OncoLog: MD Anderson's report to physicians about advances in cancer care and research.


From OncoLog, October 2011, Vol. 56, No. 10

Compass: Non–Small Cell Lung Cancer: Stage IIIA

By Sunni Hosemann


The two major categories of lung cancer defined by the World Health Organization—small cell lung cancer and non–small cell lung cancer (NSCLC)—have different biological behaviors and are staged and treated differently. NSCLC is by far the more prevalent of the two, accounting for 85%–90% of diagnosed lung cancers.

This discussion is limited to NSCLC and will focus on stage IIIA as its treatment is the most controversial among lung cancers. Stage IIIA NSCLC is by no means homogeneous; within this stage, there is a wide range of primary tumor sizes and distribution, disease spread into the mediastinum may be absent or pronounced, and there may be variable involvement of the lung and/or surrounding structures. These factors have significant implications for treatment choices.

According to Anne Tsao, M.D., an associate professor in the Department of Thoracic/Head and Neck Medical Oncology at The University of Texas MD Anderson Cancer Center, most patients with stage IIIA NSCLC require all three major cancer treatment modalities—surgery, radiation therapy, and chemotherapy. “Determining the order in which these should be given is the challenge,” she said.

The roles and timing of chemotherapy and radiation therapy—whether they will be given concurrently or sequentially and whether they will be given as definitive treatment or adjuvant treatment before or after surgery—are best determined before any treatment begins. According to Melenda Jeter, M.D., an associate professor in the Department of Radiation Oncology, these are important considerations because different doses and regimens are used for each scenario. For example, if chemoradiation is given as preoperative treatment, lower doses of radiation are necessary than would be used if chemoradiation is given as the definitive treatment. Similarly, if chemotherapy and radiation therapy are administered concurrently, the toxicity of the treatments may necessitate giving lower doses of each than if they were given sequentially.

When a patient’s disease is classified as stage IIIA before any treatment begins, surgery is rarely the preferred initial treatment, even if the disease is deemed operable. According to the National Comprehensive Cancer Network, approximately half of its member institutions favor chemoradiation as the first treatment, and the other half prefer chemotherapy first. At MD Anderson, chemotherapy is preferred as the initial treatment. The rationale for this is discussed below.

Treatment decisions

The keys to the optimal treatment sequence for any patient with NSCLC are a very thorough pretreatment staging evaluation and a multidisciplinary consultation that includes medical, radiation, and surgical oncologists. The treatment decisions for a given patient with stage IIIA NSCLC are whether surgery will be part of the treatment plan, whether chemotherapy and radiation therapy will be definitive or adjuvant treatments, whether chemotherapy and radiation therapy will be given concurrently or sequentially, and whether chemotherapy and radiation therapy will be given neoadjuvantly or adjuvantly if surgery is done.

Neoadjuvant therapy

When a patient’s disease is deemed resectable or potentially resectable, neoadjuvant therapy is the next consideration. Although neoadjuvant chemotherapy and chemoradiation are generally considered equivalent, at MD Anderson, chemotherapy is preferred over chemoradiation as a preoperative treatment for the following reasons:

  • A higher chemotherapy dose can be used if chemotherapy is given alone than if combined with radiation therapy. The higher dose is more likely to control micrometastases, which if present could ultimately override any benefit of radiation and surgery, which are local therapies.
  • Chemoradiation prior to surgery requires that a smaller dose of radiation be used than would be used as a definitive treatment. If further radiation therapy is to be given after surgery, a break in therapy is required for an undetermined time period. This limits the ability to give a definitive dose and should be avoided if possible, according to Dr. Jeter. “Instead, we prefer to give treatment without breaks and either give definitive radiation therapy or reserve it for use postoperatively where needed,” she said.
  • Chemotherapy as an induction therapy allows for reassessment of mediastinal disease and perhaps reconsideration of a surgical option in patients who have a response. A patient whose disease does not respond appropriately or progresses during induction chemotherapy would not have benefited from surgery. “Induction chemotherapy doesn’t burn any bridges,” said Wayne Hofstetter, M.D., an associate professor in the Department of Thoracic and Cardiovascular Surgery. “It doesn’t preclude any other treatment as a potential next step for an individual patient.”

Is surgery feasible?

The role of surgery in stage IIIA NSCLC is one of the most controversial issues in cancer treatment. “Surgery is not appropriate for all patients,” Dr. Hofstetter said. “Stage IIIA NSCLC is diagnosed in a very heterogeneous group of patients—the presentation varies by tumor size and location and by the amount and distribution of disease, in lymph nodes for example. These factors influence whether surgery will be helpful.”

