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Non-Small Cell Lung Cancer Treatment (PDQ®)

Last modified: 2013-05-30
Last downloaded: Tuesday, September 03, 2013

General Information About Non-Small Cell Lung Cancer (NSCLC)

NSCLC is any type of epithelial lung cancer other than small cell lung cancer (SCLC). The most common types of NSCLC are squamous cell carcinoma, large cell carcinoma, and adenocarcinoma, but there are several other types that occur less frequently, and all types can occur in unusual histologic variants. Although NSCLCs are associated with cigarette smoke, adenocarcinomas may be found in patients who have never smoked. As a class, NSCLCs are relatively insensitive to chemotherapy and radiation therapy compared with SCLC. Patients with resectable disease may be cured by surgery or surgery followed by chemotherapy. Local control can be achieved with radiation therapy in a large number of patients with unresectable disease, but cure is seen only in a small number of patients. Patients with locally advanced unresectable disease may achieve long-term survival with radiation therapy combined with chemotherapy. Patients with advanced metastatic disease may achieve improved survival and palliation of symptoms with chemotherapy, targeted agents, and other supportive measures.

Incidence and Mortality

Estimated new cases and deaths from lung cancer (NSCLC and SCLC combined) in the United States in 2013:

  • New cases: 228,190.
  • Deaths: 159,480.

Lung cancer is the leading cause of cancer-related mortality in the United States. The 5-year relative survival rate from 1995 to 2001 for patients with lung cancer was 15.7%. The 5-year relative survival rate varies markedly depending on the stage at diagnosis, from 49% to 16% to 2% for patients with local, regional, and distant stage disease, respectively.

Anatomy

NSCLC arises from the epithelial cells of the lung of the central bronchi to terminal alveoli. The histological type of NSCLC correlates with site of origin, reflecting the variation in respiratory tract epithelium of the bronchi to alveoli. Squamous cell carcinoma usually starts near a central bronchus. Adenocarcinoma and bronchioloalveolar carcinoma usually originate in peripheral lung tissue.

Anatomy of the respiratory system.

Pathogenesis

Smoking-related lung carcinogenesis is a multistep process. Squamous cell carcinoma and adenocarcinoma have defined premalignant precursor lesions. Before becoming invasive, lung epithelium may undergo morphological changes that include the following:

  • Hyperplasia.
  • Metaplasia.
  • Dysplasia.
  • Carcinoma in situ.

Dysplasia and carcinoma in situ are considered the principal premalignant lesions because they are more likely to progress to invasive cancer and less likely to spontaneously regress.

In addition, after resection of a lung cancer, there is a 1% to 2% risk per patient per year that a second lung cancer will occur.

Pathology

NSCLC is a heterogeneous aggregate of histologies. The most common histologies include the following:

  • Epidermoid or squamous cell carcinoma.
  • Adenocarcinoma.
  • Large cell carcinoma.

These histologies are often classified together because approaches to diagnosis, staging, prognosis, and treatment are similar.

Risk Factors

Several risk factors contribute to the development of lung cancer. These risk factors may include the following:

  • Cigarette, pipe, or cigar smoking.
  • Exposure to second-hand smoke, radon, arsenic, asbestos, chromates, chloromethyl ethers, nickel, polycyclic aromatic hydrocarbons, radon progeny, other agents, and air pollution.
  • Radiation therapy to the breast or chest.

The single most important risk factor for the development of lung cancer is smoking. For smokers, the risk for lung cancer is on average tenfold higher than in lifetime nonsmokers (defined as a person who has smoked <100 cigarettes in his or her lifetime). The risk increases with the quantity of cigarettes, duration of smoking, and starting age.

Smoking cessation results in a decrease in precancerous lesions and a reduction in the risk of developing lung cancer. Former smokers continue to have an elevated risk for lung cancer for years after quitting. Asbestos exposure may exert a synergistic effect of cigarette smoking on the lung cancer risk.

Prevention

A significant number of patients cured of their smoking-related lung cancer may develop a second malignancy. In the Lung Cancer Study Group trial of 907 patients with stage T1, N0 resected tumors, the rate was 1.8% per year for nonpulmonary second cancers and 1.6% per year for new lung cancers. Other studies have reported even higher risks of second tumors in long-term survivors, including rates of 10% for second lung cancers and 20% for all second cancers.

Because of the persistent risk of developing second lung cancers in former smokers, various chemoprevention strategies have been evaluated in randomized control trials. None of the phase III trials with the agents beta carotene, retinol, 13-cis-retinoic acid, [alpha]-tocopherol, N-acetylcysteine, or acetylsalicylic acid has demonstrated beneficial, reproducible results.[Level of evidence: 1iiA] Chemoprevention of second primary cancers of the upper aerodigestive tract is undergoing clinical evaluation in patients with early-stage lung cancer.

Refer to the PDQ summaries on Lung Cancer Prevention and Smoking in Cancer Care for more information.

Screening

In patients considered at high risk for developing lung cancer, the only screening modality for early detection that has been shown to alter mortality is low-dose helical CT scanning. Studies of lung cancer screening with chest radiography and sputum cytology have failed to demonstrate that screening lowers lung cancer mortality rates.

(Refer to the Screening by low-dose helical computed tomography subsection in the PDQ summary on Lung Cancer Screening for more information.)

Clinical Features

Lung cancer may present with symptoms or be found incidentally on chest imaging. Symptoms and signs may result from the location of the primary local invasion or compression of adjacent thoracic structures, distant metastases, or paraneoplastic phenomena. The most common symptoms at presentation are worsening cough or chest pain. Other presenting symptoms include the following:

  • Hemoptysis.
  • Malaise.
  • Weight loss.
  • Dyspnea.
  • Hoarseness.

Symptoms may result from local invasion or compression of adjacent thoracic structures such as compression involving the esophagus causing dysphagia, compression involving the laryngeal nerves causing hoarseness, or compression involving the superior vena cava causing facial edema and distension of the superficial veins of the head and neck. Symptoms from distant metastases may also be present and include neurological defect or personality change from brain metastases or pain from bone metastases. Infrequently, patients may present with symptoms and signs of paraneoplastic diseases such as hypertrophic osteoarthropathy with digital clubbing or hypercalcemia from parathyroid hormone-related protein. Physical examination may identify enlarged supraclavicular lymphadenopathy, pleural effusion or lobar collapse, unresolved pneumonia, or signs of associated disease such as chronic obstructive pulmonary disease or pulmonary fibrosis.

Diagnosis

Treatment options for patients are determined by histology, stage, and general health and comorbidities of the patient. Investigations of patients with suspected NSCLC focus on confirming the diagnosis and determining the extent of the disease.

The procedures used to determine the presence of cancer include the following:

  • History.
  • Physical examination.
  • Routine laboratory evaluations.
  • Chest x-ray.
  • Chest CT scan with infusion of contrast material.
  • Biopsy.

Before a patient begins lung cancer treatment, an experienced lung cancer pathologist must review the pathologic material. This is critical because SCLC, which responds well to chemotherapy and is generally not treated surgically, can be confused on microscopic examination with NSCLC. Immunohistochemistry and electron microscopy are invaluable techniques for diagnosis and subclassification, but most lung tumors can be classified by light microscopic criteria.

(Refer to the Staging Evaluation section of this summary for more information on tests and procedures used for staging.)

Molecular Features

The identification of mutations in lung cancer has led to the development of molecularly targeted therapy to improve the survival of subsets of patients with metastatic disease. In particular, subsets of adenocarcinoma now can be defined by specific mutations in genes encoding components of the epidermal growth factor receptor (EGFR) and downstream mitogen-activated protein kinases (MAPK) and phosphatidylinositol 3-kinases (PI3K) signaling pathways. These mutations may define mechanisms of drug sensitivity and primary or acquired resistance to kinase inhibitors.

