Non-Small Cell Lung Cancer Treatment (PDQ®): Treatment - Health Professional Information [NCI]

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Non-Small Cell Lung Cancer Treatment

Purpose of This PDQ Summary

This PDQ cancer information summary for health professionals provides comprehensive, peer-reviewed, evidence-based information about the treatment of non-small cell lung cancer. This summary is reviewed regularly and updated as necessary by the PDQ Adult Treatment Editorial Board.

Information about the following is included in this summary:

  • Prognostic factors.
  • Cellular classification.
  • Staging.
  • Treatment options by cancer stage.

This summary is intended as a resource to inform and assist clinicians who care for cancer patients. It does not provide formal guidelines or recommendations for making health care decisions.

Some of the reference citations in the summary are accompanied by a level-of-evidence designation. These designations are intended to help readers assess the strength of the evidence supporting the use of specific interventions or approaches. The PDQ Adult Treatment Editorial Board uses a formal evidence ranking system in developing its level-of-evidence designations. Based on the strength of the available evidence, treatment options are described as either "standard" or "under clinical evaluation." These classifications should not be used as a basis for reimbursement determinations.

This summary is available in a patient version, written in less technical language, and in Spanish.

General Information About Non-Small Cell Lung Cancer

Related Summaries

Other PDQ summaries containing information related to lung cancer include:

  • Small Cell Lung Cancer Treatment
  • Lung Cancer Prevention
  • Lung Cancer Screening
  • Smoking Cessation and Continued Risk in Cancer Patients.

Statistics

Estimated new cases and deaths from lung cancer (non-small cell and small cell combined) in the United States in 2009:[1]

  • New cases: 219,440.
  • Deaths: 159,390.

Lung cancer is the leading cause of cancer-related mortality in the United States.[1] The 5-year relative survival rate for the period of 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.[2]

Patients with resectable disease may be cured by surgery or surgery with adjuvant 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 have long-term survival with radiation therapy combined with chemotherapy. Patients with advanced metastatic disease may achieve improved survival and palliation of symptoms with chemotherapy.

Histology

Non-small cell lung cancer (NSCLC) is a heterogeneous aggregate of histologies. The most common histologies are epidermoid or squamous carcinoma, adenocarcinoma, and large cell carcinoma. These histologies are often classified together because approaches to diagnosis, staging, prognosis, and treatment are similar.

Risk Factors

Risk factors that contribute to the development of lung cancer include:

  • 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.[3]
  • 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 their 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.[3]

Pathology

Smoking-related lung carcinogenesis is a multistep process. Squamous carcinoma and adenocarcinoma have defined premalignant precursor lesions. Before becoming invasive, lung epithelium may undergo morphological changes that include hyperplasia, metaplasia, dysplasia, and 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 for a second lung cancer per patient per year.[4] Screening for early detection of lung cancer and chemoprevention strategies are currently under evaluation for this patient population.

(Refer to the PDQ summary on Lung Cancer Prevention for more information.)

Screening

In patients considered at high risk for developing lung cancer, no screening modality for early detection has been shown to alter mortality.[5] Studies of lung cancer screening with chest radiography and sputum cytology have failed to demonstrate that screening lowers lung cancer mortality rates. Published studies of newer screening technologies such as low-dose computed tomography (CT) scans and biomarker screenings report primarily on lung cancer detection rates and do not present sufficient data to determine whether the newer technologies will benefit or harm people. Currently, randomized trials are evaluating low-dose spiral CT scanning.

(Refer to the PDQ summary on Lung Cancer Screening for more information.)

Diagnosis and Treatment

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

Surgically resectable disease

The first group of patients has tumors that are surgically resectable (generally stage I, stage II, and selected stage III tumors). This group has the best prognosis, which depends on a variety of tumor and host factors. Patients with resectable disease who have medical contraindications to surgery are candidates for curative radiation therapy. Adjuvant cisplatin-based combination chemotherapy may provide a survival advantage to patients with resected stage II or stage IIIA NSCLC.

Locally and/or regionally advanced disease

The second group includes patients with either locally (T3–T4) and/or regionally (N2–N3) advanced lung cancer. This group has a diverse natural history. Selected patients with locally advanced tumors may benefit from combined modality treatments. Patients with unresectable or N2–N3 disease are treated with radiation therapy in combination with chemotherapy. Selected patients with T3 or N2 disease can be treated effectively with surgical resection and either preoperative or postoperative chemotherapy or chemoradiation therapy.

Distant metastatic disease

The final group includes patients with distant metastases (M1) that were found at the time of diagnosis. This group can be treated with radiation therapy or chemotherapy for palliation of symptoms from the primary tumor. Patients with good performance status (PS), women, and patients with distant metastases confined to a single site live longer than others.[6] Platinum-based chemotherapy has been associated with short-term palliation of symptoms and with a survival advantage. Currently, no single chemotherapy regimen can be recommended for routine use. Patients previously treated with platinum combination chemotherapy may derive symptom control and survival benefit from docetaxel, pemetrexed, or epidermal growth factor receptor inhibitor.

Prognostic Factors

Multiple studies have attempted to identify prognostic determinants after surgery and have yielded conflicting evidence as to the prognostic importance of a variety of clinicopathologic factors.[6,7,8,9,10] 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.[11,12,13,14,15,16,17,18,19,20,21]
  • Vascular invasion.[7,22,23,24]

Similarly, conflicting results regarding the prognostic importance of aberrant expression of a number of proteins within lung cancers have been reported. For patients with inoperable disease, prognosis is adversely affected by poor PS 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.[25]

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.

References:

1. American Cancer Society.: Cancer Facts and Figures 2009. Atlanta, Ga: American Cancer Society, 2009. Also available online. Last accessed January 6, 2010.
2. Ries L, Eisner M, Kosary C, et al., eds.: Cancer Statistics Review, 1975-2002. Bethesda, Md: National Cancer Institute, 2005 Available online. Last accessed April 9, 2009 .
3. Wingo PA, Ries LA, Giovino GA, et al.: Annual report to the nation on the status of cancer, 1973-1996, with a special section on lung cancer and tobacco smoking. J Natl Cancer Inst 91 (8): 675-90, 1999.
4. Johnson BE: Second lung cancers in patients after treatment for an initial lung cancer. J Natl Cancer Inst 90 (18): 1335-45, 1998.
5. Bach PB, Silvestri GA, Hanger M, et al.: Screening for lung cancer: ACCP evidence-based clinical practice guidelines (2nd edition). Chest 132 (3 Suppl): 69S-77S, 2007.
6. Albain KS, Crowley JJ, LeBlanc M, et al.: Survival determinants in extensive-stage non-small-cell lung cancer: the Southwest Oncology Group experience. J Clin Oncol 9 (9): 1618-26, 1991.
7. Macchiarini P, Fontanini G, Hardin MJ, et al.: Blood vessel invasion by tumor cells predicts recurrence in completely resected T1 N0 M0 non-small-cell lung cancer. J Thorac Cardiovasc Surg 106 (1): 80-9, 1993.
8. Ichinose Y, Yano T, Asoh H, et al.: Prognostic factors obtained by a pathologic examination in completely resected non-small-cell lung cancer. An analysis in each pathologic stage. J Thorac Cardiovasc Surg 110 (3): 601-5, 1995.
9. Martini N, Bains MS, Burt ME, et al.: Incidence of local recurrence and second primary tumors in resected stage I lung cancer. J Thorac Cardiovasc Surg 109 (1): 120-9, 1995.
10. Fontanini G, Bigini D, Vignati S, et al.: Microvessel count predicts metastatic disease and survival in non-small cell lung cancer. J Pathol 177 (1): 57-63, 1995.
11. Sayar A, Turna A, Kiliçgün A, et al.: Prognostic significance of surgical-pathologic multiple-station N1 disease in non-small cell carcinoma of the lung. Eur J Cardiothorac Surg 25 (3): 434-8, 2004.
12. Osaki T, Nagashima A, Yoshimatsu T, et al.: Survival and characteristics of lymph node involvement in patients with N1 non-small cell lung cancer. Lung Cancer 43 (2): 151-7, 2004.
13. Ichinose Y, Kato H, Koike T, et al.: Overall survival and local recurrence of 406 completely resected stage IIIa-N2 non-small cell lung cancer patients: questionnaire survey of the Japan Clinical Oncology Group to plan for clinical trials. Lung Cancer 34 (1): 29-36, 2001.
14. Tanaka F, Yanagihara K, Otake Y, et al.: Prognostic factors in patients with resected pathologic (p-) T1-2N1M0 non-small cell lung cancer (NSCLC). Eur J Cardiothorac Surg 19 (5): 555-61, 2001.
15. Asamura H, Suzuki K, Kondo H, et al.: Where is the boundary between N1 and N2 stations in lung cancer? Ann Thorac Surg 70 (6): 1839-45; discussion 1845-6, 2000.
16. Riquet M, Manac'h D, Le Pimpec-Barthes F, et al.: Prognostic significance of surgical-pathologic N1 disease in non-small cell carcinoma of the lung. Ann Thorac Surg 67 (6): 1572-6, 1999.
17. van Velzen E, Snijder RJ, Brutel de la Rivière A, et al.: Lymph node type as a prognostic factor for survival in T2 N1 M0 non-small cell lung carcinoma. Ann Thorac Surg 63 (5): 1436-40, 1997.
18. Vansteenkiste JF, De Leyn PR, Deneffe GJ, et al.: Survival and prognostic factors in resected N2 non-small cell lung cancer: a study of 140 cases. Leuven Lung Cancer Group. Ann Thorac Surg 63 (5): 1441-50, 1997.
19. Izbicki JR, Passlick B, Karg O, et al.: Impact of radical systematic mediastinal lymphadenectomy on tumor staging in lung cancer. Ann Thorac Surg 59 (1): 209-14, 1995.
20. Martini N, Burt ME, Bains MS, et al.: Survival after resection of stage II non-small cell lung cancer. Ann Thorac Surg 54 (3): 460-5; discussion 466, 1992.
21. Naruke T, Goya T, Tsuchiya R, et al.: Prognosis and survival in resected lung carcinoma based on the new international staging system. J Thorac Cardiovasc Surg 96 (3): 440-7, 1988.
22. Thomas P, Doddoli C, Thirion X, et al.: Stage I non-small cell lung cancer: a pragmatic approach to prognosis after complete resection. Ann Thorac Surg 73 (4): 1065-70, 2002.
23. Macchiarini P, Fontanini G, Hardin MJ, et al.: Relation of neovascularisation to metastasis of non-small-cell lung cancer. Lancet 340 (8812): 145-6, 1992.
24. Khan OA, Fitzgerald JJ, Field ML, et al.: Histological determinants of survival in completely resected T1-2N1M0 nonsmall cell cancer of the lung. Ann Thorac Surg 77 (4): 1173-8, 2004.
25. Earle CC, Tsai JS, Gelber RD, et al.: Effectiveness of chemotherapy for advanced lung cancer in the elderly: instrumental variable and propensity analysis. J Clin Oncol 19 (4): 1064-70, 2001.

Cellular Classification of Non-Small Cell Lung Cancer

Before a patient begins lung cancer treatment, an experienced lung cancer pathologist must review the pathologic material. This is critical because small cell lung cancer (SCLC), which responds well to chemotherapy and is generally not treated surgically, can be confused on microscopic examination with non-small cell carcinoma.[1]

In 1999, the World Health Organization (WHO) classification of lung tumors was updated.[1] Major changes in the revised classification as compared with the previous one (WHO 1981) included:

  • The addition of two preinvasive lesions to squamous dysplasia and carcinoma in situ, namely:
    • Atypical adenomatous hyperplasia.
    • Diffuse idiopathic pulmonary neuroendocrine cell hyperplasia.
  • The subclassification of adenocarcinoma, namely, the definition of bronchioalveolar carcinoma has been restricted to noninvasive tumors.
  • A substantial evolution of concepts in neuroendocrine lung tumor classification, including:
    • Large-cell neuroendocrine carcinoma (LCNEC) is now recognized as an histologically high-grade non-small cell carcinoma showing histopathological features of neuroendocrine differentiation as well as immunohistochemical neuroendocrine markers.
    • The large-cell carcinoma class now includes several variants, including the LCNEC and the basaloid carcinoma, both with a dismal prognosis.
    • A new class was defined called carcinoma with pleomorphic, sarcomatoid, or sarcomatous elements that are characterized by a spectrum of epithelial to mesenchymal differentiation.

Immunohistochemistry and electron microscopy are invaluable techniques for diagnosis and subclassification, but most lung tumors can be classified by light microscopic criteria.

Malignant non-small epithelial tumors of the lung are detailed in the following list.

The changes in the WHO classification are described in greater detail in the following sections.

