the cancer. In general, surgical removal of stage I cancers results in over 60% of patients surviving without evidence of cancer recurrence within 5 years of treatment. The size and specific location of the cancer may improve or diminish an individual patient’s chance of cure.
Administration of chemotherapy after surgery, referred to as adjuvant therapy, is a technique that is gaining acceptance in the treatment of NSCLC. Evidence presented at the 2003 and 2004 annual meetings of the American Society of Clinical Oncology suggests that chemotherapy treatment following surgery appears to improve survival for patients with NSCLC.
The following is a general overview of treatment for stage I NSCLC. Treatment may consist of surgery, radiation, chemotherapy, or a combination of these treatment techniques. Multi-modality treatment, which is treatment using two or more techniques, may be the most promising approach for increasing a patient's chance of cure or prolonging a patient's survival. However, circumstances unique to each patient’s situation may influence how these general treatment principles are applied and whether the patient decides to receive treatment. The potential benefits of receiving 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.
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 stage I NSCLC undergoing surgery to remove cancer.1
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 stages I-II 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.2,3
It is important to realize that patients with stage I 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 40% of relapses that follow treatment with surgery or radiation alone. An effective treatment is needed to cleanse the body of micrometastases in order to improve the approximate 60% cure rate achieved with surgical removal of the cancer. Efforts are currently underway to find such a therapy.
Neoadjuvant chemotherapy is treatment administered before surgery and adjuvant chemotherapy is treatment administered after surgery. Adjuvant and neoadjuvant therapy are used to eradicate the micrometastases that can result in relapse of the cancer in patients who undergo treatment with radiation or surgery alone. As researchers continue to refine the multi-modality treatment of NSCLC, studies that evaluate neoadjuvant, adjuvant, and combined chemotherapy will be undertaken. Clinical trials will be necessary to determine which approach is more effective. While current research indicates that both may be beneficial, adjuvant chemotherapy appears to be promising based on recent clinical study results that were reported at the ASCO 2003 annual conference.
Adjuvant chemotherapy: While surgery is the cornerstone of treatment for the management of stage I NSCLC for patients who have surgically removable cancers, treatment with chemotherapy after surgery is emerging as a standard treatment. The results of four clinical trials, two presented at the 2003 annual meeting of the American Society of Clinical Oncology (ASCO)45 and two presented at the 2004 meeting6,7 suggest that chemotherapy treatment in addition to surgery improves survival.
The clinical trials presented at the 2004 ASCO meeting produced the most dramatic results. A study completed by the National Cancer Institute of Canada showed that adjuvant chemotherapy increased the number of patients who lived 5 years or more from 54% to 69%.6 The second trial, conducted by US researchers, showed that adjuvant chemotherapy increased the number of patients who survived 3 years or more from 69% to 82%.7
Neoadjuvant chemotherapy: Neoadjuvant therapy has the potential advantage of immediately delivering treatment, thereby ensuring that therapy is delivered to any cancer cells that may have spread outside the lung. Neoadjuvant therapy may also decrease the size of the primary cancer, thereby allowing more complete surgical removal of the cancer.
In May of 1999, doctors from France reported that neoadjuvant chemotherapy is beneficial in the treatment of patients with large cancers or those involving lymph nodes. In this clinical study, 11% of patients treated with neoadjuvant chemotherapy had complete disappearance of their cancer confirmed at surgery. Patients treated with neoadjuvant chemotherapy experienced more side effects following surgery than patients treated with surgery alone; however, they survived longer and were less likely to experience cancer recurrence.
Combined neoadjuvant and adjuvant chemotherapy: Some doctors have advocated combining both adjuvant and neoadjuvant chemotherapy to reduce the risk of cancer recurrence. Researchers from several medical centers evaluated the use of a neoadjuvant chemotherapy combination and reported the results in March 2000. They treated 94 patients with stage I to IIIA NSCLC with a chemotherapy combination of Taxol® and Paraplatin®, followed by surgery to remove the cancer. Patients who achieved a complete response after surgery received 3 additional cycles of chemotherapy. Using this combined approach, 86% of patients had complete surgical removal of all visible cancer and 85% of the patients survived one year after treatment. Longer follow-up and additional studies to directly compare this regimen with surgery alone will be necessary to determine the true effectiveness of combined neoadjuvant and adjuvant chemotherapy treatment.
Over the past several years, other new chemotherapy drugs have been discovered that are more active at destroying lung cancer cells. It may be that these newer chemotherapy drugs administered before surgical removal of stage I NSCLC will further improve patient outcomes or will provide benefit when administered following surgery. Patients with stage I NSCLC should talk with their doctor about the risks and benefits of receiving adjuvant or neoadjuvant chemotherapy or of participating in a clinical trial in which new treatments are being studied.
Although patients with stage IA NSCLC have a relatively high rate of long-term survival following therapy and some may be considered to be cured, these patients 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 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 stage IA NSCLC who appeared to be cured. These researchers evaluated 124 patients previously treated with surgery alone. Follow-up included an annual computed tomographic (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.8
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 I NSCLC will result from the continued evaluation of new treatments in clinical trials. Participation in a clinical trial may offer patients access to better treatments and advance the existing knowledge about treatment of this cancer. 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 exploration to improve the treatment of stage I NSCLC include 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 in order to further improve survival duration and decrease the side effects of neoadjuvant therapy.