Other genetic abnormalities of potential relevance to treatment decisions include translocations involving the anaplastic lymphoma kinase (ALK)-tyrosine kinase receptor, which are sensitive to ALK inhibitors, and amplification of MET (mesenchymal epithelial transition factor), which encodes the hepatocyte growth factor receptor. MET amplification has been associated with secondary resistance to EGFR tyrosine kinase inhibitors.

Prognostic Factors

Multiple studies have attempted to identify the prognostic importance of a variety of clinicopathologic factors. Factors that have correlated with adverse prognosis include the following:

  • Presence of pulmonary symptoms.
  • Large tumor size (>3 cm).
  • Nonsquamous histology.
  • Metastases to multiple lymph nodes within a TNM-defined nodal station. (Refer to the Evaluation of Mediastinal Lymph Node Metastasis section of this summary for more information.)
  • Vascular invasion.

For patients with inoperable disease, prognosis is adversely affected by poor performance status and weight loss of more than 10%. These patients have been excluded from clinical trials evaluating aggressive multimodality interventions.

In multiple retrospective analyses of clinical trial data, advanced age alone has not been shown to influence response or survival with therapy.

Refer to the separate treatment sections for each stage of NSCLC in this summary for more information about prognosis.

Because treatment is not satisfactory for almost all patients with NSCLC, eligible patients should be considered for clinical trials. Information about ongoing clinical trials is available from the NCI Web site.

Related Summaries

Other PDQ summaries containing information related to lung cancer include the following:


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Cellular Classification of NSCLC

Malignant non-small cell epithelial tumors of the lung are classified by the World Health Organization (WHO)/International Association for the Study of Lung Cancer (IASLC). There are three main subtypes of non-small cell lung cancer (NSCLC), including the following:

  • Squamous cell carcinoma (25% of lung cancers).
  • Adenocarcinoma (40% of lung cancers).
  • Large cell carcinoma (10% of lung cancers).

There are numerous additional subtypes of decreasing frequency.

WHO/IASLC Histologic Classification of NSCLC

Squamous cell carcinoma

Most squamous cell carcinomas of the lung are located centrally, in the larger bronchi of the lung. Squamous cell carcinomas are linked more strongly with smoking than other forms of NSCLC. The incidence of squamous cell carcinoma of the lung has been decreasing in recent years.

Adenocarcinoma

Adenocarcinoma is now the most common histologic subtype in many countries, and subclassification of adenocarcinoma is important. One of the biggest problems with lung adenocarcinomas is the frequent histologic heterogeneity. In fact, mixtures of adenocarcinoma histologic subtypes are more common than tumors consisting purely of a single pattern of acinar, papillary, bronchioloalveolar, and solid adenocarcinoma with mucin formation.

Criteria for the diagnosis of bronchioloalveolar carcinoma have varied widely in the past. The current WHO/IASLC definition is much more restrictive than that previously used by many pathologists because it is limited to only noninvasive tumors.

If stromal, vascular, or pleural invasion are identified in an adenocarcinoma that has an extensive bronchioloalveolar carcinoma component, the classification would be an adenocarcinoma of mixed subtype with predominant bronchioloalveolar pattern and a focal acinar, solid, or papillary pattern, depending on which pattern is seen in the invasive component. However, the future of bronchioloalveolar carcinoma as a distinct clinical entity is unclear; a multidisciplinary expert panel representing the IASLC, the American Thoracic Society, and the European Respiratory Society proposed a major revision of the classification of adenocarcinomas in 2011 that entails a reclassification of what was called bronchioloalveolar carcinoma into newly defined histologic subgroups.

The following variants of adenocarcinoma are recognized in the WHO/IASLC classification:

  • Well-differentiated fetal adenocarcinoma.
  • Mucinous (colloid) adenocarcinoma.
  • Mucinous cystadenocarcinoma.
  • Signet ring adenocarcinoma.
  • Clear cell adenocarcinoma.

Large cell carcinoma

In addition to the general category of large cell carcinoma, several uncommon variants are recognized in the WHO/IASLC classification, including the following:

  • LCNEC.
  • Basaloid carcinoma.
  • Lymphoepithelioma-like carcinoma.
  • Clear cell carcinoma.
  • Large cell carcinoma with rhabdoid phenotype.

Basaloid carcinoma is also recognized as a variant of squamous cell carcinoma, and rarely, adenocarcinomas may have a basaloid pattern; however, in tumors without either of these features, they are regarded as a variant of large cell carcinoma.

Neuroendocrine tumors

LCNEC is recognized as a histologically high-grade non-small cell carcinoma. It has a very poor prognosis similar to that of small cell lung cancer (SCLC). Atypical carcinoid is recognized as an intermediate-grade neuroendocrine tumor with a prognosis that falls between typical carcinoid and high-grade SCLC and LCNEC.

Neuroendocrine differentiation can be demonstrated by immunohistochemistry or electron microscopy in 10% to 20% of common NSCLCs that do not have any neuroendocrine morphology. These tumors are not formally recognized within the WHO/IASLC classification scheme because the clinical and therapeutic significance of neuroendocrine differentiation in NSCLC is not firmly established. These tumors are referred to collectively as NSCLC with neuroendocrine differentiation.

Carcinomas with pleomorphic, sarcomatoid, or sarcomatous elements

This is a group of rare tumors. Spindle cell carcinomas and giant cell carcinomas comprise only 0.4% of all lung malignancies, and carcinosarcomas comprise only 0.1% of all lung malignancies. In addition, this group of tumors reflects a continuum in histologic heterogeneity as well as epithelial and mesenchymal differentiation. On the basis of clinical and molecular data, biphasic pulmonary blastoma is regarded as part of the spectrum of carcinomas with pleomorphic, sarcomatoid, or sarcomatous elements.

Molecular Features

The identification of mutations in lung cancer has led to the development of molecularly targeted therapy to improve the survival of subsets of patients with metastatic disease. In particular, subsets of adenocarcinoma now can be defined by specific mutations in genes encoding components of the epidermal growth factor receptor (EGFR) and downstream mitogen-activated protein kinases (MAPK) and phosphatidylinositol 3-kinases (PI3K) signaling pathways. These mutations may define mechanisms of drug sensitivity and primary or acquired resistance to kinase inhibitors. Other mutations of potential relevance to treatment decisions include:

  • Kirsten rat sarcoma viral oncogene (KRAS).
  • Anaplastic lymphoma kinase receptor (ALK).
  • Human epidermal growth factor receptor 2 (HER2).
  • V-raf murine sarcoma viral oncogene homolog B1 (BRAF).
  • PIK3 catalytic protein alpha (PI3KCA).
  • AKT1.
  • MAPK kinase 1 (MAP2K1 or MEK1).
  • MET, which encodes the hepatocyte growth factor receptor (HGFR).

These mutations are mutually exclusive, except for those in PIK3CA and EGFR mutations and ALK translocations.

EGFR and ALK mutations predominate in adenocarcinomas that develop in nonsmokers, and KRAS and BRAF mutations are more common in smokers or former smokers. EGFR mutations strongly predict the improved response rate and progression-free survival of EGFR inhibitors. In a set of 2,142 lung adenocarcinoma specimens from patients treated at Memorial Sloan Kettering Cancer Center, EGFR exon 19 deletions and L858R were found in 15% of tumors from former smokers (181 of 1,218; 95% CI, 13–17), 6% from current smokers (20 of 344; 95% CI, 4–9), and 52% from never-smokers (302 of 580; 95% CI, 48–56; P < .001 for ever- vs. never-smokers).