THE NEW WHO/INTERNATIONAL ASSOCIATION FOR THE STUDY OF LUNG CANCER HISTOLOGIC CLASSIFICATION OF NON-SMALL CELL LUNG CARCINOMAS (NSCLC)

1. Squamous cell carcinoma.
  • Papillary.
  • Clear cell.
  • Small cell.
  • Basaloid.
2. Adenocarcinoma.
  • Acinar.
  • Papillary.
  • Bronchioloalveolar carcinoma.
    • Nonmucinous.
    • Mucinous.
    • Mixed mucinous and nonmucinous or indeterminate cell type.
  • Solid adenocarcinoma with mucin.
  • Adenocarcinoma with mixed subtypes.
  • Variants.
    • Well-differentiated fetal adenocarcinoma.
    • Mucinous (colloid) adenocarcinoma.
    • Mucinous cystadenocarcinoma.
    • Signet ring adenocarcinoma.
    • Clear cell adenocarcinoma.
3. Large cell carcinoma.
  • Variants.
    • Large-cell neuroendocrine carcinoma.
    • Combined large-cell neuroendocrine carcinoma.
    • Basaloid carcinoma.
    • Lymphoepithelioma-like carcinoma.
    • Clear cell carcinoma.
    • Large cell carcinoma with rhabdoid phenotype.
4. Adenosquamous carcinoma.
5. Carcinomas with pleomorphic, sarcomatoid, or sarcomatous elements.
  • Carcinomas with spindle and/or giant cells.
  • Spindle cell carcinoma.
  • Giant cell carcinoma.
  • Carcinosarcoma.
  • Pulmonary blastoma.
6. Carcinoid tumor.
  • Typical carcinoid.
  • Atypical carcinoid.
7. Carcinomas of salivary-gland type.
  • Mucoepidermoid carcinoma.
  • Adenoid cystic carcinoma.
  • Others.
8. Unclassified carcinoma.

ADENOCARCINOMA

Adenocarcinoma is now the predominant histologic subtype in many countries, and issues relating to subclassification of adenocarcinoma are very 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/International Association for the Study of Lung Cancer (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 either a focal acinar, solid, or papillary pattern, depending on which pattern is seen in the invasive component. Several variants of adenocarcinoma are recognized in the new classification, including:

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

NEUROENDOCRINE TUMORS

A substantial evolution of concepts of neuroendocrine lung tumor classification has occurred. LCNEC is recognized as an histologically high-grade non-small cell carcinoma. It has a very poor prognosis similar to that of SCLC. Atypical carcinoid is recognized as an intermediate-grade neuroendocrine tumor with a prognosis that falls between typical carcinoid and the high-grade SCLC and LCNEC. Neuroendocrine differentiation can be demonstrated by immunohistochemistry or electron microscopy in 10% to 20% of common NSCLC that do not have any neuroendocrine morphology. These tumors are not formally recognized within the WHO/IASLC classification scheme since 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.

LARGE CELL CARCINOMA

In addition to the general category of large cell carcinoma, several uncommon variants are recognized, including:

  • 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.

CARCINOMAS WITH PLEOMORPHIC, SARCOMATOID, OR SARCOMATOUS ELEMENTS

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

References:

1. Travis WD, Colby TV, Corrin B, et al.: Histological typing of lung and pleural tumours. 3rd ed. Berlin: Springer-Verlag, 1999.

Stage Information for Non-Small Cell Lung Cancer

In non-small cell lung cancer (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.

Stage has a critical role in the selection of therapy. The stage of disease is based on a combination of clinical factors (i.e., physical examination, radiology, and laboratory studies) and pathological factors (i.e., biopsy of lymph nodes, bronchoscopy, mediastinoscopy, or anterior mediastinotomy).[1] The distinction between clinical stage and pathologic stage should be considered when evaluating reports of survival outcome.

The process to determine staging includes the following:

  • History.
  • Physical examination.
  • Routine laboratory evaluations.
  • Chest x-ray.
  • Chest-computed tomography (CT) scan with infusion of contrast material.

The CT scan should extend inferiorly to include the liver and adrenal glands. Magnetic resonance imaging (MRI) scans of the thorax and upper abdomen do not appear to yield advantages over CT scans.[2]

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 CT/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. Surgical staging of the mediastinum is considered standard if accurate evaluation of the nodal status is needed to determine therapy. The wider availability and use of fluorodeoxyglucose-positron emission tomography (FDG-PET) for staging has modified this approach to staging mediastinal lymph nodes and distant metastases.

A systematic review of the medical literature relating to the accuracy of CT scanning for noninvasive staging of the mediastinum in patients with lung cancer has been conducted.[3] In the 35 studies published from 1991 through June, 2006, 5,111 evaluable patients were identified. The median prevalence of mediastinal metastasis was 28% (range, 18%–56%). Almost all studies specified that CT scanning was performed following the administration of IV contrast material and that a positive test result was defined as the presence of one or more lymph nodes that measured larger than 1 cm on the short-axis diameter. The pooled sensitivity and specificity of CT scanning for identifying mediastinal lymph node metastasis were 51% (95% confidence interval [CI], 47%–54%) and 86% (95% CI, 84%–88%), respectively. The corresponding positive and negative likelihood ratios were 3.4 and 0.6, respectively. These results are similar to those of a large meta-analysis that reported the median sensitivity and specificity of CT scanning for identifying malignant mediastinal nodes as 61% and 79%, respectively.[4] An earlier meta-analysis reported average sensitivity and specificity of 64% and 74%, respectively.[5]

Another systematic review, an expansion of a health technology assessment conducted in 2001 by the Institute for Clinical and Evaluative Sciences, evaluated the accuracy and utility of 18-FDG-PET in the diagnosis and staging of lung cancer.[6] Through a systematic search of the literature, 12 evidence summary reports and 15 prospective studies of the diagnostic accuracy of positron emission tomography (PET) were identified. PET appears to have high sensitivity and reasonable specificity for differentiating benign from malignant lesions as small as 1 cm. PET also appears superior to CT imaging for mediastinal staging in NSCLC. Randomized trials evaluating the utility of PET 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, PET 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.

If there is no evidence of distant metastatic disease on CT scan, FDG-PET scanning complements CT scan staging of the mediastinum. The combination of CT scanning and PET scanning has greater sensitivity and specificity than CT scanning alone.[7] Numerous nonrandomized studies of FDG-PET have evaluated mediastinal lymph nodes using surgery (i.e., mediastinoscopy and/or thoracotomy with mediastinal lymph node dissection) as the gold standard of comparison.

A systematic review of the medical literature relating to the accuracy of FDG-PET scanning for noninvasive staging of the mediastinum in patients with lung cancer identified 44 studies published between 1994 and 2006 with 2,865 evaluable patients.[3] The median prevalence of mediastinal metastases was 29% (range, 5%–64%). Pooled estimates of sensitivity and specificity for identifying mediastinal metastasis were 74% (95% CI, 69%–79%) and 85% (95% CI, 82%–88%), respectively. Corresponding positive and negative likelihood ratios for mediastinal staging with PET scanning were 4.9 and 0.3, respectively. These findings demonstrate that PET scanning is more accurate than CT scanning for staging of the mediastinum in patients with lung cancer.

In a meta-analysis evaluating the conditional test performance of FDG-PET and CT scanning, the median sensitivity and specificity of PET scans were reported as 100% and 78%, respectively, in patients with enlarged lymph nodes.[4] PET scanning is considered very accurate in identifying malignant nodal involvement when nodes are enlarged. However, PET scanning will falsely identify a malignancy in approximately one-fourth of patients with nodes that are enlarged for other reasons, usually as a result of inflammation or infection.[8,9]

The median sensitivity and specificity of PET scanning in patients with normal-sized mediastinal lymph nodes were 82% and 93%, respectively.[4] These data indicate that nearly 20% of patients with normal-sized nodes but with malignant involvement had falsely negative PET scan findings. For patients with clinically operable NSCLC, the recommendation is for a biopsy of mediastinal lymph nodes that were found on chest CT scan to be larger than 1 cm in shortest transverse axis or were found to be positive on FDG-PET scanning. 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 do not corroborate each other.

Numerous nonrandomized, prospective and retrospective studies have demonstrated that FDG-PET 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 is not reliable for detection of metastases in these sites.[10]

Decision analyses demonstrate that FDG-PET 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.[11,12,13] 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.[11,12,13] A randomized study found that the addition of FDG-PET to conventional staging was associated with significantly fewer thoracotomies.[14] A second randomized trial evaluating the impact of PET on clinical management found that PET provided additional information regarding appropriate stage but did not lead to significantly fewer thoracotomies.[15].

Accurate staging of the mediastinal lymph nodes provides important prognostic information. The association between survival and the number of examined lymph nodes during surgery for patients with stage I NSCLC treated with definitive surgical resection was assessed from the population-based Surveillance, Epidemiology and End Results database for the period from 1990 to 2000.[16] A total of 16,800 patients were included in the study. The overall survival analysis for patients without radiation therapy demonstrated that in comparison to the reference group (1–4 lymph nodes), patients with five to eight lymph nodes examined during surgery had a modest but statistically significant increase in survival, with a proportionate hazard ratio (HR) of 0.90 (95% CI, 0.84–0.97). For patients with nine to 12 lymph nodes and 13 to 16 lymph nodes examined, HRs were 0.86 (95% CI, 0.79–0.95) and 0.78 (95% CI, 0.68–0.90), respectively. There appeared to be no incremental improvement after evaluating more than 16 lymph nodes. The corresponding results for lung cancer-specific mortality and for patients receiving radiation therapy were not substantially different.

These results indicate that patient survival following resection for NSCLC is associated with the number of lymph nodes evaluated during surgery.[16] Because this is most likely the result of a reduction of staging error, namely, a decreased likelihood of missing positive lymph nodes with an increasing number of lymph nodes sampled, it suggests that an evaluation of nodal status should include between 11 to 16 lymph nodes.

Patients at risk for brain metastases may be staged with CT or MRI scans. One study randomly assigned 332 patients with potentially operable NSCLC but without neurological symptoms to brain CT or MRI imaging to detect occult brain metastasis before lung surgery. MRI showed a trend toward a higher preoperative detection rate than CT (P = .069), with an overall detection rate of approximately 7% from pretreatment to 12 months after surgery.[10] 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.

Pathological staging requires:

  • 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.

The Revised International Staging System for 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 1997 by the American Joint Committee on Cancer (AJCC) and the Union Internationale Contre le Cancer.[17,18] These revisions provide greater prognostic specificity for patient groups; however, the correlation between stage and prognosis predates the widespread availability of PET imaging.

Stage I is divided into two categories by the size of the tumor: IA (T1, N0, M0) and IB (T2, N0, M0). Stage II is divided into two categories by the size of the tumor and by the nodal status: IIA (T1, N1, M0) and IIB (T2, N1, M0). T3, N0 has been moved from stage IIIA in the 1986 version of the staging system to stage IIB in the latest version. This change reflects the slightly superior prognosis of these patients and shows that many patients with invasion of the parietal pleura or chest wall caused by pleural-based or superior sulcus tumors (T3) but with negative lymph nodes (N0) are often treated with surgery, sometimes combined with radiation therapy or chemoradiation therapy, and the results are similar to those of patients with resected stage II disease. Another change clarifies the classification of multiple tumor nodules. Satellite tumor nodules located in the same lobe as the primary lesion, which are not lymph nodes, should be classified as T4 lesions. Intrapulmonary ipsilateral metastasis in a lobe other than the lobe containing the primary lesions should be classified as an M1 lesion (stage IV).

The AJCC has designated staging by TNM classification.[18]

TNM Definitions

Primary tumor (T)

  • TX: Primary tumor cannot be assessed, or tumor is proven by the presence of malignant cells in sputum or bronchial washings but is not visualized by imaging or bronchoscopy
  • T0: No evidence of primary tumor
  • Tis: Carcinoma in situ
  • T1: A tumor that is 3 cm or smaller in greatest dimension, is surrounded by lung or visceral pleura, and is without bronchoscopic evidence of invasion more proximal than the lobar bronchus (i.e., not in the main bronchus). The uncommon superficial tumor of any size with its invasive component limited to the bronchial wall, which may extend proximal to the main bronchus, is also classified as T1.
  • T2: A tumor with any of the following features of size or extent:
    • Larger than 3 cm in greatest dimension
    • Involves the main bronchus and is 2 cm or larger distal to the carina
    • Invades the visceral pleura
    • Associated with atelectasis or obstructive pneumonitis that extends to the hilar region but does not involve the entire lung
  • T3: A tumor of any size that directly invades any of the following: chest wall (including superior sulcus tumors), diaphragm, mediastinal pleura, parietal pericardium; or, tumor in the main bronchus less than 2 cm distal to the carina but without involvement of the carina; or, associated atelectasis or obstructive pneumonitis of the entire lung
  • T4: A tumor of any size that invades any of the following: mediastinum, heart, great vessels, trachea, esophagus, vertebral body, carina; or, separate tumor nodules in the same lobe; or, tumor with a malignant pleural effusion. Most pleural effusions associated with lung cancer are due to tumor; however, in a few patients multiple cytopathologic examinations of pleural fluid are negative for tumor. In these cases, fluid is nonbloody and is not an exudate. Such patients may be further evaluated by videothoracoscopy and direct pleural biopsies. When these elements and clinical judgment dictate that the effusion is not related to the tumor, the effusion should be excluded as a staging element, and the patient should be staged as T1, T2, or T3. (For more information on pleural effusions, refer to the Cardiopulmonary Syndromes summary.)