A thoracic surgical oncologist must therefore determine whether the patient is medically able to tolerate the required surgery and whether the disease can be removed with acceptable margins and with sufficient functional lung for adequate pulmonary reserve remaining postoperatively.

Today’s imaging technologies make more accurate pretreatment staging possible than was available in the past and enable better treatment sequences to be planned for individual patients—maximizing the potential efficacy of each modality while avoiding treatments that will not help. At MD Anderson, positron emission tomography (PET) and PET/ computed tomography imaging and endobronchial ultrasonography with fine-needle aspiration biopsy are used for the pretreatment workup. Mediastinoscopy is added if needed to verify whether there is disease in the mediastinal lymph nodes. “It is very important to have a proven diagnosis before we treat,” Dr. Hofstetter said. Noting that chronic inflammation or histoplasmosis (more common in the southern United States) can cause false-positive lymph nodes on PET scans, he recommends that histological confirmation of NSCLC be obtained before a patient undergoes any treatment. “We also want to rule out IIIB disease—contralateral lymph node involvement—for which surgery is not helpful.”

Dr. Hofstetter believes that surgery is most helpful where mediastinal disease is absent or there is nonbulky mediastinal disease with few lymph node stations affected. For multistation or bulky mediastinal disease, surgery is less effective and, if considered, would be preceded by chemotherapy and/or radiation therapy. Further, he noted that when pneumonectomy would be necessary for complete resection in a patient with stage IIIA N2 disease, definitive nonsurgical treatments should be considered instead, citing unacceptable surgical mortality rates associated with pneumonectomy—particularly when performed after chemoradiation.

Dr. Hofstetter further noted that if surgery is done, it must include appropriate lymph node dissection of all reachable mediastinal stations. “It is never appropriate to forego a thorough evaluation of lymph node stations,” he said.

Definitive chemoradiation

Patients who are not surgical candidates should receive definitive chemoradiation. Whether chemotherapy and radiation therapy are given concurrently or sequentially must be determined for each patient. According to Dr. Jeter, as a definitive treatment, concurrent chemoradiation is more effective than chemotherapy followed by radiation therapy but is also more toxic and is associated with higher rates of grade 3 or 4 esophagitis than sequential therapy, so patient tolerance becomes a consideration. She noted that many patients who are unable to tolerate concurrent therapy are also unable to tolerate sequential therapy, so radiation therapy alone or combined with targeted therapies might be considered for them.

According to Dr. Jeter, radiation for lung cancers is preferably given with intensity-modulated radiation therapy (IMRT) or, more recently, proton therapy, as lung tissue is very sensitive and surrounded by critical structures (the heart, esophagus, and spinal cord). “This is particularly true where there is bulky or central disease, the patient has cardiac disease, or the patient had previous radiation to the area—for breast cancer, for example—and we want to avoid re-irradiating tissues,” she said. A trial to compare proton therapy with IMRT is currently accruing patients with unresectable stage II or III NSCLC, or stage IV NSCLC with treated solitary brain metastasis; the study is being done at MD Anderson and Massachusetts General Hospital.


“In the adjuvant therapy trials where systemic chemotherapy is given, there is an increase of about 5% in 5-year overall survival rates,” Dr. Tsao said.

Chemotherapy—whether given neoadjuvantly alone or with radiation or given postoperatively—is tailored to tumor histology. Chemotherapy regimens administered with curative intent usually include a platinum-based drug paired with another agent, but future regimens may ultimately incorporate targeted therapies. “We know that certain chemotherapies and targeted agents work only with certain histological subtypes,” Dr. Tsao said. This further underscores the need for preoperative pathological analysis, which should include the status of tumor biomarkers, such as epidermal growth factor receptor mutation and the EML4-ALK translocation, as specific mutations in these molecular pathways respond differently to specific novel drugs.

Future directions

According to Dr. Tsao, a new clinical trial being planned at MD Anderson for stage III NSCLC will be a triple-modality trial in which treatment is tailored to the individual based on response to initial therapy. Treatment will include proton therapy and chemotherapy specific to histology, followed by either surgery or more chemoradiation. “The arms of this trial will be unique because they will be individualized,” Dr. Tsao said. “We are trying to push the envelope.”

The need for more individualized approaches to treatment will likely continue to be the driving force behind research initiatives.