Fusions of ALK with EML4 genes form translocation products that occur in ranges from 3% to 7% in unselected NSCLC and are responsive to pharmacological inhibition of ALK by agents such as crizotinib. Other mutations that occur in less than 5% of NSCLC tumors include:

  • HER2, present in 2% of tumors.
  • PI3KCA, present in 2% of tumors.
  • AKT1, present in 1% of tumors.
  • BRAF mutations, present in 1% to 3% of tumors.

BRAF mutations are mutually exclusive of EGFR and KRAS mutations. Somatic mutations in MAP2K1 (also known as MEK) have been identified in 1% of NSCLC. MET oncogene encodes hepatocyte growth factor receptor. Amplification of this gene has been associated with secondary resistance to EGFR tyrosine kinase inhibitors.


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Stage Information for NSCLC

Background

In NSCLC, the determination of stage is important in terms of therapeutic and prognostic implications. Careful initial diagnostic evaluation to define the location and to determine the extent of primary and metastatic tumor involvement is critical for the appropriate care of patients.

In general, symptoms, physical signs, laboratory findings, or perceived risk of distant metastasis lead to an evaluation for distant metastatic disease. Additional tests such as bone scans and computed tomography (CT)/magnetic resonance imaging (MRI) of the brain may be performed if initial assessments suggest metastases or if patients with stage III disease are under consideration for aggressive local and combined modality treatments.

Stage has a critical role in the selection of therapy. The stage of disease is based on a combination of clinical factors and pathological factors. The distinction between clinical stage and pathological stage should be considered when evaluating reports of survival outcome.

Procedures used to determine staging include the following:

  • History.
  • Physical examination.
  • Routine laboratory evaluations.
  • Chest x-ray.
  • Chest CT scan with infusion of contrast material.
  • Fluorodeoxyglucose-positron emission tomography (FDG-PET) scanning.

Procedures used to obtain tissue samples include bronchoscopy, mediastinoscopy, or anterior mediastinotomy. Pathological staging of NSCLC requires the following:

  • Examination of the tumor.
  • Resection margins.
  • Lymph nodes.

Prognostic and treatment decisions are based on some of the following factors:

  • Knowledge of histologic type.
  • Tumor size and location.
  • Involvement of pleura.
  • Surgical margins.
  • Status and location of lymph nodes by station.
  • Tumor grade.
  • Lymphovascular invasion.

At diagnosis, patients with NSCLC can be divided into the following three groups that reflect both the extent of the disease and the treatment approach:

Staging Evaluation

Evaluation of mediastinal lymph node metastasis

Surgical evaluation

Surgical staging of the mediastinum is considered standard if accurate evaluation of the nodal status is needed to determine therapy.

Accurate staging of the mediastinal lymph nodes provides important prognostic information.

Evidence (nodal status):

CT imaging

CT scanning is primarily used for determining the size of the tumor. The CT scan should extend inferiorly to include the liver and adrenal glands. MRI scans of the thorax and upper abdomen do not appear to yield advantages over CT scans.

Evidence (CT scan):

FDG-PET scanning

The wider availability and use of FDG-PET scanning for staging has modified the approach to staging mediastinal lymph nodes and distant metastases.

Randomized trials evaluating the utility of FDG-PET scanning in potentially resectable NSCLC report conflicting results in terms of the relative reduction in the number of noncurative thoracotomies.

Although the current evidence is conflicting, FDG-PET scanning may improve results of early-stage lung cancer by identifying patients who have evidence of metastatic disease that is beyond the scope of surgical resection and that is not evident by standard preoperative staging procedures.

Evidence (FDG-PET scan):

Cost effectiveness of FDG-PET scanning

Decision analyses demonstrate that FDG-PET scanning may reduce the overall costs of medical care by identifying patients with falsely negative CT scans in the mediastinum or otherwise undetected sites of metastases. Studies concluded that the money saved by forgoing mediastinoscopy in FDG-PET-positive mediastinal lesions was not justified because of the unacceptably high number of false-positive results. A randomized study found that the addition of FDG-PET scanning to conventional staging was associated with significantly fewer thoracotomies. A second randomized trial evaluating the impact of FDG-PET scanning on clinical management found that FDG-PET scanning provided additional information regarding appropriate stage but did not lead to significantly fewer thoracotomies.

Combination of CT imaging and FDG-PET scanning

The combination of CT imaging and FDG-PET scanning has greater sensitivity and specificity than CT imaging alone.

Evidence (CT/FDG-PET scan):

For patients with clinically operable NSCLC, the recommendation is for a biopsy of mediastinal lymph nodes that were found to be larger than 1 cm in shortest transverse axis on chest CT scan or were found to be positive on FDG-PET scan. Negative FDG-PET scanning does not preclude biopsy of radiographically enlarged mediastinal lymph nodes. Mediastinoscopy is necessary for the detection of cancer in mediastinal lymph nodes when the results of the CT scan and FDG-PET scan do not corroborate each other.

Evaluation of brain metastasis

Patients at risk for brain metastases may be staged with CT or MRI scans. One study randomly assigned 332 patients with potentially operable NSCLC and no neurological symptoms to brain CT or MRI imaging to detect occult brain metastasis before lung surgery. MRI showed a trend towards a higher preoperative detection rate than CT scan (P = .069), with an overall detection rate of approximately 7% from pretreatment to 12 months after surgery. Patients with stage I or stage II disease had a detection rate of 4% (i.e., eight detections out of 200 patients); however, individuals with stage III disease had a detection rate of 11.4% (i.e., 15 detections out of 132 patients). The mean maximal diameter of the brain metastases was significantly smaller in the MRI group. Whether the improved detection rate of MRI translates into improved outcome remains unknown. Not all patients are able to tolerate MRI, and for these patients contrast-enhanced CT scan is a reasonable substitute.

Evaluation of distant metastasis other than the brain

Numerous nonrandomized, prospective, and retrospective studies have demonstrated that FDG-PET scanning seems to offer diagnostic advantages over conventional imaging in staging distant metastatic disease; however, standard FDG-PET scans have limitations. FDG-PET scans may not extend below the pelvis and may not detect bone metastases in the long bones of the lower extremities. Because the metabolic tracer used in FDG-PET scanning accumulates in the brain and urinary tract, FDG-PET scanning is not reliable for detection of metastases in these sites.

The Revised International System for Staging Lung Cancer

The Revised International System for Staging Lung Cancer, based on information from a clinical database of more than 5,000 patients, was adopted in 2010 by the American Joint Committee on Cancer (AJCC) and the Union Internationale Contre le Cancer. These revisions provide greater prognostic specificity for patient groups; however, the correlation between stage and prognosis predates the widespread availability of PET imaging.

Summary of Changes

This staging system is now recommended for the classification of both NSCLC and small cell lung carcinomas and for carcinoid tumors of the lung.

The T (primary tumor) classifications have been redefined as follows:

  • T1 has been subclassified into T1a (≤2 cm in size) and T1b (>2–3 cm in size).
  • T2 has been subclassified into T2a (>3–5 cm in size) and T2b (>5–7 cm in size).
  • T2 (>7 cm in size) has been reclassified as T3.
  • Multiple tumor nodules in the same lobe have been reclassified from T4 to T3.
  • Multiple tumor nodules in the same lung but a different lobe have been reclassified from M1 to T4.

No changes have been made to the N (regional lymph nodes) classification. However, a new international lymph node map defining the anatomical boundaries for lymph node stations has been developed.

The M (distant metastasis) classifications have been redefined as follows:

  • M1 has been subdivided into M1a and M1b.
  • Malignant pleural and pericardial effusions have been reclassified from T4 to M1a.
  • Separate tumor nodules in the contralateral lung are considered M1a.
  • M1b designates distant metastasis.

AJCC Stage Groupings and TNM Definitions

The AJCC has designated staging by TNM classification to define NSCLC.