Regional lymph nodes (N)

  • NX: Regional lymph nodes cannot be assessed
  • N0: No regional lymph node metastasis
  • N1: Metastasis to ipsilateral peribronchial and/or ipsilateral hilar lymph nodes and intrapulmonary nodes including involvement by direct extension of the primary tumor
  • N2: Metastasis to ipsilateral mediastinal and/or subcarinal lymph node(s)
  • N3: Metastasis to contralateral mediastinal, contralateral hilar, ipsilateral or contralateral scalene, or supraclavicular lymph node(s)

Distant metastasis (M)

  • MX: Distant metastasis cannot be assessed
  • M0: No distant metastasis
  • M1: Distant metastasis present M1 includes separate tumor nodule(s) in a different lobe (ipsilateral or contralateral).

Specify sites according to the following notations:

Notation Key for Tumor Sites

BRA = brain EYE = eye HEP = hepatic
LYM = lymph nodes MAR = bone marrow OSS = osseous
OTH = other OVR = ovary PER = peritoneal
PLE = pleura PUL = pulmonary SKI = skin

AJCC Stage Groupings

Occult carcinoma

  • TX, N0, M0

Stage 0

  • Tis, N0, M0

Stage IA

  • T1, N0, M0

Stage IB

  • T2, N0, M0

Stage IIA

  • T1, N1, M0

Stage IIB

  • T2, N1, M0
  • T3, N0, M0

Stage IIIA

  • T1, N2, M0
  • T2, N2, M0
  • T3, N1, M0
  • T3, N2, M0

Stage IIIB

  • Any T, N3, M0
  • T4, any N, M0

Stage IV

  • Any T, any N, M1

References:

1. Pfister DG, Johnson DH, Azzoli CG, et al.: American Society of Clinical Oncology treatment of unresectable non-small-cell lung cancer guideline: update 2003. J Clin Oncol 22 (2): 330-53, 2004.
2. Webb WR, Gatsonis C, Zerhouni EA, et al.: CT and MR imaging in staging non-small cell bronchogenic carcinoma: report of the Radiologic Diagnostic Oncology Group. Radiology 178 (3): 705-13, 1991.
3. Toloza EM, Harpole L, McCrory DC: Noninvasive staging of non-small cell lung cancer: a review of the current evidence. Chest 123 (1 Suppl): 137S-146S, 2003.
4. Gould MK, Kuschner WG, Rydzak CE, et al.: Test performance of positron emission tomography and computed tomography for mediastinal staging in patients with non-small-cell lung cancer: a meta-analysis. Ann Intern Med 139 (11): 879-92, 2003.
5. Dwamena BA, Sonnad SS, Angobaldo JO, et al.: Metastases from non-small cell lung cancer: mediastinal staging in the 1990s--meta-analytic comparison of PET and CT. Radiology 213 (2): 530-6, 1999.
6. Ung YC, Maziak DE, Vanderveen JA, et al.: 18Fluorodeoxyglucose positron emission tomography in the diagnosis and staging of lung cancer: a systematic review. J Natl Cancer Inst 99 (23): 1753-67, 2007.
7. Vansteenkiste JF, Stroobants SG, De Leyn PR, et al.: Lymph node staging in non-small-cell lung cancer with FDG-PET scan: a prospective study on 690 lymph node stations from 68 patients. J Clin Oncol 16 (6): 2142-9, 1998.
8. Roberts PF, Follette DM, von Haag D, et al.: Factors associated with false-positive staging of lung cancer by positron emission tomography. Ann Thorac Surg 70 (4): 1154-9; discussion 1159-60, 2000.
9. Liewald F, Grosse S, Storck M, et al.: How useful is positron emission tomography for lymphnode staging in non-small-cell lung cancer? Thorac Cardiovasc Surg 48 (2): 93-6, 2000.
10. Yokoi K, Kamiya N, Matsuguma H, et al.: Detection of brain metastasis in potentially operable non-small cell lung cancer: a comparison of CT and MRI. Chest 115 (3): 714-9, 1999.
11. Dietlein M, Weber K, Gandjour A, et al.: Cost-effectiveness of FDG-PET for the management of potentially operable non-small cell lung cancer: priority for a PET-based strategy after nodal-negative CT results. Eur J Nucl Med 27 (11): 1598-609, 2000.
12. Scott WJ, Shepherd J, Gambhir SS: Cost-effectiveness of FDG-PET for staging non-small cell lung cancer: a decision analysis. Ann Thorac Surg 66 (6): 1876-83; discussion 1883-5, 1998.
13. Gambhir SS, Hoh CK, Phelps ME, et al.: Decision tree sensitivity analysis for cost-effectiveness of FDG-PET in the staging and management of non-small-cell lung carcinoma. J Nucl Med 37 (9): 1428-36, 1996.
14. van Tinteren H, Hoekstra OS, Smit EF, et al.: Effectiveness of positron emission tomography in the preoperative assessment of patients with suspected non-small-cell lung cancer: the PLUS multicentre randomised trial. Lancet 359 (9315): 1388-93, 2002.
15. Viney RC, Boyer MJ, King MT, et al.: Randomized controlled trial of the role of positron emission tomography in the management of stage I and II non-small-cell lung cancer. J Clin Oncol 22 (12): 2357-62, 2004.
16. Ludwig MS, Goodman M, Miller DL, et al.: Postoperative survival and the number of lymph nodes sampled during resection of node-negative non-small cell lung cancer. Chest 128 (3): 1545-50, 2005.
17. Mountain CF: Revisions in the International System for Staging Lung Cancer. Chest 111 (6): 1710-7, 1997.
18. Lung. In: American Joint Committee on Cancer.: AJCC Cancer Staging Manual. 6th ed. New York, NY: Springer, 2002, pp 167-181.

Treatment Option Overview

In non-small cell lung cancer (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. Adjuvant 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.[1,2] In patients with advanced-stage disease, chemotherapy offers modest improvements in median survival, though overall survival is poor.[3,4]

Chemotherapy has produced short-term improvement in disease-related symptoms. 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;[5,6] 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.

Current areas under evaluation include:

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

Chemoprevention of second primary cancers of the upper aerodigestive tract is undergoing clinical evaluation in patients with early stage lung cancer.

Current Clinical Trials

Check for U.S. clinical trials from NCI's PDQ Cancer Clinical Trials Registry 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.

References:

1. Lester JF, MacBeth FR, Coles B: Prophylactic cranial irradiation for preventing brain metastases in patients undergoing radical treatment for non-small-cell lung cancer: a Cochrane Review. Int J Radiat Oncol Biol Phys 63 (3): 690-4, 2005.
2. Pöttgen C, Eberhardt W, Grannass A, et al.: Prophylactic cranial irradiation in operable stage IIIA non small-cell lung cancer treated with neoadjuvant chemoradiotherapy: results from a German multicenter randomized trial. J Clin Oncol 25 (31): 4987-92, 2007.
3. Chemotherapy for non-small cell lung cancer. Non-small Cell Lung Cancer Collaborative Group. Cochrane Database Syst Rev (2): CD002139, 2000.
4. Chemotherapy in non-small cell lung cancer: a meta-analysis using updated data on individual patients from 52 randomised clinical trials. Non-small Cell Lung Cancer Collaborative Group. BMJ 311 (7010): 899-909, 1995.
5. Spiro SG, Rudd RM, Souhami RL, et al.: Chemotherapy versus supportive care in advanced non-small cell lung cancer: improved survival without detriment to quality of life. Thorax 59 (10): 828-36, 2004.
6. Clegg A, Scott DA, Hewitson P, et al.: Clinical and cost effectiveness of paclitaxel, docetaxel, gemcitabine, and vinorelbine in non-small cell lung cancer: a systematic review. Thorax 57 (1): 20-8, 2002.

Occult Non-Small Cell Lung Cancer

Occult non-small cell lung cancer (NSCLC) is defined by the following clinical stage grouping:

  • TX, N0, M0

In occult lung cancer, a diagnostic evaluation often includes chest x-ray and selective bronchoscopy with close follow-up (e.g., computed tomographic 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.

Current Clinical Trials

Check for U.S. clinical trials from NCI's PDQ Cancer Clinical Trials Registry 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.

Stage 0 Non-Small Cell Lung Cancer

Note: Some citations in the text of this section are followed by a level of evidence. The PDQ editorial boards use a formal ranking system to help the reader judge the strength of evidence linked to the reported results of a therapeutic strategy. (Refer to the PDQ summary on Levels of Evidence for more information.)

Stage 0 non-small cell lung cancer (NSCLC) is defined by the following clinical stage grouping:

  • Tis, N0, M0

Stage 0 NSCLC is carcinoma in situ of the lung. Carcinoma in situ frequently progresses to invasive cancer.[1,2,3] Patients may be offered surveillance bronchoscopies and, if lesions are detected, potentially curative therapies. 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.

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.[3,4,5,6] Small case series have reported high complete response rates and long-term survival in selected patients.[7,8][Level of evidence: 3iiiDiii] 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.[1,2]

STANDARD TREATMENT OPTIONS:

1. Surgical resection using the least extensive technique possible (segmentectomy or wedge resection) to preserve maximum normal pulmonary tissue because these patients are at high risk for second lung cancers.
2. Endoscopic photodynamic therapy.
3. Other endobronchial therapies, including electrocautery, cryotherapy, and Nd-YAG laser therapy.

Current Clinical Trials

Check for U.S. clinical trials from NCI's PDQ Cancer Clinical Trials Registry 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.

References:

1. Woolner LB, Fontana RS, Cortese DA, et al.: Roentgenographically occult lung cancer: pathologic findings and frequency of multicentricity during a 10-year period. Mayo Clin Proc 59 (7): 453-66, 1984.
2. Venmans BJ, van Boxem TJ, Smit EF, et al.: Outcome of bronchial carcinoma in situ. Chest 117 (6): 1572-6, 2000.
3. Jeremy George P, Banerjee AK, Read CA, et al.: Surveillance for the detection of early lung cancer in patients with bronchial dysplasia. Thorax 62 (1): 43-50, 2007.
4. Kennedy TC, McWilliams A, Edell E, et al.: Bronchial intraepithelial neoplasia/early central airways lung cancer: ACCP evidence-based clinical practice guidelines (2nd edition). Chest 132 (3 Suppl): 221S-233S, 2007.
5. Corti L, Toniolo L, Boso C, et al.: Long-term survival of patients treated with photodynamic therapy for carcinoma in situ and early non-small-cell lung carcinoma. Lasers Surg Med 39 (5): 394-402, 2007.
6. Deygas N, Froudarakis M, Ozenne G, et al.: Cryotherapy in early superficial bronchogenic carcinoma. Chest 120 (1): 26-31, 2001.
7. van Boxem TJ, Venmans BJ, Schramel FM, et al.: Radiographically occult lung cancer treated with fibreoptic bronchoscopic electrocautery: a pilot study of a simple and inexpensive technique. Eur Respir J 11 (1): 169-72, 1998.
8. van Boxem AJ, Westerga J, Venmans BJ, et al.: Photodynamic therapy, Nd-YAG laser and electrocautery for treating early-stage intraluminal cancer: which to choose? Lung Cancer 31 (1): 31-6, 2001.

Stage I Non-Small Cell Lung Cancer

Note: Some citations in the text of this section are followed by a level of evidence. The PDQ editorial boards use a formal ranking system to help the reader judge the strength of evidence linked to the reported results of a therapeutic strategy. (Refer to the PDQ summary on Levels of Evidence for more information.)

Stage I non-small cell lung cancer (NSCLC) is defined by the following clinical stage groupings:

  • T1, N0, M0
  • T2, N0, M0

Surgery is the treatment of choice for patients with stage I NSCLC. 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.[1] Patients with impaired pulmonary function are candidates for segmental or wedge resection of the primary tumor.