A second trial will focus on patients with stage III NSCLC whose disease does not respond to chemoradiation or who have residual disease after chemoradiation. The goal is to determine whether additional chemotherapy or chemoradiation will help. “The 5-year overall survival rate among stage III NSCLC patients is 25%–30%,” Dr. Tsao said, “so we are trying to find additional treatments for them—we are still pursuing a possible cure.”

Two trials are in progress for patients with local-regionally advanced NSCLC whose performance status precludes surgery or conventional chemotherapies. One of these trials uses radiation therapy and celecoxib, and the other uses stereotactic radiation therapy. Patients with limited stage IV disease are included in the latter trial. “We are still committed to finding curative outcomes for our patients,” Dr. Tsao said, “even in the presence of advanced disease or inability to tolerate conventional treatments.”

Contributing Faculty
The University of Texas MD Anderson Cancer Center

Wayne L. Hofstetter, M.D.
Associate Professor, Thoracic and Cardiovascular Surgery

Melenda Jeter, M.D.
Associate Professor, Radiation Oncology

Anne Tsao, M.D.
Associate Professor, Thoracic/Head and Neck Medical Oncology

American Cancer Society. Lung Cancer (Non–Small Cell).
American Joint Committee on Cancer. Summary of Changes (PDF).
National Cancer Institute. Non–Small Lung Cancer.
National Comprehensive Cancer Network. Clinical Practice Guidelines in Oncology, Non–Small Cell Lung Cancer, V.3.2011 (PDF, subscription only).

Lung Cancer Staging

The American Joint Committee on Cancer staging system differentiates cancer stages by tumor size (T), lymph node involvement (N), and presence of distant metastasis (M), to classify disease into groups with prognostic significance and treatment implications. For non–small cell lung cancer (NSCLC), the TNM classifications are defined as follows:

T classification includes not just tumor size but also the location and the extent of spread to specific nearby structures. For NSCLC, these classifications include:

  • T1, the tumor is 3 cm or less in diameter, has not reached the visceral pleura, and does not affect the main branches of the bronchi;
  • T2, the tumor is 3–7 cm in diameter, or it involves a main bronchus but is not closer than 2 cm to the carina, or it has grown into the visceral pleura, or it obstructs the airways but has not caused the entire lung to collapse or develop pneumonia;
  • T3, the tumor is larger than 7 cm in diameter; or it has grown into the chest wall, diaphragm, mediastinal pleura, or parietal pericardium; or it invades a main bronchus and is closer than 2 cm to the carina but does not involve the carina itself; or it obstructs the airways enough to cause an entire lung to collapse or develop pneumonia; or two or more tumor nodules are present in the same lobe of a lung;
  • T4, the tumor has grown into the mediastinum, heart, large blood vessels near the heart, trachea, esophagus, spine, or carina; or two or more separate tumor nodules are present in different lobes of the same lung.

N classification describes not just the number of involved lymph nodes but also their location. For NSCLC, the N classifications are:

  • N1, lymph nodes within the lung on the same (ipsilateral) side as the primary tumor;
  • N2, lymph nodes in the mediastinum on the same (ipsilateral) side as the primary tumor;
  • N3, mediastinal or hilar lymph nodes on the contralateral side or beyond the mediastinal pleural envelope, which would include involvement of scalene or supraclavicular nodes on either side.

These designations reflect the prognostic significance of the pattern of lymph node involvement—lung cancers tend to affect nearby nodes in the lung first, followed by nodes in the mediastinum on the affected side. Migration of disease across the mediastinum or to more distant nodes is considered a significant advance.

The American Thoracic Society uses a mapping system that defines the anatomical boundaries of 14 lymph node stations—five inside the lung and nine mediastinal stations. Lymph node involvement in more than one station is considered significant.

M classification refers to metastatic spread to distant sites. In the case of NSCLC, M1 disease would include spread to the contralateral lung, lymph nodes beyond the regional stations, or other organs.

These refinements result in considerable heterogeneity of patient presentation within a given stage of NSCLC. Stage IIIA NSCLC is designated as T1–4, N0–2, M0.

A revision of lung cancer staging effective in January 2010 resulted in the upstaging or downstaging of several NSCLC categories. One important change was the reclassification of multiple tumor nodules in the same lobe from T4 to T3 and in different lobes of the same lung from M1 to T4. Malignant pericardial and pleural effusions, previously considered T4, are now designated M1a, as are tumor nodules in the contralateral lung. M1b is now the designation for distant metastases in this disease.

For more information, contact Dr. Jennifer Litton at 713-792-2817, Dr. Andrea Milbourne at 713-745-6986,
or Dr. Richard Theriault at 713-792-2817.


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