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Treatment Option Overview for NSCLC

In NSCLC, results of standard treatment are poor except for the most localized cancers. All newly diagnosed patients with NSCLC are potential candidates for studies evaluating new forms of treatment.

Surgery is the most potentially curative therapeutic option for this disease. Postoperative chemotherapy may provide an additional benefit to patients with resected NSCLC. Radiation therapy combined with chemotherapy can produce a cure in a small number of patients and can provide palliation in most patients. Prophylactic cranial irradiation (PCI) may reduce the incidence of brain metastases, but there is no evidence of a survival benefit and the effect of PCI on quality of life is not known. In patients with advanced-stage disease, chemotherapy or epidermal growth factor receptor (EGFR) kinase inhibitors offer modest improvements in median survival, though overall survival is poor.

Chemotherapy has produced short-term improvement in disease-related symptoms in patients with advanced NSCLC. Several clinical trials have attempted to assess the impact of chemotherapy on tumor-related symptoms and quality of life. In total, these studies suggest that tumor-related symptoms may be controlled by chemotherapy without adversely affecting overall quality of life; however, the impact of chemotherapy on quality of life requires more study. In general, medically fit elderly patients with good performance status obtain the same benefits from treatment as younger patients.

The identification of mutations in lung cancer has led to the development of molecularly targeted therapy to improve the survival of subsets of patients with metastatic disease. In particular, genetic abnormalities in EGFR, MAPK, PI3K signaling pathways in subsets of NSCLC may define mechanisms of drug sensitivity and primary or acquired resistance to kinase inhibitors. EGFR mutations strongly predict the improved response rate and progression-free survival of inhibitors of EGFR. Fusions of ALK with EML4 genes form translocation products that occur in ranges from 3% to 7% in unselected NSCLC and are responsive to pharmacological inhibition of ALK by agents such as crizotinib. MET oncogene encodes hepatocyte growth factor receptor. Amplification of this gene has been associated with secondary resistance to EGFR tyrosine kinase inhibitors.

The standard treatment options for each stage of NSCLC are presented in Table 11.

In addition to the standard treatment options presented in Table 11, treatment options under clinical evaluation include the following:

  • Combining local treatment (surgery).
  • Regional treatment (radiation therapy).
  • Systemic treatments (chemotherapy, immunotherapy, and targeted agents).
  • Developing more effective systemic therapy.

Follow-Up

Several small series have reported that reduction in fluorodeoxyglucose-positron emission tomography (FDG-PET) after chemotherapy, radiation therapy, or chemoradiation therapy correlates with pathological complete response and favorable prognosis. Studies have used different timing of assessments, FDG-PET parameters, and cutpoints to define FDG-PET response. Reduction in maximum standardized uptake value (SUV) of more than 80% predicted for complete pathological response with a sensitivity of 90%, specificity of 100%, and accuracy of 96%. Median survival after resection was greater for patients with tumor SUV values of less than 4 (56 mo vs. 19 mo). Patients with complete metabolic response following radiation therapy were reported to have median survivals of 31 months versus 11 months.

FDG-PET may be more sensitive and specific than computed tomography scan in assessing response to induction therapy. Optimal timing imaging remains to be defined; however, one study suggests that greater sensitivity and specificity of FDG-PET is achieved if repeat imaging is delayed until 30 days after radiation therapy.

Current Clinical Trials

Check for U.S. clinical trials from NCI's list of cancer clinical trials that are now accepting patients with non-small cell lung cancer. The list of clinical trials can be further narrowed by location, drug, intervention, and other criteria.

General information about clinical trials is also available from the NCI Web site.


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Occult NSCLC Treatment

In occult lung cancer, a diagnostic evaluation often includes chest x-ray and selective bronchoscopy with close follow-up (e.g., computed tomography scan), when needed, to define the site and nature of the primary tumor; tumors discovered in this fashion are generally early stage and curable by surgery.

After discovery of the primary tumor, treatment involves establishing the stage of the tumor. Therapy is identical to that recommended for other NSCLC patients with similar stage disease.

Standard Treatment Options for Occult NSCLC

Standard treatment options for occult NSCLC include the following:

Current Clinical Trials

Check for U.S. clinical trials from NCI's list of cancer clinical trials that are now accepting patients with occult non-small cell lung cancer. The list of clinical trials can be further narrowed by location, drug, intervention, and other criteria.

General information about clinical trials is also available from the NCI Web site.


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Stage 0 NSCLC Treatment

Stage 0 NSCLC frequently progresses to invasive cancer. Patients may be offered surveillance bronchoscopies and, if lesions are detected, potentially curative therapies.

Standard Treatment Options for Stage 0 NSCLC

Standard treatment options for stage 0 NSCLC include the following:

Surgery

Segmentectomy or wedge resection are used to preserve maximum normal pulmonary tissue since patients with stage 0 NSCLC are at a high risk for second lung cancers. Because these tumors are by definition noninvasive and incapable of metastasizing, they should be curable with surgical resection; however, such lesions, when identified, are often centrally located and may require a lobectomy.

Endobronchial therapies

Patients with central lesions may be candidates for curative endobronchial therapy. Endobronchial therapies that preserve lung function include photodynamic therapy, electrocautery, cryotherapy, and Nd-YAG laser therapy.

Evidence (endobronchial therapies):

Efficacy of these treatment modalities in the management of patients with early NSCLC remains to be proven in definitive randomized controlled trials.

There is a high incidence of second primary cancers developing.

Current Clinical Trials

Check for U.S. clinical trials from NCI's list of cancer clinical trials that are now accepting patients with stage 0 non-small cell lung cancer. The list of clinical trials can be further narrowed by location, drug, intervention, and other criteria.

General information about clinical trials is also available from the NCI Web site.


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Stages IA and IB NSCLC Treatment

Standard Treatment Options for Stages IA and IB NSCLC

Standard treatment options for stage IA NSCLC and IB NSCLC include the following:

Chemotherapy and radiation therapy have not been shown to improve outcomes in stage I NSCLC that has been completely resected.

Surgery

Surgery is the treatment of choice for patients with stage I NSCLC. A lobectomy or segmental, wedge, or sleeve resection may be performed as appropriate. Patients with impaired pulmonary function are candidates for segmental or wedge resection of the primary tumor. Careful preoperative assessment of the patient’s overall medical condition, especially the patient’s pulmonary reserve, is critical in considering the benefits of surgery. The immediate postoperative mortality rate is age related, but a 3% to 5% mortality rate with lobectomy can be expected.

Evidence (surgery):

Limitations of evidence (surgery):

Conclusions about the efficacy of surgery for patients with local and locoregional NSCLC are limited by the small number of participants studied to date and the potential methodological weaknesses of the trials.

Adjuvant therapy

Many patients treated surgically subsequently develop regional or distant metastases. Such patients are candidates for entry into clinical trials evaluating postoperative treatment with chemotherapy or radiation therapy following surgery. At present, neither chemotherapy nor radiation therapy has been found to improve the outcome of patients with stage I NSCLC that has been completely resected.

Adjuvant radiation therapy

The value of postoperative (adjuvant) radiation therapy (PORT) has been evaluated and has not been found to improve the outcome of patients with completely resected stage I NSCLC.

Evidence (adjuvant radiation therapy):

Further analysis is needed to determine whether these outcomes can potentially be modified with technical improvements, better definitions of target volumes, and limitation of cardiac volume in the radiation portals.

Adjuvant chemotherapy

Based on a meta-analysis, postoperative chemotherapy is not recommended outside of a clinical trial for patients with completely resected stage I NSCLC.[Level of evidence: 1iiA]

Evidence (adjuvant chemotherapy for stage I NSCLC):

Although there is sufficient evidence that postoperative chemotherapy is effective in patients with stage II or stage IIIA NSCLC, its usefulness in patients with stage IB NSCLC is less clear.