The Lung Cancer Study Group conducted a randomized study (LCSG-821) to compare lobectomy with limited resection for patients with stage I lung cancer. Results of the study showed a reduction in local recurrence for patients treated with lobectomy compared with those treated with limited excision, but the outcome showed no significant difference in overall survival (OS).[2] Similar results have been reported from a nonrandomized comparison of anatomic segmentectomy and lobectomy.[3] A survival advantage was noted with lobectomy for patients with tumors larger than 3 cm but not for those with tumors smaller than 3 cm; however, the rate of locoregional recurrence was significantly less after lobectomy, regardless of primary tumor size. A study of stage I patients showed that those treated with wedge or segment resections had a local recurrence rate of 50% (i.e., 31 recurrences out of 62 patients) despite having undergone complete resections.[4]

The Cochrane Collaboration group reviewed 11 randomized trials with a total of 1,910 patients who underwent surgical interventions for early stage (I–IIIA) lung cancer.[5] From a pooled analysis of three trials, 4-year survival was superior in patients with resectable stage I to IIIA NSCLC who underwent resection and complete ipsilateral mediastinal lymph node dissection (CMLND) compared with those who underwent resection and lymph node sampling; the HR was estimated to be 0.78 (95% CI, 0.65–0.93, P = .005).[5][Level of evidence: 1iiA]

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. However, there was a significant reduction in any cancer recurrence (local or distant) in the CMLND group (relative risk [RR] = 0.79; 95% confidence interval [CI], 0.66–0.95; P = .01) that appeared mainly because of a reduction in the number of distant recurrences (RR = 0.78; 95% CI, 0.61–1.00; P = .05). There was no difference in operative mortality. Air leak lasting more than 5 days was significantly more common in patients assigned to CMLND (RR = 2.94; 95% CI, 1.01–8.54; P = .05). Current evidence suggests that lung cancer resection combined with 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 to IIIA NSCLC.[5][Level of evidence: 1iiA] CMLND versus lymph node sampling has been evaluated in a large randomized phase III trial (ACOSOG-Z0030). Preliminary analyses of operative morbidity and mortality showed comparable rates from the procedures.[6]

Patients with inoperable stage I disease and with sufficient pulmonary reserve may be candidates for radiation therapy with curative intent. In a single report of patients older than 70 years who had resectable lesions smaller than 4 cm but who had medically inoperable disease or who refused surgery, survival at 5 years after radiation therapy with curative intent was comparable with an historical control group of patients of similar age who were resected with curative intent.[7] 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%.[8,9] 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.

Primary radiation therapy should consist 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. A small case series using matched controls reported that the addition of endobronchial brachytherapy improved local disease control compared to external beam radiation therapy.[4][Level of evidence: 3iiiDiii]

Many patients treated surgically subsequently develop regional or distant metastases.[10] Such patients are candidates for entry into clinical trials evaluating adjuvant 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.

The value of postoperative radiation therapy (PORT) has been evaluated.[11] The meta-analysis, based on the results of ten randomized controlled trials and 2,232 individuals, reported an 18% relative increase in the risk of death for patients who received PORT compared to surgery alone (hazard ratio [HR] = 1.18; P = .002). This is equivalent to an absolute detriment of 6% at 2 years (95% CI, 2%–9%), reducing OS from 58% to 52%. Exploratory subgroup analyses suggested that this detrimental effect was most pronounced for patients with stage I/II, N0–N1 disease, whereas for stage III, N2 patients there was no clear evidence of an adverse effect. Results for local (HR = 1.13; P = .02), distant (HR = 1.14; P = .02) and overall (HR = 1.10; P = .06) recurrence-free survival similarly show a detriment of PORT.[11][Level of evidence: 1iiA] 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.

Several randomized controlled trials and meta-analyses have evaluated the use of adjuvant chemotherapy in patients with stage I, II, and IIIA NSCLC.[12,13,14,15,16,17,18] In the largest meta-analysis based on individual patient outcomes, data were collected and pooled from the five largest trials (4,584 patients) that were conducted after 1995 of cisplatin-based chemotherapy in patients with completely resected NSCLC.[14] With a median follow-up time of 5.2 years, the overall HR of death was 0.89 (95% CI, 0.82–0.96; P = .005), corresponding to a 5-year absolute benefit of 5.4% from chemotherapy. The benefit varied with stage (test for trend, P = .04; HR for stage IA = 1.40; 95% CI, 0.95–2.06; HR for stage IB = 0.93; 95% CI, 0.78–1.10; HR for stage II = 0.83; 95% CI, 0.73–0.95; and HR for stage III = 0.83; 95% CI, 0.72–0.94). The effect of chemotherapy did not vary significantly (test for interaction, P = .11) with the associated drugs, including vinorelbine (HR = 0.80; 95% CI, 0.70–0.91), etoposide or vinca alkaloid (HR = 0.92; 95% CI, 0.80–1.07), or other (HR = 0.97; 95% CI, 0.84–1.13). The apparent greater benefit seen with vinorelbine should be interpreted cautiously as vinorelbine and cisplatin combinations generally required that a higher dose of cisplatin be given. Chemotherapy effect was higher in patients with better performance status.

There was no interaction between chemotherapy effect and any of the following:

  • Sex.
  • Age.
  • Histology.
  • Type of surgery.
  • Planned radiation therapy.
  • Planned total dose of cisplatin.

Based on this meta-analysis, postoperative chemotherapy is not recommended outside of a clinical trial for patients with completely resected stage I NSCLC.[19,20][Level of evidence: 1iiA].

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.[21] Others 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.[10] (Refer to the PDQ summary on Smoking Cessation and Continued Risk in Cancer Patients for more information.)

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.[22,23,24,25,26][Level of evidence: 1iiA] (Refer to the PDQ summary on Lung Cancer Prevention for more information.)

TREATMENT OPTIONS:

1. Lobectomy or segmental, wedge, or sleeve resection as appropriate.
2. Radiation therapy with curative intent (for potentially resectable tumors in patients with medical contraindications to surgery).
3. Clinical trials of adjuvant chemoprevention (as evidenced in the ECOG-5597 trial, for example).
4. Endoscopic photodynamic therapy and other endobronchial therapies (under clinical evaluation in highly selected patients with T1, N0, M0 tumors).

Current Clinical Trials

Check for U.S. clinical trials from NCI's PDQ Cancer Clinical Trials Registry 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.

References:

1. Ginsberg RJ, Hill LD, Eagan RT, et al.: Modern thirty-day operative mortality for surgical resections in lung cancer. J Thorac Cardiovasc Surg 86 (5): 654-8, 1983.
2. Ginsberg RJ, Rubinstein LV: Randomized trial of lobectomy versus limited resection for T1 N0 non-small cell lung cancer. Lung Cancer Study Group. Ann Thorac Surg 60 (3): 615-22; discussion 622-3, 1995.
3. Warren WH, Faber LP: Segmentectomy versus lobectomy in patients with stage I pulmonary carcinoma. Five-year survival and patterns of intrathoracic recurrence. J Thorac Cardiovasc Surg 107 (4): 1087-93; discussion 1093-4, 1994.
4. Mantz CA, Dosoretz DE, Rubenstein JH, et al.: Endobronchial brachytherapy and optimization of local disease control in medically inoperable non-small cell lung carcinoma: a matched-pair analysis. Brachytherapy 3 (4): 183-90, 2004.
5. Manser R, Wright G, Hart D, et al.: Surgery for early stage non-small cell lung cancer. Cochrane Database Syst Rev (1): CD004699, 2005.
6. Allen MS, Darling GE, Pechet TT, et al.: Morbidity and mortality of major pulmonary resections in patients with early-stage lung cancer: initial results of the randomized, prospective ACOSOG Z0030 trial. Ann Thorac Surg 81 (3): 1013-9; discussion 1019-20, 2006.
7. Noordijk EM, vd Poest Clement E, Hermans J, et al.: Radiotherapy as an alternative to surgery in elderly patients with resectable lung cancer. Radiother Oncol 13 (2): 83-9, 1988.
8. Dosoretz DE, Katin MJ, Blitzer PH, et al.: Radiation therapy in the management of medically inoperable carcinoma of the lung: results and implications for future treatment strategies. Int J Radiat Oncol Biol Phys 24 (1): 3-9, 1992.
9. Gauden S, Ramsay J, Tripcony L: The curative treatment by radiotherapy alone of stage I non-small cell carcinoma of the lung. Chest 108 (5): 1278-82, 1995.
10. Martini N, Bains MS, Burt ME, et al.: Incidence of local recurrence and second primary tumors in resected stage I lung cancer. J Thorac Cardiovasc Surg 109 (1): 120-9, 1995.
11. PORT Meta-analysis Trialists Group.: Postoperative radiotherapy for non-small cell lung cancer. Cochrane Database Syst Rev (2): CD002142, 2005.
12. Winton T, Livingston R, Johnson D, et al.: Vinorelbine plus cisplatin vs. observation in resected non-small-cell lung cancer. N Engl J Med 352 (25): 2589-97, 2005.
13. Arriagada R, Bergman B, Dunant A, et al.: Cisplatin-based adjuvant chemotherapy in patients with completely resected non-small-cell lung cancer. N Engl J Med 350 (4): 351-60, 2004.
14. Pignon JP, Tribodet H, Scagliotti GV, et al.: Lung adjuvant cisplatin evaluation: a pooled analysis by the LACE Collaborative Group. J Clin Oncol 26 (21): 3552-9, 2008.
15. Scagliotti GV, Fossati R, Torri V, et al.: Randomized study of adjuvant chemotherapy for completely resected stage I, II, or IIIA non-small-cell Lung cancer. J Natl Cancer Inst 95 (19): 1453-61, 2003.
16. Hotta K, Matsuo K, Ueoka H, et al.: Role of adjuvant chemotherapy in patients with resected non-small-cell lung cancer: reappraisal with a meta-analysis of randomized controlled trials. J Clin Oncol 22 (19): 3860-7, 2004.
17. Edell ES, Cortese DA: Photodynamic therapy in the management of early superficial squamous cell carcinoma as an alternative to surgical resection. Chest 102 (5): 1319-22, 1992.
18. Corti L, Toniolo L, Boso C, et al.: Long-term survival of patients treated with photodynamic therapy for carcinoma in situ and early non-small-cell lung carcinoma. Lasers Surg Med 39 (5): 394-402, 2007.
19. Deygas N, Froudarakis M, Ozenne G, et al.: Cryotherapy in early superficial bronchogenic carcinoma. Chest 120 (1): 26-31, 2001.
20. van Boxem TJ, Venmans BJ, Schramel FM, et al.: Radiographically occult lung cancer treated with fibreoptic bronchoscopic electrocautery: a pilot study of a simple and inexpensive technique. Eur Respir J 11 (1): 169-72, 1998.
21. Thomas P, Rubinstein L: Cancer recurrence after resection: T1 N0 non-small cell lung cancer. Lung Cancer Study Group. Ann Thorac Surg 49 (2): 242-6; discussion 246-7, 1990.
22. van Boxem AJ, Westerga J, Venmans BJ, et al.: Photodynamic therapy, Nd-YAG laser and electrocautery for treating early-stage intraluminal cancer: which to choose? Lung Cancer 31 (1): 31-6, 2001.
23. Blumberg J, Block G: The Alpha-Tocopherol, Beta-Carotene Cancer Prevention Study in Finland. Nutr Rev 52 (7): 242-5, 1994.
24. Omenn GS, Goodman GE, Thornquist MD, et al.: Effects of a combination of beta carotene and vitamin A on lung cancer and cardiovascular disease. N Engl J Med 334 (18): 1150-5, 1996.
25. Lippman SM, Lee JJ, Karp DD, et al.: Randomized phase III intergroup trial of isotretinoin to prevent second primary tumors in stage I non-small-cell lung cancer. J Natl Cancer Inst 93 (8): 605-18, 2001.
26. van Zandwijk N, Dalesio O, Pastorino U, et al.: EUROSCAN, a randomized trial of vitamin A and N-acetylcysteine in patients with head and neck cancer or lung cancer. For the EUropean Organization for Research and Treatment of Cancer Head and Neck and Lung Cancer Cooperative Groups. J Natl Cancer Inst 92 (12): 977-86, 2000.

Stage II Non-Small Cell Lung Cancer

Note: Some citations in the text of this section are followed by a level of evidence. The PDQ editorial boards use a formal ranking system to help the reader judge the strength of evidence linked to the reported results of a therapeutic strategy. (Refer to the PDQ summary on Levels of Evidence for more information.)

Stage II non-small cell lung cancer (NSCLC) is defined by the following clinical stage groupings:

  • T1, N1, M0
  • T2, N1, M0
  • T3, N0, M0

Surgery is the treatment of choice for patients with stage II NSCLC. 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.