Management of anemia in NSCLC: Anemia is a term that refers to low levels of circulating red blood cells (RBCs) in the blood. Red blood cells are responsible for delivering oxygen to tissues throughout the entire body. Bone marrow is stimulated to produce RBCs by a chemical substance called erythropoietin, which is secreted by the kidneys. Cancer patients, particularly those receiving chemotherapy, often suffer from anemia. Common symptoms caused by anemia include severe fatigue, shortness of breath, greatly diminished activity levels and a reduced overall feeling of well-being. Severe anemia often necessitates blood transfusions, which have associated risks of infection, intolerance and increased medical costs. In addition, anemia can delay the administration of treatment or cause dose reductions, impeding optimal treatment benefits.
Erythropoietin can be manufactured outside the body and administered to patients. Recombinant human erythropoietin (rHuEPO), a commonly used drug for cancer patients receiving treatment, is comprised of manufactured erythropoietin. It has been shown to reduce the severity of anemia and reduce symptoms of fatigue in patients by stimulating the bone marrow to produce more RBCs. rHuEPO is administered daily or three times a week for the treatment of chemotherapy induced anemia.
Researchers have developed Aranesp®, a new form of erythropoietin, that stimulates production of RBCs in the same manner as erythropoietin, and may only need to be administered once every two to three weeks. This allows for less frequent dosing while maintaining benefits of the medication. In essence, patients may be able to avoid several trips to the physician and receive fewer subcutaneous injections.
A clinical study evaluating the use of Aranesp® in over 300 patients with lung cancer who were being treated with chemotherapy showed that patients who received Aranesp® required fewer transfusions and had fewer hospitalization days. Half of the patients received Aranesp® once every three weeks during treatment and the other half received a placebo. Patients receiving Aranesp® had a significantly lower incidence and/or severity of anemia compared to those receiving placebo. Only 21% of patients receiving Aranesp® required a blood transfusion during treatment, compared with 51% of patients receiving placebo. The average number of hospitalization days during treatment was 13.5 for patients receiving Aranesp® and 17.7 for patients receiving placebo. Additionally, patients receiving Aranesp® reported a higher quality of life compared to those receiving placebo.
The authors concluded that Aranesp® reduces the severity and incidence of anemia in lung cancer patients receiving chemotherapy, ultimately reducing blood transfusions, allowing optimal treatment schedules and enhancing a patient’s quality of life.9
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.10
Epidermal growth factor receptor (EGFR) inhibitors: EGFRs are small proteins that are found on the surface of cells. EGFRs bind exclusively with small proteins circulating in the blood called growth factors. The binding action between EGFR and growth factors stimulates biological processes within the cell to promote controlled growth of the cell. However, in many cancer cells, EGFR is either abundantly overexpressed or the EGFR biological processes that normally stimulate cell growth are constantly active, leading to the uncontrolled and excessive growth of the cancer cell. Inhibition of EGFRs is believed to decrease cancer growth by facilitating apoptosis, or cell death. Research is ongoing to evaluate the effectiveness of EGFR inhibitors as single agents and in combination with chemotherapy The EGFR-inhibitor, Iressa®, has demonstrated anti-cancer activity in patients with recurrent NSCLC, and may soon be evaluated in patients with earlier stage disease.
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 treatment approaches which 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 bevacizumab to standard chemotherapy treatment may soon be evaluated in patients with NSCLC.
Bestatin: Bestatin is a novel agent still in clinical trials that has demonstrated anti-cancer activity as well as stimulatory effects on the immune system. Researchers from Japan recently conducted a clinical trial to evaluate bestatin as adjuvant therapy in patients with stage I squamous cell lung cancer. This trial involved approximately 400 patients who had their cancer surgically removed. Patients were randomly selected to be treated with bestatin following surgery or placebo (inactive substitute) for 2 years following surgery and outcomes between the two groups of patients were directly compared. Five years following the initiation of treatment, overall survival was 81% for patients treated with bestatin, compared to 74% for patients who received placebo. Cancer-free survival at 5 years was 71% for patients treated with bestatin, compared to 62% for patients treated with placebo. Side effects were reportedly mild in both groups of patients.11
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.12
Gene therapy: Currently, there are no gene therapies approved for the treatment of lung cancer. Gene therapy is defined as the transfer of new genetic material into a cell for therapeutic benefit. This can be accomplished by replacing or inactivating a dysfunctional gene or replacing or adding a functional gene into a cell to make it function normally. Gene therapy has been directed towards the control of rapid growth of cancer cells, control of cancer death or efforts to make the immune system kill cancer cells. A few gene therapy studies are being carried out in patients with advanced lung cancer. If successful, this therapy could be applied to patients with earlier stage disease.
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9 Pirker G, Vansteenkiste J, Gateley J, Yates P, et al. A Phase III, Double-Blind, Placebo-Controlled, Randomized Study of Novel Erythropoiesis Stimulating Protein (NESP) in Patients Undergoing Platinum Treatment for Lung Cancer. Proceedings from the 37th annual meeting of the American Society of Clinical Oncology, 2001, San Francisco CA, Abstract #1572.
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11 Ichinose Y, Genka K, Koike T, et al. Randomized double-blind placebo-controlled trial of bestatin in patients with resected stage I squamous-cell lung carcinoma. Journal of the National Cancer Institute. 2003;95:605-610.
12 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 I non-small cell lung carcinomas. Cancer. 2002;95:1546-1553.