Evidence (adjuvant chemotherapy for stage IB NSCLC):

Given the magnitude of observed survival differences, CALGB-9633 may have been underpowered to detect small but clinically meaningful improvements in survival. In addition, the use of a carboplatin versus a cisplatin combination might have affected the results. At present, there is no reliable evidence that postoperative chemotherapy improves survival of patients with stage IB NSCLC. [Level of evidence: 1iiA]

Radiation therapy

Patients with potentially resectable tumors with medical contraindications to surgery or those with inoperable stage I disease and with sufficient pulmonary reserve may be candidates for radiation therapy with curative intent. Primary radiation therapy often consists of approximately 60 Gy delivered with megavoltage equipment to the midplane of the known tumor volume using conventional fractionation. A boost to the cone down field of the primary tumor is frequently used to enhance local control. Careful treatment planning with precise definition of target volume and avoidance of critical normal structures to the extent possible is needed for optimal results; this requires the use of a simulator.

Prognosis:

In the two largest retrospective radiation therapy series, patients with inoperable disease treated with definitive radiation therapy achieved 5-year survival rates of 10% and 27%. Both series found that patients with T1, N0 tumors had better outcomes, and 5-year survival rates of 60% and 32% were found in this subgroup.

Evidence (radiation therapy):

A substantial number of patients are ineligible for standard surgical resection because of comorbid conditions that are associated with unacceptably high perioperative risk. Observation and radiation therapy may be considered for these patients. Nonrandomized observation studies comparing treatment outcomes associated with resection, radiation therapy, and observation have demonstrated shorter survival times and higher mortality for patients treated with observation only. There are a number of approaches to delivery of radiation therapy, including conventional external-beam radiation therapy, stereotactic total-body radiation therapy, and others, and limited reliable data from comparative trials to determine which yield superior outcomes.

Treatment Options Under Clinical Evaluation

Treatment options under clinical evaluation include the following:

Current Clinical Trials

Check for U.S. clinical trials from NCI's list of cancer clinical trials that are now accepting patients with stage I non-small cell lung cancer. The list of clinical trials can be further narrowed by location, drug, intervention, and other criteria.

General information about clinical trials is also available from the NCI Web site.


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Stages IIA and IIB NSCLC Treatment

Standard Treatment Options for Stages IIA and IIB NSCLC

Standard treatment options for stages IIA NSCLC and IIB NSCLC include the following:

Adjuvant radiation therapy has not been show to improve outcomes in patients with stages II NSCLC.

Surgery

Surgery is the treatment of choice for patients with stage II NSCLC. A lobectomy, pneumonectomy, or segmental resection, wedge resection, or sleeve resection may be performed as appropriate. Careful preoperative assessment of the patient’s overall medical condition, especially the patient’s pulmonary reserve, is critical in considering the benefits of surgery. Despite the immediate and age-related postoperative mortality rate, a 5% to 8% mortality rate with pneumonectomy or a 3% to 5% mortality rate with lobectomy can be expected.

Evidence (surgery):

Limitations of evidence (surgery):

Conclusions about the efficacy of surgery for patients with local and locoregional NSCLC are limited by the small number of participants studied to date and potential methodological weaknesses of the trials.

Neoadjuvant chemotherapy

The role of chemotherapy prior to surgery was tested in clinical trials. The proposed benefits of preoperative chemotherapy include the following:

  • A reduction in tumor size that may facilitate surgical resection.
  • Early eradication of micrometastases.
  • Better tolerability.

Preoperative chemotherapy may, however, delay potentially curative surgery.

Evidence (neoadjuvant chemotherapy):

Adjuvant radiation therapy

The value of postoperative (adjuvant) radiation therapy (PORT) has been evaluated.

Evidence (adjuvant radiation therapy):

Further analysis is needed to determine whether these outcomes can potentially be modified with technical improvements, better definitions of target volumes, and limitation of cardiac volume in the radiation portals.

Adjuvant chemotherapy

The preponderance of evidence indicates that postoperative cisplatin combination chemotherapy provides a significant survival advantage to patients with resected stage II NSCLC. Preoperative chemotherapy may also provide survival benefit. The optimal sequence of surgery and chemotherapy and the benefits and risks of postoperative radiation therapy in patients with resectable NSCLC remain to be determined.

After surgery, many patients develop regional or distant metastases. Several randomized, controlled trials and meta-analyses have evaluated the use of postoperative chemotherapy in patients with stage I, II, and IIIA NSCLC.

Evidence (adjuvant chemotherapy):

Based on these data, patients with completely resected stage II lung cancer may benefit from postoperative cisplatin-based chemotherapy.[Level of evidence: 1iiA]

Radiation therapy

Patients with potentially operable tumors with medical contraindications to surgery or those with inoperable stage II disease and with sufficient pulmonary reserve are candidates for radiation therapy with curative intent. Primary radiation therapy often consists of approximately 60 Gy delivered with megavoltage equipment to the midplane of the volume of the known tumor using conventional fractionation. A boost to the cone down field of the primary tumor is frequently used to enhance local control. Careful treatment planning with precise definition of target volume and avoidance of critical normal structures, to the extent possible, is needed for optimal results; this requires the use of a simulator.

Prognosis:

Among patients with excellent PS, a 3-year survival rate of 20% may be expected if a course of radiation therapy with curative intent can be completed.

Evidence (radiation therapy):

Treatment Options Under Clinical Evaluation

Treatment options under clinical evaluation include the following:

Current Clinical Trials

Check for U.S. clinical trials from NCI's list of cancer clinical trials that are now accepting patients with stage II non-small cell lung cancer. The list of clinical trials can be further narrowed by location, drug, intervention, and other criteria.

General information about clinical trials is also available from the NCI Web site.


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Stage IIIA NSCLC Treatment

Patients with stage IIIA NSCLC are a heterogenous group. Patients may have metastases to ipsilateral mediastinal nodes, potentially resectable T3 tumors invading chest wall, or mediastinal involvement with metastases to peribronchial or hilar lymph nodes (N1). Presentations of disease range from resectable tumors with microscopic metastases to lymph nodes to unresectable, bulky disease involving multiple nodal stations.

Prognosis:

Patients with clinical stage IIIA-N2 disease have a 5-year overall survival rate of 10% to 15%; however, patients with bulky mediastinal involvement (i.e., visible on chest radiography) have a 5-year survival rate of 2% to 5%. Depending on clinical circumstances, the principal forms of treatment that are considered for patients with stage IIIA NSCLC are radiation therapy, chemotherapy, surgery, and combinations of these modalities.

Treatment options vary according to the location of the tumor and whether it is resectable.

Standard Treatment Options for Resected/Resectable Stage IIIA N2 NSCLC

Despite careful preoperative staging, some patients will be found to have metastases to mediastinal N2 lymph nodes at thoracotomy.

Standard treatment options for resected/resectable disease include the following:

The preponderance of evidence indicates that postoperative cisplatin combination chemotherapy provides a significant survival advantage to patients with resected NSCLC with occult N2 disease discovered at surgery. The optimal sequence of surgery and chemotherapy and the benefits and risks of postoperative radiation therapy in patients with resectable NSCLC are yet to be determined.

Surgery

If complete resection of tumor and lymph nodes is possible, such patients may benefit from surgery followed by postoperative chemotherapy. Current evidence suggests that lung cancer resection combined with complete ipsilateral mediastinal lymph node dissection (CMLND) is associated with a small-to-modest improvement in survival compared with lung cancer resection combined with systematic sampling of mediastinal nodes in patients with stage I, II, or IIIA NSCLC.[Level of evidence: 1iiA]

Evidence (surgery):

Limitations of evidence (surgery):

Conclusions about the efficacy of surgery for patients with local and locoregional NSCLC are limited by the small number of participants studied to date and by the potential methodological weaknesses of the trials.