The Cochrane Collaboration group reviewed 11 randomized trials with a total of 1,910 patients who underwent surgical interventions for early stage (I–IIIA) lung cancer.[1] From a pooled analysis of three trials, 4-year survival was superior in patients with resectable stage I to IIIA NSCLC who underwent resection and complete ipsilateral mediastinal lymph node dissection (CMLND) compared with those who underwent resection and lymph node sampling; the HR was estimated to be 0.78 (95% CI, 0.65–0.93; P = .005).[1][Level of evidence: 1iiA]

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. However, there was a significant reduction in any cancer recurrence (local or distant) in the CMLND group (relative risk [RR] = 0.79; 95% CI, 0.66–0.95; P = .01) that appeared mainly due to a reduction in the number of distant recurrences (RR = 0.78; 95%CI, 0.61–1.00; P = .05). There was no difference in operative mortality. Air leak lasting more than 5 days was significantly more common in patients assigned to CMLND (RR = 2.94; 95% CI, 1.01–8.54; P = .05). Current evidence suggests that lung cancer resection combined with 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 to IIIA NSCLC.[1][Level of evidence: 1iiA] CMLND versus lymph node sampling has been evaluated in a large randomized phase III trial (ACOSOG-Z0030). Preliminary analyses of operative morbidity and mortality showed comparable rates from the procedures.[2]

The value of postoperative radiation therapy (PORT) has been evaluated.[3] The meta-analysis, based on the results of ten randomized controlled trials and 2,232 individuals, reported an 18% relative increase in the risk of death for patients who received PORT compared to surgery alone (hazard ratio [HR] = 1.18; P = .002). This is equivalent to an absolute detriment of 6% at 2 years (95% CI, 2%–9%), reducing OS from 58% to 52%. Exploratory subgroup analyses suggested that this detrimental effect was most pronounced for patients with stage I/II, N0–N1 disease, whereas for stage III, N2 patients there was no clear evidence of an adverse effect. Results for local (HR = 1.13; P = .02), distant (HR = 1.14; P = .02) and overall (HR = 1.10; P = .06) recurrence-free survival similarly show a detriment of PORT.[3][Level of evidence: 1iiA] 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.

Patients with inoperable stage II disease and with sufficient pulmonary reserve are candidates for radiation therapy with curative intent.[4] Among patients with excellent performance status (PS) , a 3-year survival rate of 20% may be expected if a course of radiation therapy with curative intent can be completed. In the largest retrospective series reported to date, 152 patients with medically inoperable NSCLC, who were treated with definitive radiation therapy, achieved a 5-year OS rate of 10%; however, the 44 patients with T1 tumors achieved an actuarial disease-free survival (DFS) rate of 60%. This retrospective study also suggested that improved DFS was obtained with radiation therapy doses larger than 60 Gy.[5] Primary radiation therapy should consist 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.

After surgery, many patients develop regional or distant metastases.[6] Several randomized controlled trials and meta-analyses have evaluated the use of adjuvant chemotherapy in patients with stage I, II, and IIIA NSCLC.[7,8,9,10,11,12,13] In the largest meta-analysis based on individual patient outcomes, data were collected and pooled from the five largest trials (4,584 patients) that were conducted after 1995 of cisplatin-based chemotherapy in patients with completely resected NSCLC.[9] With a median follow-up time of 5.2 years, the overall HR of death was 0.89 (95% CI, 0.82–0.96; P = .005), corresponding to a 5-year absolute benefit of 5.4% from chemotherapy. The benefit varied with stage (test for trend, P = .04; HR for stage IA = 1.40; 95% CI, 0.95–2.06; HR for stage IB = 0.93; 95% CI, 0.78–1.10; HR for stage II = 0.83; 95% CI, 0.73–0.95; and HR for stage III = 0.83; 95% CI, 0.72–0.94). The effect of chemotherapy did not vary significantly (test for interaction, P = .11) with the associated drugs, including vinorelbine (HR = 0.80; 95% CI, 0.70–0.91), etoposide or vinca alkaloid (HR = 0.92; 95% CI, 0.80–1.07), or other (HR = 0.97; 95% CI, 0.84–1.13). The greater effect on survival observed with the doublet of cisplatin plus vinorelbine compared with other regimens should be interpreted with caution as the total dose of cisplatin received was significantly higher in patients treated with vinorelbine. However, the meta-analysis as well as the individual studies [7,14] support the administration of adjuvant cisplatin-based chemotherapy in combination with vinorelbine. For these studies, the LACE pooled analysis (NCT00576914), ANITA (NCT00238849), and NCIC-CTG JBR.10 (NCT00002583) trials all reported superior OS for the trial population as well as for the patients with stage II disease (pooled HR = 0.83, 95% CI, 0.73–0.95; HR = 0.71, 95% CI, 0.49–1.03; HR = 0.59, 95% CI, 0.42–0.85, respectively). Chemotherapy effect was higher in patients with better PS.

There was no interaction between chemotherapy effect and any of the following:

  • Sex.
  • Age.
  • Histology.
  • Type of surgery.
  • Planned radiation therapy.
  • Planned total dose of cisplatin.

In a retrospective analysis of a phase III trial of adjuvant cisplatin and vinorelbine, patients older than 65 years were found to benefit from treatment. Chemotherapy significantly prolonged OS for elderly patients (HR = 0.61; 95% CI, 0.38–0.98; P = .04). There were no significant differences in toxic effects, hospitalization, or treatment-related death by age group, although elder patients received less treatment.[15] Based on these data, patients with completed resected stage II lung cancer may benefit from adjuvant cisplatin-based chemotherapy.[15][Level of evidence: 1iiA]

The role of chemotherapy prior to surgery has been tested in clinical trials. The proposed benefits of preoperative chemotherapy are a reduction in tumor size that may facilitate surgical resection, early eradication of micrometastases, and better tolerability. Preoperative chemotherapy may, however, delay potentially curative surgery. The Cochrane Collaboration Review group reported a systematic review and meta-analysis of seven randomized controlled trials including 988 patients evaluating the addition of preoperative chemotherapy to surgery versus surgery alone. Included trials evaluated patients with stages I, II, and IIIa NSCLC.[16] Preoperative chemotherapy provided an absolute benefit in survival of 6% across all stages of disease from 14% to 20% at 5 years (HR = 0.82; 95% CI, 0.69–0.97; P = .022).[16][Level of evidence: 1iiA] This analysis was unable to address questions such as whether particular types of patients may benefit more or less from preoperative chemotherapy.

Although the Cochrane Collaboration group's analysis indicates an OS advantage for preoperative chemotherapy, in the largest trial reported to date, no survival advantage was seen.[17] In that trial, 519 patients were randomized to receive either surgery alone or three cycles of platinum-based chemotherapy followed by surgery. Most patients (61%) had clinical stage I disease; 31% had stage II disease, and 7% had stage III disease. Postoperative complications were similar between groups, and no impairment of quality of life was observed. There was no evidence of a benefit in terms of OS (HR = 1.02; 95% CI, 0.80–1.31, P = .86). Updating the systematic review by addition of the present result suggests a 12% relative survival benefit with the addition of neoadjuvant chemotherapy (1,507 patients; HR = 0.88, 95% CI, 0.76–1.01, P = .07), equivalent to an absolute improvement in survival of 5% at 5 years.

In summary, the preponderance of evidence indicates that adjuvant 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 adjuvant radiation therapy in patients with resectable NSCLC remain to be determined.

TREATMENT OPTIONS:

1. Lobectomy; pneumonectomy; or segmental, wedge, or sleeve resection as appropriate.
2. Radiation therapy with curative intent (for potentially operable tumors in patients with medical contraindications to surgery).
3. Adjuvant chemotherapy after curative surgery.
4. Clinical trials of radiation therapy after curative surgery.

Current Clinical Trials

Check for U.S. clinical trials from NCI's PDQ Cancer Clinical Trials Registry 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.

References:

1. Manser R, Wright G, Hart D, et al.: Surgery for early stage non-small cell lung cancer. Cochrane Database Syst Rev (1): CD004699, 2005.
2. Allen MS, Darling GE, Pechet TT, et al.: Morbidity and mortality of major pulmonary resections in patients with early-stage lung cancer: initial results of the randomized, prospective ACOSOG Z0030 trial. Ann Thorac Surg 81 (3): 1013-9; discussion 1019-20, 2006.
3. PORT Meta-analysis Trialists Group.: Postoperative radiotherapy for non-small cell lung cancer. Cochrane Database Syst Rev (2): CD002142, 2005.
4. Komaki R, Cox JD, Hartz AJ, et al.: Characteristics of long-term survivors after treatment for inoperable carcinoma of the lung. Am J Clin Oncol 8 (5): 362-70, 1985.
5. Dosoretz DE, Katin MJ, Blitzer PH, et al.: Radiation therapy in the management of medically inoperable carcinoma of the lung: results and implications for future treatment strategies. Int J Radiat Oncol Biol Phys 24 (1): 3-9, 1992.
6. Martini N, Bains MS, Burt ME, et al.: Incidence of local recurrence and second primary tumors in resected stage I lung cancer. J Thorac Cardiovasc Surg 109 (1): 120-9, 1995.
7. Winton T, Livingston R, Johnson D, et al.: Vinorelbine plus cisplatin vs. observation in resected non-small-cell lung cancer. N Engl J Med 352 (25): 2589-97, 2005.
8. Arriagada R, Bergman B, Dunant A, et al.: Cisplatin-based adjuvant chemotherapy in patients with completely resected non-small-cell lung cancer. N Engl J Med 350 (4): 351-60, 2004.
9. Pignon JP, Tribodet H, Scagliotti GV, et al.: Lung adjuvant cisplatin evaluation: a pooled analysis by the LACE Collaborative Group. J Clin Oncol 26 (21): 3552-9, 2008.
10. Scagliotti GV, Fossati R, Torri V, et al.: Randomized study of adjuvant chemotherapy for completely resected stage I, II, or IIIA non-small-cell Lung cancer. J Natl Cancer Inst 95 (19): 1453-61, 2003.
11. Hotta K, Matsuo K, Ueoka H, et al.: Role of adjuvant chemotherapy in patients with resected non-small-cell lung cancer: reappraisal with a meta-analysis of randomized controlled trials. J Clin Oncol 22 (19): 3860-7, 2004.
12. Edell ES, Cortese DA: Photodynamic therapy in the management of early superficial squamous cell carcinoma as an alternative to surgical resection. Chest 102 (5): 1319-22, 1992.
13. Corti L, Toniolo L, Boso C, et al.: Long-term survival of patients treated with photodynamic therapy for carcinoma in situ and early non-small-cell lung carcinoma. Lasers Surg Med 39 (5): 394-402, 2007.
14. Douillard JY, Rosell R, De Lena M, et al.: Adjuvant vinorelbine plus cisplatin versus observation in patients with completely resected stage IB-IIIA non-small-cell lung cancer (Adjuvant Navelbine International Trialist Association [ANITA]): a randomised controlled trial. Lancet Oncol 7 (9): 719-27, 2006.
15. Pepe C, Hasan B, Winton TL, et al.: Adjuvant vinorelbine and cisplatin in elderly patients: National Cancer Institute of Canada and Intergroup Study JBR.10. J Clin Oncol 25 (12): 1553-61, 2007.
16. Burdett SS, Stewart LA, Rydzewska L: Chemotherapy and surgery versus surgery alone in non-small cell lung cancer. Cochrane Database Syst Rev (3): CD006157, 2007.
17. Gilligan D, Nicolson M, Smith I, et al.: Preoperative chemotherapy in patients with resectable non-small cell lung cancer: results of the MRC LU22/NVALT 2/EORTC 08012 multicentre randomised trial and update of systematic review. Lancet 369 (9577): 1929-37, 2007.

Stage IIIA Non-Small Cell Lung Cancer

Note: Some citations in the text of this section are followed by a level of evidence. The PDQ editorial boards use a formal ranking system to help the reader judge the strength of evidence linked to the reported results of a therapeutic strategy. (Refer to the PDQ summary on Levels of Evidence for more information.)

Stage IIIA non-small cell lung cancer (NSCLC) is defined by the following clinical stage groupings:

  • T1, N2, M0
  • T2, N2, M0
  • T3, N1, M0
  • T3, N2, M0

Patients with stage IIIA NSCLC are a heterogenous group. Patients may have metastases to ipsilateral mediastinal nodes or 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.

Patients with clinical stage IIIA-N2 disease have a 5-year survival rate of 10% to 15% overall; 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.

Resected/Resectable Stage IIIA N2 Disease

Despite careful preoperative staging, some patients will be found to have metastases to mediastinal N2 lymph nodes at thoracotomy. Preoperative staging typically includes the following:

  • Computed tomography (CT) scan.
  • Positron emission tomography (PET).
  • Mediastinoscopy.

If complete resection of tumor and lymph nodes is possible, such patients may benefit from surgery followed by postoperative adjuvant chemotherapy. The Cochrane Collaboration group reviewed 11 randomized trials with a total of 1,910 patients who underwent surgical interventions for early stage (I–IIIA) lung cancer.[1] From a pooled analysis of three trials, 4-year survival was superior in patients with resectable stage I to IIIA NSCLC who underwent resection and complete ipsilateral mediastinal lymph node dissection (CMLND) compared with those who underwent resection and lymph node sampling; the hazard ratio (HR) was estimated to be 0.78 (95% confidence interval [CI], 0.65–0.93, P = .005).[1][Level of evidence: 1iiA]

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. Current evidence suggests that lung cancer resection combined with 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 to IIIA NSCLC.[1][Level of evidence: 1iiA] CMLND versus lymph node sampling has been evaluated in a large randomized phase III trial (ACOSOG-Z0030). Preliminary analyses of operative morbidity and mortality showed comparable rates from the procedures.[2]

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 adjuvant chemotherapy in patients with stage I, II, and IIIA NSCLC.[3,4,5,6,7,8,9]

In the largest meta-analysis based on individual patient outcomes, data were collected and pooled from the five largest trials (4,584 patients) that were conducted after 1995 of cisplatin-based chemotherapy in patients with completely resected NSCLC.[5] With a median follow-up time of 5.2 years, the overall HR of death was 0.89 (95% CI, 0.82–0.96; P = .005), corresponding to a 5-year absolute benefit of 5.4% from chemotherapy. The effect of chemotherapy did not vary significantly (test for interaction, P = .11) with the associated drugs, including vinorelbine (HR = 0.80; 95% CI, 0.70–0.91), etoposide or vinca alkaloid (HR = 0.92; 95% CI, 0.80–1.07), or other (HR = 0.97; 95% CI, 0.84–1.13). The greater effect on survival observed with the doublet of cisplatin plus vinorelbine compared with other regimens should be interpreted with caution as the total dose of cisplatin received was significantly higher in patients treated with vinorelbine. The benefit varied with stage, however, the HR for stage IIIA was 0.83; 95% CI, 0.72–0.94.

Two trials (FRE-IALT and NCT00238849) report significant overall survival (OS) benefits associated with adjuvant chemotherapy in stage IIIA disease.[4,10] For the subgroup of stage IIIA patients in ANITA (n = 325), the HR was 0.69 (95% CI, 0.53–0.90), and the result for the IALT trial (n = 728) was HR = 0.79 (95% CI, 0.66–0.95). Chemotherapy effect was higher in patients with better PS.

There was no interaction between the chemotherapy effect and any of the following:

  • Sex.
  • Age.
  • Histology.
  • Type of surgery.
  • Planned radiation therapy.
  • Planned total dose of cisplatin.

In a retrospective analysis of a phase III trial of adjuvant cisplatin and vinorelbine, patients greater than 65 years were found to benefit from treatment.[11] Chemotherapy significantly prolonged OS for elderly patients (HR = 0.61; 95% CI, 0.38 to 0.98; P = .04). There were no significant differences in toxic effects, hospitalization, or treatment-related death by age group although elder patients received less treatment. Based on these data, patients with completed resected stage IIIA NSCLC may benefit from adjuvant cisplatin-based chemotherapy.[5] [Level of evidence: 1iiA]

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 chemotherapy are:

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

The Cochrane Collaboration group provided a systematic review and meta-analysis of seven randomized controlled trials that included 988 patients and an evaluation of the addition of preoperative chemotherapy to surgery versus surgery alone.[12] Included trials evaluated patients with stages I, II, and IIIa NSCLC. Preoperative chemotherapy provided an absolute benefit in survival of 6% across all stages of disease from 14% to 20% at 5 years (HR = 0.82; 95% CI, 0.69–0.97; P = .022).[12][Level of evidence: 1iiA] This analysis was unable to address questions such as whether particular types of patients may benefit more or less from preoperative chemotherapy.[10]

In the largest trial reported to date, 519 patients were randomized to receive either surgery alone, or three cycles of platinum-based chemotherapy followed by surgery.[13] Most patients (61%) had clinical stage I disease, 31% had stage II disease, and 7% had stage III disease. Postoperative complications were similar between groups, and no impairment of quality of life was observed. There was no evidence of a benefit in terms of OS (HR = 1.02; 95% CI, 0.80–1.31; P = .86). Updating the systematic review by addition of the present result suggests a 12% relative survival benefit with the addition of neoadjuvant chemotherapy (1,507 patients, HR = 0.88; 95% CI, 0.76–1.01; P = .07), equivalent to an absolute improvement in survival of 5% at 5 years.[13]

The value of postoperative radiation therapy (PORT) has been assessed.[14] 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. A meta-analysis of 10 randomized trials that evaluated PORT versus surgery alone showed no difference in OS for the entire PORT group or for the subset of N2 patients.[4][Level of evidence: 1iiA]

Results from a nonrandomized subanalysis from one randomized trial of adjuvant chemotherapy [10] and from SEER suggest that there is benefit of PORT in stage IIIA-N2 disease, and the role of PORT should be clarified in ongoing phase III trials. The large (n = 7,465) SEER retrospective study found superior survival rates associated with radiation therapy in N2 disease (HR = 0.855; 95% CI, 0.762–0.959). In addition, a nonrandomized subanalysis of the ANITA trial, comparing 5-year OS in N2 patients who did or did not receive PORT, found higher survival rates in patients receiving radiation therapy in both the observation and chemotherapy arms (21% vs. 17% and 47% vs. 34%, respectively; [statistical tests of comparison were not conducted]).[15] The majority of studies cited used doses ranging from 30 Gy to 60 Gy, typically provided in 2 Gy to 2.5 Gy fractions.

The optimal dose of postoperative thoracic radiation therapy is not known at this time. 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.[4]

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 there is:[11]

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

Five randomized trials have assessed the value of adjuvant combination chemoradiation therapy versus radiation following surgical resection.[12,13,14,15,16][Level of evidence: 1iiA] Only one trial reported improved disease-free survival (DFS) and no trial reported improved OS. Combination chemotherapy and radiation administered before or following surgery should be viewed as investigational and requiring evaluation in future clinical trials.

Three trials have evaluated platinum-based combination chemotherapy followed by surgery versus combined platinum-combination chemoradiation therapy (60 Gy–69.6 Gy) alone to determine which local treatment modality (surgery or radiation therapy) was most efficacious.[16,17,18] Although studies were small, enrolling 73, 107, and 333 patients with stage IIIA-N2 disease, respectively, no trial reported a difference in local control or survival.[16,17,18][Level of evidence: 1iiA].

In the largest series (EORTC-08941), 579 patients with histologic- or cytologic-proven stage IIIA-N2 NSCLC were given three cycles of platinum-based induction chemotherapy.[18] The 333 responding patients were subsequently randomly assigned to surgical resection or radiation therapy. Of the 154 (92%) patients who underwent surgery, 50% had a radical resection, 42% had a pathologic downstaging, and 5% had a pathologic complete response; 4% died after surgery. PORT was administered to 62 (40%) patients in the surgery arm. Among the 154 (93%) patients who received radiation therapy, overall compliance to the radiation therapy prescription was 55%, and grade 3–4 acute and late esophageal and pulmonary toxic effects occurred in 4% and 7% of patients; one patient died of radiation pneumonitis. Median and 5-year OS for patients randomly assigned to resection versus radiation therapy were 16.4 versus 17.5 months and 15.7% versus 14%, respectively (HR = 1.06; 95% CI, 0.84–1.35). Rates of progression-free survival were also similar in both groups. In view of its low morbidity and mortality, it was concluded that radiation therapy should be considered the preferred locoregional treatment for these patients.

In summary, the preponderance of evidence indicates that adjuvant 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 adjuvant radiation therapy in patients with resectable NSCLC are yet to be determined.

TREATMENT OPTIONS FOR PATIENTS WITH RESECTED/RESECTABLE DISEASE:

1. Surgery followed by postoperative adjuvant chemotherapy.
2. Clinical trials of combined modality therapy.

Unresectable Stage IIIA N2 NSCLC

Radiation therapy alone, administered sequentially with chemotherapy and 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. Radiation therapy with traditional dose and fractionation schedules (1.8–2.0 Gy per fraction per day to 60–70 Gy in 6 to 7 weeks) results in reproducible long-term survival benefit in 5% to 10% of patients and significant palliation of symptoms.[19] One prospective randomized clinical study showed that radiation therapy given continuously (including weekends) as three daily fractions (CHART) improved OS compared with radiation therapy given as one daily fraction.[20][Level of evidence: 1iiA] Patterns of failure for patients treated with radiation therapy alone included both locoregional and distant failures.

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. The addition of sequential and concurrent chemotherapy to radiation therapy has been evaluated in prospective randomized trials. A meta-analysis of patient data from 11 randomized clinical trials showed that cisplatin-based combinations plus radiation therapy resulted in a 10% reduction in the risk of death compared with radiation therapy alone.[21][Level of evidence: 1iiA] Meta-analysis of the 13 trials (based on 2,214 evaluable patients) showed that the addition of concurrent chemotherapy to radical radiation therapy reduced the risk of death at 2 years (RR = 0.93; 95% CI, 0.88–0.98, P = .01). For the 11 trials with platinum-based chemotherapy, RR was 0.93 (95% CI, 0.87–0.99, P = .02).[22] In a meta-analysis of individual data from 1,764 patients, which was based on nine trials, the HR of death among patients treated with radiation chemotherapy compared to radiation therapy alone was 0.89 (95% CI, 0.81–0.98; P = .02) corresponding to an absolute benefit of chemotherapy of 4% at 2 years. The combination of platinum with etoposide seemed more effective than platinum alone. 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.[23]

Two randomized trials (including RTOG-9410) and a meta-analysis (NCT00870116) indicate that concurrent chemotherapy and radiation therapy provide greater survival benefit albeit with more toxic effects than sequential chemotherapy and radiation therapy.[24,25,26][Level of evidence: 1iiA] In the first trial, the combination of mitomycin C, vindesine, and cisplatin were given concurrently with split-course daily radiation therapy to 56 Gy compared to chemotherapy followed by continuous daily radiation therapy to 56 Gy. Five-year OS favored concurrent therapy (27% vs. 9%). Myelosuppression was greater among patients in the concurrent arm, but treatment-related mortality was less than 1% in both arms.[24]

In the second trial, 610 patients were randomly assigned to sequential chemotherapy with cisplatin and vinblastine followed by 60 Gy of radiation therapy, concurrent chemotherapy or concurrent chemotherapy with cisplatin and vinblastine with twice-daily radiation therapy. Median and-4 year survival were superior in the concurrent chemotherapy with daily radiation therapy (17 mo vs. 14.6 mo and 21% vs. 12% for sequential regimen [P = .046]).[25] Two smaller studies also reported OS results that favored concurrent over sequential chemotherapy and radiation, although the results did not reach statistical significance.[26,27][Level of evidence: 1iiA]

Meta-analysis of three trials of concurrent versus sequential treatment (711 patients) indicated a significant benefit of concurrent over sequential treatment (RR = 0.86; 95% CI, 0.78–0.95; P = .003). All studies used cisplatin-based regimens and once-daily radiation therapy.[22] More deaths (3% OS rate) were reported in the concurrent arm, but this did not reach statistical significance (RR = 1.60;CI, 0.75–3.44; P = .2).There was more acute esophagitis (grade 3 or worse with concurrent treatment (range = 17%–26%) compared to sequential treatment (range = 0%–4%; RR= 6.77; P = .001). Overall, the incidence of neutropenia (grade 3 or worse) was similar in both arms.

Several small series have reported that reduction in fluorodeoxyglucose-positron emission tomography (FDG-PET) after chemotherapy, radiation therapy, or chemoradiation therapy correlate with pathological complete response and favorable prognosis.[22,25,26,27,28,29,30,31] Series have used different timing of assessments, positron emission tomography (PET) parameters, and cutpoints to define 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%.[32] Median survival after resection was greater for patients with tumor SUV values of less than 4 (56 mo vs. 19 mo).[31] Patients with complete metabolic response following radiation therapy were reported to have median survivals of 31 months versus 11 months.[33]. PET may be more sensitive and specific than the CT scan in assessing response to induction therapy. Optimal timing imaging remains to be defined; however, one study suggests that greater sensitivity and specificity of PET is achieved if repeat imaging is delayed until 30 days after radiation therapy.[32]

Radiation therapy may be effective in palliating symptomatic local involvement with NSCLC, such as tracheal, esophageal, or bronchial compression; pain; vocal cord paralysis; hemoptysis; or superior vena cava syndrome. (Refer to the PDQ summary on Cardiopulmonary Syndromes for more information.) In some cases, endobronchial laser therapy and/or brachytherapy has been used to alleviate proximal obstructing lesions.[34] A systematic review identified six randomized trials of high-dose rate brachytherapy (HDREB) alone or with external-beam radiation therapy (EBRT) or laser therapy.[35] Better overall symptom palliation and fewer retreatments were required in previously untreated patients using EBRT alone.[35][Level of evidence: 1iiC]. HDREB did provide palliation of symptomatic patients with recurrent endobronchial obstruction previously treated by EBRT, providing it is technically feasible. Although EBRT is frequently prescribed for symptom palliation, there is no consensus about when the fractionation scheme should be used. Although different multifraction regimens appear to provide similar symptom relief, [36,37,38,39,40,41] single-fraction radiation may be insufficient for symptom relief compared with hypofractionated or standard regimens, as evidenced in the NCIC Clinical Trials' Group trial NCT00003685.[38][Level of evidence: 1iiC] Evidence is available of a modest increase in survival in patients with better PS given high-dose radiation therapy.[36,37][Level of evidence: 1iiA]

TREATMENT OPTIONS FOR PATIENTS WITH UNRESECTABLE DISEASE:

1. Chemoradiation therapy for patients with stage IIIA-N2 disease.
2. Radiation therapy alone for patients medically unfit for combined modality therapy.