Neoadjuvant therapy

Neoadjuvant chemotherapy

The role of chemotherapy prior to surgery in patients with stage III-N2 NSCLC has been extensively tested in clinical trials. The proposed benefits of preoperative (neoadjuvant) chemotherapy include the following:

  • A reduction in tumor size that may facilitate surgical resection.
  • Early eradication of micrometastases.
  • Better tolerability.

Evidence (neoadjuvant chemotherapy):

Adjuvant therapy

Adjuvant chemotherapy

Patients with completely resected stage IIIA NSCLC may benefit from postoperative cisplatin-based chemotherapy.[Level of evidence: 1iiA]

Evidence (adjuvant chemotherapy):

Evidence from randomized controlled clinical trials indicates that when stage IIIA NSCLC is encountered unexpectedly at surgery, chemotherapy given after complete resection improves survival.

Several randomized, controlled trials and meta-analyses have evaluated the use of postoperative chemotherapy in patients with stage I, II, and IIIA NSCLC.

Adjuvant chemoradiation therapy

Combination chemotherapy and radiation administered before or following surgery should be viewed as investigational and requiring evaluation in future clinical trials.

Evidence (adjuvant chemoradiation therapy):

Adjuvant radiation therapy

The value of PORT has been assessed. Although some studies suggest that PORT can improve local control for node-positive patients whose tumors were resected, it remains controversial whether it can improve survival. The optimal dose of thoracic PORT is not known at this time. The majority of studies cited used doses ranging from 30 Gy to 60 Gy, typically provided in 2 Gy to 2.5 Gy fractions.

As referred to in the National Cancer Institute of Canada and Intergroup Study JBR.10 study (NCT00002583), PORT may be considered in selected patients to reduce the risk of local recurrence, if any of the following are present:

  • Involvement of multiple nodal stations.
  • Extracapsular tumor spread.
  • Close or microscopically positive resection margins.

Evidence (adjuvant radiation therapy):

Evidence from one large meta-analysis, subset analyses of randomized trials, and one large population study suggest that PORT may reduce local recurrence. Results from these studies on the effect of PORT on OS are conflicting.

There is benefit of PORT in stage IIIA-N2 disease, and the role of PORT in early stages of NSCLC should be clarified in ongoing phase III trials. Further analysis is needed to determine whether these outcomes can be modified with technical improvements, better definitions of target volumes, and limitation of cardiac volume in the radiation portals.

Standard Treatment Options for Unresectable Stage IIIA N2 NSCLC

Standard treatment options for patients with unresectable NSCLC include the following:

Radiation therapy

For treatment of locally advanced unresectable tumor

Radiation therapy alone, administered sequentially with chemotherapy and concurrently with chemotherapy, may provide benefit to patients with locally advanced unresectable stage III NSCLC.

Prognosis:

Radiation therapy with traditional dose and fractionation schedules (1.8–2.0 Gy per fraction per day to 60–70 Gy in 6–7 weeks) results in reproducible long-term survival benefit in 5% to 10% of patients and significant palliation of symptoms.

Evidence (radiation therapy for locally advanced unresectable tumor):

Although patients with unresectable stage IIIA disease may benefit from radiation therapy, long-term outcomes have generally been poor because of local and systemic relapse.

For palliative treatment

Radiation therapy may be effective in palliating symptomatic local involvement with NSCLC, such as the following:

  • Tracheal, esophageal, or bronchial compression.
  • Pain.
  • Vocal cord paralysis.
  • Hemoptysis.
  • Superior vena cava syndrome.

In some cases, endobronchial laser therapy and/or brachytherapy has been used to alleviate proximal obstructing lesions.

Evidence (radiation therapy for palliative treatment):

Chemoradiation therapy

The addition of sequential and concurrent chemotherapy to radiation therapy has been evaluated in prospective randomized trials and meta-analyses. Overall, concurrent treatment may provide the greatest benefit in survival with increase in toxic effects.

Concomitant platinum-based radiation chemotherapy may improve survival of patients with locally advanced NSCLC. However, the available data are insufficient to accurately define the size of such a potential treatment benefit and the optimal schedule of chemotherapy.

Evidence (chemoradiation therapy):

Concurrent versus sequential chemoradiation therapy

The results from two randomized trials (including RTOG-9410) and a meta-analysis indicate that concurrent chemotherapy and radiation therapy may provide greater survival benefit, albeit with more toxic effects, than sequential chemotherapy and radiation therapy.[Level of evidence: 1iiA]

Evidence (concurrent vs. sequential chemoradiation therapy):

Standard Treatment Options for Superior Sulcus Tumors (T3, N0 or N1, M0)

Standard treatment options for superior sulcus tumors include the following:

NSCLC of the superior sulcus, frequently termed Pancoast tumors, occurs in less than 5% of patients. Superior sulcus tumors usually arise from the apex of the lung and are challenging to treat because of their proximity to structures at the thoracic inlet. At this location, tumors may invade the parietal pleura, chest wall, brachial plexus, subclavian vessels, stellate ganglion, and adjacent vertebral bodies. However, Pancoast tumors are amenable to curative treatment, especially in patients with T3, N0 disease.

Adverse prognostic factors include the presence of mediastinal nodal metastases (N2 disease), spine or subclavian-vessel involvement (T4 disease), and limited resection (R1 or R2).

Radiation therapy alone

While radiation therapy is an integral part of the treatment of Pancoast tumors, variations in dose, treatment technique, and staging that were used in various published series make it difficult to determine its effectiveness.

Prognosis:

Small, retrospective series of radiation therapy in patients who were only clinically staged have reported 5-year survival rates of 0% to 40%, depending on T stage, total radiation dose, and other prognostic factors. Induction radiation therapy and en-bloc resection was shown to be potentially curative.

Evidence (radiation therapy):

Surgery

Evidence (surgery):

Chemoradiation therapy

Evidence (chemoradiation therapy):

Standard Treatment Options for Tumors That Invade the Chest Wall (T3, N0 or N1, M0)

Standard treatment options for tumors that invade the chest wall include the following:

Selected patients with bulky primary tumors that directly invade the chest wall can obtain long-term survival with surgical management provided that their tumor is completely resected. Radical surgery, including chest wall resection, may result in a 5-year survival rate of up to 50%.

Evidence (radical surgery):

Adjuvant chemotherapy is recommended and radiation therapy is reserved for cases with unclear resection margins. Survival rates were lower in patients who underwent incomplete resection and had mediastinal lymph node involvement. Combined modality approaches have been evaluated to improve ability to achieve complete resection.

Treatment Options Under Clinical Evaluation

Treatment options under clinical evaluation include the following:

Current Clinical Trials

Check for U.S. clinical trials from NCI's list of cancer clinical trials that are now accepting patients with stage IIIA non-small cell lung cancer. The list of clinical trials can be further narrowed by location, drug, intervention, and other criteria.

General information about clinical trials is also available from the NCI Web site.


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Stage IIIB NSCLC Treatment

Based on the Surveillance, Epidemiology, and End Registry, the estimated incidence of stage IIIB NSCLC is 17.6%. The anticipated 5-year survival for the vast majority of patients who present with clinical stage IIIB NSCLC is 3% to 7%. In small case series, selected patients with T4, N0-1 disease, solely as the result of satellite tumor nodule(s) within the primary lobe, have been reported to have 5-year survival rates of 20%.[Level of evidence: 3iiiA]

Standard Treatment Options for Stage IIIB NSCLC

Standard treatment options for stage IIIB NSCLC include the following:

In general, patients with stage IIIB NSCLC do not benefit from surgery alone and are best managed by initial chemotherapy, chemotherapy plus radiation therapy, or radiation therapy alone, depending on the following:

  • Sites of tumor involvement.
  • The patient's performance status (PS).

Most patients with excellent PS are candidates for combined modality chemotherapy and radiation therapy with the following exceptions:

  • Selected patients with T4, N0 disease may be treated with combined modality therapy and surgery similar to patients with superior sulcus tumors.

Sequential or concurrent chemotherapy and radiation therapy

Many randomized studies of patients with unresectable stage III NSCLC show that treatment with preoperative or concurrent cisplatin-based chemotherapy and radiation therapy to the chest is associated with improved survival compared with treatment that uses radiation therapy alone. Although patients with unresectable stage IIIB disease may benefit from radiation therapy, long-term outcomes have generally been poor, often the result of local and systemic relapse. The addition of sequential and concurrent chemotherapy to radiation therapy has been evaluated in prospective randomized trials.

Evidence (sequential or concurrent chemotherapy and radiation therapy):

Radiation therapy alone

For treatment of locally advanced unresectable tumor

Radiation therapy alone, administered sequentially or concurrently with chemotherapy, may provide benefit to patients with locally advanced unresectable stage III NSCLC. However, combination chemoradiation therapy delivered concurrently provides the greatest benefit in survival with increase in toxic effects.

Prognosis:

Radiation therapy with traditional dose and fractionation schedules (1.8 Gy–2.0 Gy per fraction per day to 60 Gy–70 Gy in 6–7 weeks) results in reproducible long-term survival benefit in 5% to 10% of patients and significant palliation of symptoms.

Evidence (radiation therapy for locally advanced unresectable tumor):

For palliative treatment

Radiation therapy may be effective in palliating symptomatic local involvement with NSCLC, such as the following:

  • Tracheal, esophageal, or bronchial compression.
  • Pain.
  • Vocal cord paralysis.
  • Hemoptysis.
  • Superior vena cava syndrome.

In some cases, endobronchial laser therapy and/or brachytherapy has been used to alleviate proximal obstructing lesions.

Evidence (radiation therapy for palliative treatment):

Patients with stage IIIB disease with poor PS are candidates for chest radiation therapy to palliate pulmonary symptoms (e.g., cough, shortness of breath, hemoptysis, or pain).[Level of evidence: 3iiiC] (Refer to the PDQ summaries on Cardiopulmonary Syndromes and Pain for more information.)

Treatment Options Under Clinical Evaluation

Because of the poor overall results, patients with stage IIIB NSCLC are candidates for clinical trials, which may lead to improvement in the control of disease.

Treatment options under clinical evaluation include the following:

Current Clinical Trials

Check for U.S. clinical trials from NCI's list of cancer clinical trials that are now accepting patients with stage IIIB non-small cell lung cancer. The list of clinical trials can be further narrowed by location, drug, intervention, and other criteria.

General information about clinical trials is also available from the NCI Web site.


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Stage IV NSCLC Treatment

Forty percent of patients with newly diagnosed non-small cell lung cancer (NSCLC) have stage IV disease. Treatment goals are to prolong survival and control disease-related symptoms. Treatment options include cytotoxic chemotherapy and targeted agents. Factors influencing treatment selection include comorbidity, performance status (PS), histology, and molecular genetic features of the cancer. Radiation therapy and surgery are generally used in selective cases for symptom palliation.

Standard Treatment Options for Stage IV NSCLC

Standard treatment options for stage IV NSCLC include the following:

Randomized controlled trials of patients with stage IV disease and good PS have shown that cisplatin-based chemotherapy improves survival and palliates disease-related symptoms.[Level of evidence: 1iiA] Patients with nonsquamous cell histology, good PS, no history of hemoptysis or other bleeding, or recent history of cardiovascular events may benefit from the addition of bevacizumab to paclitaxel and carboplatin. Patients with tumors harboring mutations in EGFR, particularly those from East Asia, never smokers, and those with adenocarcinoma may benefit from EGFR tyrosine kinase inhibitors as an alternative to first- or second-line chemotherapy. Second-line chemotherapy with docetaxel, pemetrexed, or erlotinib also improves survival in patients with good PS.[Level of evidence: 1iiA] The role of chemotherapy in patients with poor PS was less certain.

Cytotoxic combination chemotherapy (first line)

The type and number of chemotherapy drugs to be used for the treatment of patients with advanced NSCLC has been extensively evaluated in randomized controlled trials and meta-analyses.

Several randomized trials have evaluated various drugs combined with either cisplatin or carboplatinum in previously untreated patients with advanced NSCLC. Based on meta-analyses of the trials, the following conclusions can be drawn:

  • Certain three-drug combinations that add so-called targeted agents may result in superior survival.
  • EGFR inhibitors may benefit selected patients with EGFR mutations.
  • Maintenance chemotherapy following four cycles of platinum combination chemotherapy may improve progression-free survival (PFS).
  • Platinum combinations with vinorelbine, paclitaxel, docetaxel, gemcitabine, irinotecan, and pemetrexed yield similar improvements in survival. Types and frequencies of toxic effects differ, and these may determine the preferred regimen for an individual patient. Patients with adenocarcinoma may benefit from pemetrexed.
  • Cisplatin and carboplatinum yield similar improvements in outcome with different toxic effects. Some, but not all, trials and meta-analyses of trials suggest that outcomes with cisplatin may be superior, although with a higher risk of certain toxicities such as nausea and vomiting.
  • Nonplatinum combinations offer no advantage to platinum-based chemotherapy, and some studies demonstrate inferiority.
  • Three-drug combinations of the commonly used chemotherapy drugs do not result in superior survival and are more toxic than two-drug combinations.

Evidence (combination chemotherapy):

Among the active combinations, definitive recommendations regarding drug dose and schedule cannot be made, with the exception of pemetrexed for patients with adenocarcinoma.

Evidence (drug and dose schedule):

Factors influencing treatment

Histology

Patients with adenocarcinoma may benefit from pemetrexed, EGFR inhibitors, and bevacizumab.

Age versus comorbidity

Evidence supports that elderly patients with good PS and limited comorbidity may benefit from combination chemotherapy. Age alone should not dictate treatment-related decisions in patients with advanced NSCLC. Elderly patients with a good PS enjoy longer survival and a better quality of life when treated with chemotherapy compared with supportive care alone. Caution should be exercised when extrapolating data for elderly patients (aged 70–79 years) to patients aged 80 years or older because only a very small number of patients aged 80 years or older have been enrolled on clinical trials, and the benefit in this group is uncertain.

Evidence (age vs. comorbidity):

Performance status (PS)

PS is among the most important prognostic factors for survival of patients with NSCLC. The benefit of therapy for this group of patients has been evaluated through retrospective analyses as well as through prospective clinical trials.

The results support further evaluation of chemotherapeutic approaches for both metastatic and locally advanced NSCLC; however, the efficacy of current platinum-based chemotherapy combinations is such that no specific regimen can be regarded as standard therapy. Outside of a clinical trial setting, chemotherapy should be given only to patients with good PS and evaluable tumor lesions, who desire such treatment after being fully informed of its anticipated risks and limited benefits.

Evidence (performance status):

Combination chemotherapy with bevacizumab or cetuximab

Evidence (combination chemotherapy with bevacizumab or cetuximab):

EGFR tyrosine kinase inhibitors (first line)

Selective patients may benefit from single-agent EGFR tyrosine kinase inhibitors. Randomized controlled trials of patients with chemotherapy-naïve NSCLC and EGFR mutations have shown that EGFR inhibitors improved PFS but not OS and have favorable toxicity profiles compared with combination chemotherapy.