SUPERIOR SULCUS TUMORS (T3, N0 OR N1, M0)

NSCLC of the superior sulcus, frequently termed Pancoast tumors, occurs in less than 5% of patients.[42,43] Superior sulcus tumors (SST) 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).

While radiation therapy is an integral part of the treatment of Pancoast tumors, variations in dose, treatment technique, and staging that was used in various published series make it difficult to determine its effectiveness. In the preoperative setting, a dose of 45 Gy over 5 weeks is generally recommended, while a dose of approximately 61 Gy is required when using definitive radiation therapy as the primary modality.[42,43] Small retrospective series of radiation therapy of 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. Retrospective case series have reported complete resection was achieved in only 64% of tumor stage (T) 3, nodal stage (N) 0, and 39% of T4, N0 tumors.[44]

Two large, prospective, multicenter phase II trials have evaluated induction chemoradiation therapy followed by resection.[42,45] In the first trial (NCT00002642), 110 eligible patients were enrolled with mediastinoscopy negative, clinical T3–4 N0–1 tumors of the superior sulcus.[46] Induction treatment was two cycles of etoposide and cisplatin with 45 Gy of concurrent radiation therapy. The induction regimen was well tolerated and only five participants had grade 3 or higher toxic effects. Induction chemoradiation therapy could sterilize the primary lesion. Induction therapy was completed by 104 (95%) patients. Of 95 patients eligible for surgery, 88 (80%) underwent thoracotomy, two (1.8%) died postoperatively, and 83 (76%) had complete resections. Pathologic complete response or minimal microscopic disease was seen in 61 (56%) resection specimens. Five-year survival was 44% for all patients and 54% after complete resection, with no difference between T3 and T4 tumors. Pathologic complete response led to better survival than when any residual disease was present (P = .02). Disease progression occurred mainly in distant sites.

In the second trial, 75 patients were enrolled and treated with induction therapy with mitomycin C, vindesine, and cisplatin combined with 45 Gy of radiation therapy.[45] Fifty-seven patients (76%) underwent surgical resection, and complete resection was achieved in 51 patients (68%). There were 12 patients with pathologic complete response. Major postoperative morbidity, including chylothorax, empyema, pneumonitis, adult respiratory distress syndrome, and bleeding was observed in eight patients. There were three treatment-related deaths, The disease-free and OS rates at 3 years were 49% and 61%, respectively; at 5 years, they were 45% and 56%, respectively.[45][Level of evidence: 3iiiDi]

TREATMENT OPTIONS FOR PATIENTS WITH SUPERIOR SULCUS TUMORS:

1. Radiation therapy and surgery.
2. Radiation therapy alone.
3. Surgery alone (selected cases).
4. Concurrent chemotherapy with radiation therapy and surgery.
5. Clinical trials of combined modality therapy.

CHEST WALL TUMOR (T3, N0 OR N1, M0)

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.

TREATMENT OPTIONS FOR PATIENTS WITH CHEST WALL TUMORS:

1. Surgery.[47,48]
2. Surgery and radiation therapy.
3. Radiation therapy alone.
4. Chemotherapy combined with radiation therapy and/or surgery.

Current Clinical Trials

Check for U.S. clinical trials from NCI's PDQ Cancer Clinical Trials Registry 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.

References:

1. Manser R, Wright G, Hart D, et al.: Surgery for early stage non-small cell lung cancer. Cochrane Database Syst Rev (1): CD004699, 2005.
2. Allen MS, Darling GE, Pechet TT, et al.: Morbidity and mortality of major pulmonary resections in patients with early-stage lung cancer: initial results of the randomized, prospective ACOSOG Z0030 trial. Ann Thorac Surg 81 (3): 1013-9; discussion 1019-20, 2006.
3. Winton T, Livingston R, Johnson D, et al.: Vinorelbine plus cisplatin vs. observation in resected non-small-cell lung cancer. N Engl J Med 352 (25): 2589-97, 2005.
4. Arriagada R, Bergman B, Dunant A, et al.: Cisplatin-based adjuvant chemotherapy in patients with completely resected non-small-cell lung cancer. N Engl J Med 350 (4): 351-60, 2004.
5. Pignon JP, Tribodet H, Scagliotti GV, et al.: Lung adjuvant cisplatin evaluation: a pooled analysis by the LACE Collaborative Group. J Clin Oncol 26 (21): 3552-9, 2008.
6. Scagliotti GV, Fossati R, Torri V, et al.: Randomized study of adjuvant chemotherapy for completely resected stage I, II, or IIIA non-small-cell Lung cancer. J Natl Cancer Inst 95 (19): 1453-61, 2003.
7. Hotta K, Matsuo K, Ueoka H, et al.: Role of adjuvant chemotherapy in patients with resected non-small-cell lung cancer: reappraisal with a meta-analysis of randomized controlled trials. J Clin Oncol 22 (19): 3860-7, 2004.
8. Edell ES, Cortese DA: Photodynamic therapy in the management of early superficial squamous cell carcinoma as an alternative to surgical resection. Chest 102 (5): 1319-22, 1992.
9. Corti L, Toniolo L, Boso C, et al.: Long-term survival of patients treated with photodynamic therapy for carcinoma in situ and early non-small-cell lung carcinoma. Lasers Surg Med 39 (5): 394-402, 2007.
10. Douillard JY, Rosell R, De Lena M, et al.: Adjuvant vinorelbine plus cisplatin versus observation in patients with completely resected stage IB-IIIA non-small-cell lung cancer (Adjuvant Navelbine International Trialist Association [ANITA]): a randomised controlled trial. Lancet Oncol 7 (9): 719-27, 2006.
11. Pepe C, Hasan B, Winton TL, et al.: Adjuvant vinorelbine and cisplatin in elderly patients: National Cancer Institute of Canada and Intergroup Study JBR.10. J Clin Oncol 25 (12): 1553-61, 2007.
12. Burdett SS, Stewart LA, Rydzewska L: Chemotherapy and surgery versus surgery alone in non-small cell lung cancer. Cochrane Database Syst Rev (3): CD006157, 2007.
13. Gilligan D, Nicolson M, Smith I, et al.: Preoperative chemotherapy in patients with resectable non-small cell lung cancer: results of the MRC LU22/NVALT 2/EORTC 08012 multicentre randomised trial and update of systematic review. Lancet 369 (9577): 1929-37, 2007.
14. PORT Meta-analysis Trialists Group.: Postoperative radiotherapy for non-small cell lung cancer. Cochrane Database Syst Rev (2): CD002142, 2005.
15. Lally BE, Zelterman D, Colasanto JM, et al.: Postoperative radiotherapy for stage II or III non-small-cell lung cancer using the surveillance, epidemiology, and end results database. J Clin Oncol 24 (19): 2998-3006, 2006.
16. Johnstone DW, Byhardt RW, Ettinger D, et al.: Phase III study comparing chemotherapy and radiotherapy with preoperative chemotherapy and surgical resection in patients with non-small-cell lung cancer with spread to mediastinal lymph nodes (N2); final report of RTOG 89-01. Radiation Therapy Oncology Group. Int J Radiat Oncol Biol Phys 54 (2): 365-9, 2002.
17. Taylor NA, Liao ZX, Cox JD, et al.: Equivalent outcome of patients with clinical Stage IIIA non-small-cell lung cancer treated with concurrent chemoradiation compared with induction chemotherapy followed by surgical resection. Int J Radiat Oncol Biol Phys 58 (1): 204-12, 2004.
18. van Meerbeeck JP, Kramer GW, Van Schil PE, et al.: Randomized controlled trial of resection versus radiotherapy after induction chemotherapy in stage IIIA-N2 non-small-cell lung cancer. J Natl Cancer Inst 99 (6): 442-50, 2007.
19. Komaki R, Cox JD, Hartz AJ, et al.: Characteristics of long-term survivors after treatment for inoperable carcinoma of the lung. Am J Clin Oncol 8 (5): 362-70, 1985.
20. Saunders M, Dische S, Barrett A, et al.: Continuous hyperfractionated accelerated radiotherapy (CHART) versus conventional radiotherapy in non-small-cell lung cancer: a randomised multicentre trial. CHART Steering Committee. Lancet 350 (9072): 161-5, 1997.
21. Chemotherapy in non-small cell lung cancer: a meta-analysis using updated data on individual patients from 52 randomised clinical trials. Non-small Cell Lung Cancer Collaborative Group. BMJ 311 (7010): 899-909, 1995.
22. Rowell NP, O'rourke NP: Concurrent chemoradiotherapy in non-small cell lung cancer. Cochrane Database Syst Rev (4): CD002140, 2004.
23. Aupérin A, Le Péchoux C, Pignon JP, et al.: Concomitant radio-chemotherapy based on platin compounds in patients with locally advanced non-small cell lung cancer (NSCLC): a meta-analysis of individual data from 1764 patients. Ann Oncol 17 (3): 473-83, 2006.
24. Furuse K, Fukuoka M, Kawahara M, et al.: Phase III study of concurrent versus sequential thoracic radiotherapy in combination with mitomycin, vindesine, and cisplatin in unresectable stage III non-small-cell lung cancer. J Clin Oncol 17 (9): 2692-9, 1999.
25. Curran WJ, Scott CB, Langer CJ, et al.: Long-term benefit is observed in a phase III comparison of sequential vs concurrent chemo-radiation for patients with unresected stage III nsclc: RTOG 9410. [Abstract] Proceedings of the American Society of Clinical Oncology 22: A-2499, 2003.
26. Fournel P, Robinet G, Thomas P, et al.: Randomized phase III trial of sequential chemoradiotherapy compared with concurrent chemoradiotherapy in locally advanced non-small-cell lung cancer: Groupe Lyon-Saint-Etienne d'Oncologie Thoracique-Groupe Français de Pneumo-Cancérologie NPC 95-01 Study. J Clin Oncol 23 (25): 5910-7, 2005.
27. Zatloukal P, Petruzelka L, Zemanova M, et al.: Concurrent versus sequential chemoradiotherapy with cisplatin and vinorelbine in locally advanced non-small cell lung cancer: a randomized study. Lung Cancer 46 (1): 87-98, 2004.
28. Cerfolio RJ, Bryant AS, Winokur TS, et al.: Repeat FDG-PET after neoadjuvant therapy is a predictor of pathologic response in patients with non-small cell lung cancer. Ann Thorac Surg 78 (6): 1903-9; discussion 1909, 2004.
29. Pöttgen C, Levegrün S, Theegarten D, et al.: Value of 18F-fluoro-2-deoxy-D-glucose-positron emission tomography/computed tomography in non-small-cell lung cancer for prediction of pathologic response and times to relapse after neoadjuvant chemoradiotherapy. Clin Cancer Res 12 (1): 97-106, 2006.
30. Eschmann SM, Friedel G, Paulsen F, et al.: 18F-FDG PET for assessment of therapy response and preoperative re-evaluation after neoadjuvant radio-chemotherapy in stage III non-small cell lung cancer. Eur J Nucl Med Mol Imaging 34 (4): 463-71, 2007.
31. Hellwig D, Graeter TP, Ukena D, et al.: Value of F-18-fluorodeoxyglucose positron emission tomography after induction therapy of locally advanced bronchogenic carcinoma. J Thorac Cardiovasc Surg 128 (6): 892-9, 2004.
32. Cerfolio RJ, Bryant AS: When is it best to repeat a 2-fluoro-2-deoxy-D-glucose positron emission tomography/computed tomography scan on patients with non-small cell lung cancer who have received neoadjuvant chemoradiotherapy? Ann Thorac Surg 84 (4): 1092-7, 2007.
33. Mac Manus MP, Hicks RJ, Matthews JP, et al.: Positron emission tomography is superior to computed tomography scanning for response-assessment after radical radiotherapy or chemoradiotherapy in patients with non-small-cell lung cancer. J Clin Oncol 21 (7): 1285-92, 2003.
34. Miller JI Jr, Phillips TW: Neodymium:YAG laser and brachytherapy in the management of inoperable bronchogenic carcinoma. Ann Thorac Surg 50 (2): 190-5; discussion 195-6, 1990.
35. Ung YC, Yu E, Falkson C, et al.: The role of high-dose-rate brachytherapy in the palliation of symptoms in patients with non-small-cell lung cancer: a systematic review. Brachytherapy 5 (3): 189-202, 2006 Jul-Sep.
36. Sundstrøm S, Bremnes R, Aasebø U, et al.: Hypofractionated palliative radiotherapy (17 Gy per two fractions) in advanced non-small-cell lung carcinoma is comparable to standard fractionation for symptom control and survival: a national phase III trial. J Clin Oncol 22 (5): 801-10, 2004.
37. Lester JF, Macbeth FR, Toy E, et al.: Palliative radiotherapy regimens for non-small cell lung cancer. Cochrane Database Syst Rev (4): CD002143, 2006.
38. Bezjak A, Dixon P, Brundage M, et al.: Randomized phase III trial of single versus fractionated thoracic radiation in the palliation of patients with lung cancer (NCIC CTG SC.15). Int J Radiat Oncol Biol Phys 54 (3): 719-28, 2002.
39. Erridge SC, Gaze MN, Price A, et al.: Symptom control and quality of life in people with lung cancer: a randomised trial of two palliative radiotherapy fractionation schedules. Clin Oncol (R Coll Radiol) 17 (1): 61-7, 2005.
40. Kramer GW, Wanders SL, Noordijk EM, et al.: Results of the Dutch National study of the palliative effect of irradiation using two different treatment schemes for non-small-cell lung cancer. J Clin Oncol 23 (13): 2962-70, 2005.
41. Senkus-Konefka E, Dziadziuszko R, Bednaruk-Mlynski E, et al.: A prospective, randomised study to compare two palliative radiotherapy schedules for non-small-cell lung cancer (NSCLC). Br J Cancer 92 (6): 1038-45, 2005.
42. Rusch VW: Management of Pancoast tumours. Lancet Oncol 7 (12): 997-1005, 2006.
43. Narayan S, Thomas CR Jr: Multimodality therapy for Pancoast tumor. Nat Clin Pract Oncol 3 (9): 484-91, 2006.
44. Rusch VW, Parekh KR, Leon L, et al.: Factors determining outcome after surgical resection of T3 and T4 lung cancers of the superior sulcus. J Thorac Cardiovasc Surg 119 (6): 1147-53, 2000.
45. Kunitoh H, Kato H, Tsuboi M, et al.: Phase II trial of preoperative chemoradiotherapy followed by surgical resection in patients with superior sulcus non-small-cell lung cancers: report of Japan Clinical Oncology Group trial 9806. J Clin Oncol 26 (4): 644-9, 2008.
46. Rusch VW, Giroux DJ, Kraut MJ, et al.: Induction chemoradiation and surgical resection for superior sulcus non-small-cell lung carcinomas: long-term results of Southwest Oncology Group Trial 9416 (Intergroup Trial 0160). J Clin Oncol 25 (3): 313-8, 2007.
47. Van Raemdonck DE, Schneider A, Ginsberg RJ: Surgical treatment for higher stage non-small cell lung cancer. Ann Thorac Surg 54 (5): 999-1013, 1992.
48. McCaughan BC, Martini N, Bains MS, et al.: Chest wall invasion in carcinoma of the lung. Therapeutic and prognostic implications. J Thorac Cardiovasc Surg 89 (6): 836-41, 1985.