Evidence (EGFR tyrosine kinase inhibitors):

The above trials demonstrated that EGFR tyrosine kinase inhibitors such as gefitinib or erlotinib are superior to the platinum combination chemotherapy as an initial treatment for pulmonary adenocarcinoma among nonsmokers or former light smokers in East Asia. It is likely that these results are applicable to non-Asian populations.

Maintenance therapy following first-line chemotherapy

One treatment strategy that has been investigated extensively in NSCLC is maintenance therapy following initial response to chemotherapy. Options for maintenance therapy that have been investigated include the following:

  • Continuing the initial combination chemotherapy regimen.
  • Continuing only single-agent chemotherapy.
  • Introducing a new agent as "maintenance."

Multiple randomized trials have evaluated the efficacy of continuing first-line combination cytotoxic chemotherapy beyond three to four cycles.

Evidence (maintenance therapy following first-line chemotherapy):

These data suggest that PFS, but not OS, may be improved either by continuing an effective chemotherapy beyond four cycles or by immediate initiation of alternative chemotherapy. The improvement in PFS, however, is tempered by an increase in adverse events from additional cytotoxic chemotherapy and no consistent improvement in quality of life. For patients who have stable disease or who respond to first-line therapy, evidence does not support the continuation of cytotoxic chemotherapy until disease progression or the initiation of a different chemotherapy prior to disease progression. Collectively, these trials suggest that first-line cytotoxic combination chemotherapy should be stopped at disease progression or after four cycles in patients whose disease is not responding to treatment; it can be administered for no more than six cycles.

Evidence (first-line platinum-based combination chemotherapy followed by pemetrexed):

Evidence (maintenance erlotinib following platinum-based doublet chemotherapy):

Radiation therapy

Radiation therapy may be effective in palliating symptomatic patients with local involvement of NSCLC with any of the following:

  • Tracheal, esophageal, or bronchial compression.
  • Pain.
  • Vocal cord paralysis.
  • Hemoptysis.
  • Superior vena cava syndrome.

In some cases, endobronchial laser therapy and/or brachytherapy have been used to alleviate proximal obstructing lesions.

Although EBRT is frequently prescribed for symptom palliation, there is no consensus on which fractionation scheme should be used. Although different multifraction regimens appear to provide similar symptom relief, single-fraction radiation may be insufficient for symptom relief compared with hypofractionated or standard regimens, as evidenced in the NCT00003685 trial.[Level of evidence: 1iiC] Evidence of a modest increase in survival in patients with a better PS given high-dose radiation therapy is available.[Level of evidence: 1iiA] In closely observed asymptomatic patients, treatment may often be appropriately deferred until symptoms or signs of a progressive tumor develop.

Evidence (radiation therapy):

Treatment Options Under Clinical Evaluation

Treatment options under clinical evaluation include the following:

Current Clinical Trials

Check for U.S. clinical trials from NCI's list of cancer clinical trials that are now accepting patients with stage IV non-small cell lung cancer. The list of clinical trials can be further narrowed by location, drug, intervention, and other criteria.

General information about clinical trials is also available from the NCI Web site.


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Recurrent NSCLC Treatment

Standard Treatment Options for Recurrent NSCLC

Standard treatment options for recurrent NSCLC include the following:

Radiation therapy may provide excellent palliation of symptoms from a localized tumor mass.

The use of chemotherapy has produced objective responses and small improvement in survival for patients with metastatic disease.[Level of evidence: 1iiA] In studies that have examined symptomatic response, improvement in subjective symptoms has been reported to occur more frequently than objective response. Informed patients with good performance status (PS) and symptomatic recurrence can be offered treatment with a platinum-based chemotherapy regimen for palliation of symptoms. For patients who have relapsed after platinum-based chemotherapy, second-line therapy can be considered.

Evidence (chemotherapy and targeted therapy):

Objective response rates to erlotinib and gefitinib are higher in patients who have never smoked, in females, in East Asians, and in patients with adenocarcinoma and bronchioloalveolar carcinoma. Responses may be associated with sensitizing mutations in the tyrosine kinase domain of the EGFR and with the absence of K-RAS mutations.[Level of evidence: 3iiiDiii] Survival benefit may be greater in patients with EGFR protein expression by immunohistochemistry or increased EGFR gene copy number by fluorescence in situ hybridization studies, although the clinical utility of EGFR testing by immunohistochemistry has been questioned.

Treatment of second primary tumor

A solitary pulmonary metastasis from an initially resected bronchogenic carcinoma is unusual. The lung is frequently the site of second primary malignancies in patients with primary lung cancers. Whether the new lesion is a new primary cancer or a metastasis may be difficult to determine. Studies have indicated that in most patients the new lesion is a second primary tumor, and after its resection, some patients may achieve long-term survival. Thus, if the first primary tumor has been controlled, the second primary tumor should be resected, if possible.

Treatment of brain metastases

Patients who present with a solitary cerebral metastasis after resection of a primary NSCLC lesion and who have no evidence of extracranial tumor can achieve prolonged DFS with surgical excision of the brain metastasis and postoperative whole-brain radiation therapy (WBRT). Unresectable brain metastases in this setting may be treated with radiation surgery.

Because of the small potential for long-term survival, radiation therapy should be delivered by conventional methods in daily doses of 1.8 Gy to 2.0 Gy. Because of the high risk of toxic effects observed with such treatments, higher daily doses over a shorter period of time (i.e., hypofractionated schemes) should be avoided. Most patients who are not suitable for surgical resection should receive conventional WBRT.

Approximately 50% of patients treated with resection and postoperative radiation therapy will develop recurrence in the brain; some of these patients will be suitable for additional treatment. In those selected patients with good PS and without progressive metastases outside of the brain, treatment options include reoperation or stereotactic radiation surgery. For most patients, additional radiation therapy can be considered; however, the palliative benefit of this treatment is limited.[Level of evidence: 3iiiDiii]

Treatment Options Under Clinical Evaluation

  • Many patients with recurrent NSCLC are eligible for clinical trials.

Current Clinical Trials

Check for U.S. clinical trials from NCI's list of cancer clinical trials that are now accepting patients with recurrent non-small cell lung cancer. The list of clinical trials can be further narrowed by location, drug, intervention, and other criteria.

General information about clinical trials is also available from the NCI Web site.


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Changes to This Summary (05/30/2013)

The PDQ cancer information summaries are reviewed regularly and updated as new information becomes available. This section describes the latest changes made to this summary as of the date above.

Stages IA and IB NSCLC Treatment

Added text to state that a substantial number of patients are ineligible for standard surgical resection because of comorbid conditions that are associated with unacceptably high perioperative risk; observation and radiation therapy may be considered for these patients (cited McGarry et al., Lanni et al., and Grutterset al. as reference 22, reference 23, and reference 24, respectively). Also added text to state that nonrandomized observation studies comparing treatment outcomes associated with resection, radiation therapy, and observation have demonstrated shorter survival times and higher mortality for patients treated with observation only, there are a number of approaches to delivery of radiation therapy, and there are limited reliable data from comparative trials to determine which yield superior outcomes.

Stage IIIA NSCLC Treatment

Added Curran et al as reference 35.

This summary is written and maintained by the PDQ Adult Treatment Editorial Board, which is editorially independent of NCI. The summary reflects an independent review of the literature and does not represent a policy statement of NCI or NIH. More information about summary policies and the role of the PDQ Editorial Boards in maintaining the PDQ summaries can be found on the About This PDQ Summary and PDQ NCI's Comprehensive Cancer Database pages.


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Back to TopSource: The National Cancer Institute's Physician Data Query (PDQ®) Cancer Information Summaries (http://www.cancer.gov/cancertopics/pdq)