Stage IIIB Non-Small Cell Lung Cancer

Note: Some citations in the text of this section are followed by a level of evidence. The PDQ editorial boards use a formal ranking system to help the reader judge the strength of evidence linked to the reported results of a therapeutic strategy. (Refer to the PDQ summary on Levels of Evidence for more information.)

Stage IIIB non-small cell lung cancer (NSCLC) is defined by the following clinical stage groupings:

  • Any T, N3, M0
  • T4, any N, M0

Based on the Surveillance, Epidemiology, and End registry the estimated incidence of stage IIIB NSCLC is 17.6%.[1] The anticipated 5-year survival for the vast majority of patients who present with clinical stage IIIB NSCLC is 3% to 7%.[2] 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 sites of tumor involvement and the performance status (PS) of the patient. In small case series, selected patients with T4, N0-1 solely due to satellite tumor nodule(s) within the primary lobe have been reported to have 5-year survival rates of 20%.[3,4][Level of evidence: 3iiiA] Selected patients with T4 N0 disease may be treated with combined modality therapy and surgery similar to patients with superior sulcus tumors. Patients with T4 disease caused by malignant pleural effusions are treated similarly to patients with stage 4 disease. With the above exceptions, most patients with excellent PS are candidates for combined modality chemotherapy and radiation therapy. Many randomized studies of patients with unresectable stage III NSCLC show that treatment with neoadjuvant or concurrent cisplatin-based chemotherapy and radiation therapy to the chest is associated with improved survival compared with treatment that uses radiation therapy alone. A meta-analysis of patient data from 11 randomized clinical trials showed that cisplatin-based combinations plus radiation therapy resulted in a 10% reduction in the risk of death compared with radiation therapy alone.

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).[5][Level of evidence: 3iiiC] (Refer to the Cardiopulmonary Syndromes summary [for information on cough] and the Pain summary.)

T4 OR N3, M0

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. 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 to 7 weeks) results in reproducible long-term survival benefit in 5% to 10% of patients and significant palliation of symptoms.[5] One prospective randomized clinical study showed that radiation therapy given as three daily fractions improved OS compared with radiation therapy given as one daily fraction.[6][Level of evidence: 1iiA] Patterns of failure for patients treated with radiation therapy alone included both locoregional and distant failures.

Although patients with unresectable stage IIIB disease may benefit from radiation therapy, long-term outcomes have generally been poor, often due to local and systemic relapse. The addition of sequential and concurrent chemotherapy to radiation therapy has been evaluated in prospective randomized trials. A meta-analysis of patient data from 11 randomized clinical trials showed that cisplatin-based combinations plus radiation therapy resulted in a 10% reduction in the risk of death compared with radiation therapy alone.[7][Level of evidence: 1iiA] A meta-analysis of the 13 trials (based on 2,214 evaluable patients) showed that the addition of concurrent chemotherapy to radical radiation therapy reduced the risk of death at 2 years (relative risk [RR] = 0.93; 95% confidence interval [CI], 0.88–0.98, P = .01). For the 11 trials with platinum-based chemotherapy, RR was 0.93 (95% CI, 0.87–0.99, P = .02).[8]

In a meta-analysis of individual data from 1,764 patients, based on nine trials, the hazard ratio of death among patients treated with radiation chemotherapy compared to radiation therapy alone was 0.89 (95% confidence interval, 0.81–0.98; P = .02) corresponding to an absolute benefit of chemotherapy of 4% at 2 years. The combination of platinum with etoposide seemed more effective than platinum alone. 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.[9]

Reports from two randomized trials (including RTOG-9410) and a meta-analysis ( NCT00870116) indicate that concurrent chemotherapy and radiation therapy provide greater survival benefit albeit with more toxic effects than sequential chemotherapy and radiation therapy.[10,11,12][Level of evidence: 1iiA] In the first trial, the combination of mitomycin C, vindesine, and cisplatin were given concurrently with split-course daily radiation therapy to 56 Gy compared to chemotherapy followed by continuous daily radiation therapy to 56 Gy. Five-year OS favored concurrent therapy (27% vs. 9%). Myelosuppression was greater among patients in the concurrent arm, but treatment-related mortality was less than 1% in both arms.[10]

In the second trial, 610 patients were randomly assigned to sequential chemotherapy with cisplatin and vinblastine followed by 60 Gy of radiation therapy, concurrent chemotherapy, or concurrent chemotherapy with cisplatin and vinblastine with twice-daily radiotherapy. Median and 4-year survival were superior in the concurrent chemotherapy with daily radiation therapy (17 mo vs. 14.6 mo and 21% vs. 12% for sequential regimen [P = .046). Two smaller studies also reported OS results that favored concurrent over sequential chemotherapy and radiation, although the results did not reach statistical significance.[12][Level of evidence: 1iiA]

Meta-analysis of three trials of concurrent versus sequential treatment (711 patients) indicated a significant benefit of concurrent over sequential treatment (RR = 0.86; 95% CI, 0.78–0.95; P = .003). All used cisplatin-based regimens and once-daily radiation therapy.[8,13] More deaths (3% overall) were reported in the concurrent arm but this did not reach statistical significance (RR = 1.60; CI, 0.75–3.44; P = .2).There was more acute esophagitis (grade 3 or worse with concurrent treatment [range = 17%–26%] compared to sequential treatment (range = 0%–4%; RR = 6.77; P = .001). Overall, the incidence of neutropenia (grade 3 or worse) was similar in both arms.

Several small series have reported that reduction in fluorodeoxyglucose-positron emission tomography (FDG-PET) after chemotherapy, radiation therapy, or chemoradiation therapy predict for pathological complete response and favorable prognosis.[8,11,12,13,14,15,16,17] Studies have used different timing of assessments, positron emission tomography (PET) parameters, and cutpoints to define 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%.[14] Median survival after resection was greater for patients with tumor SUV values of less than 4 (56 mo vs. 19 mo).[17] Patients with complete metabolic response following radiation therapy were reported to have median survivals of 31 months versus 11 months.[18]. PET may be more sensitive and specific than the CT scan in assessing response to induction therapy. Optimal timing imaging remains to be defined; however, one study suggests that greater sensitivity and specificity of PET is achieved if repeat imaging is delayed until 30 days after radiation therapy.[19]

Radiation therapy may be effective in palliating symptomatic local involvement with NSCLC, such as tracheal, esophageal, or bronchial compression; pain; vocal cord paralysis; hemoptysis; or superior vena cava syndrome (Refer to the PDQ summary on Cardiopulmonary Syndromes for more information). In some cases, endobronchial laser therapy and/or brachytherapy has been used to alleviate proximal obstructing lesions.[20] A systematic review identified six randomized trials of high-dose rate brachytherapy (HDREB) alone or with external-beam radiation therapy (EBRT) or laser therapy.[21] Better overall symptom palliation and fewer retreatments were required in previously untreated patients using EBRT alone.[21][Level of evidence: 1iiC]. HDREB did provide palliation of symptomatic patients with recurrent endobronchial obstruction previously treated by EBRT, providing it is technically feasible. Although EBRT is frequently proscribed for symptom palliation, there is no consensus on which fractionation scheme should be used. Although different multifraction regimens appear to provide similar symptom relief, [22,23,24,25,26,27] single-fraction radiation may be insufficient for symptom relief compared with hypofractionated or standard regimens, as evidenced in the NCIC Clinical Trials' Group trial NCT00003685.[24][Level of evidence: 1iiC] Evidence is available of a modest increase in survival in patients with better PS given high-dose radiation therapy.[22,23][Level of evidence: 1iiA]

Because of the poor overall results, these patients are candidates for clinical trials that examine new fractionation schedules, radiosensitizers, and combined modality approaches, which may lead to improvement in the control of disease. Information about ongoing clinical trials is available from the NCI Web site.

TREATMENT OPTIONS:

1. Chemotherapy combined with radiation therapy.
2. Radiation therapy alone.

Current Clinical Trials

Check for U.S. clinical trials from NCI's PDQ Cancer Clinical Trials Registry 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.

References:

1. Wisnivesky JP, Yankelevitz D, Henschke CI: Stage of lung cancer in relation to its size: part 2. Evidence. Chest 127 (4): 1136-9, 2005.
2. Mountain CF: Revisions in the International System for Staging Lung Cancer. Chest 111 (6): 1710-7, 1997.
3. Deslauriers J, Brisson J, Cartier R, et al.: Carcinoma of the lung. Evaluation of satellite nodules as a factor influencing prognosis after resection. J Thorac Cardiovasc Surg 97 (4): 504-12, 1989.
4. Urschel JD, Urschel DM, Anderson TM, et al.: Prognostic implications of pulmonary satellite nodules: are the 1997 staging revisions appropriate? Lung Cancer 21 (2): 83-7; discussion 89-91, 1998.
5. Langendijk JA, ten Velde GP, Aaronson NK, et al.: Quality of life after palliative radiotherapy in non-small cell lung cancer: a prospective study. Int J Radiat Oncol Biol Phys 47 (1): 149-55, 2000.
6. Komaki R, Cox JD, Hartz AJ, et al.: Characteristics of long-term survivors after treatment for inoperable carcinoma of the lung. Am J Clin Oncol 8 (5): 362-70, 1985.
7. Chemotherapy in non-small cell lung cancer: a meta-analysis using updated data on individual patients from 52 randomised clinical trials. Non-small Cell Lung Cancer Collaborative Group. BMJ 311 (7010): 899-909, 1995.
8. Rowell NP, O'rourke NP: Concurrent chemoradiotherapy in non-small cell lung cancer. Cochrane Database Syst Rev (4): CD002140, 2004.
9. Aupérin A, Le Péchoux C, Pignon JP, et al.: Concomitant radio-chemotherapy based on platin compounds in patients with locally advanced non-small cell lung cancer (NSCLC): a meta-analysis of individual data from 1764 patients. Ann Oncol 17 (3): 473-83, 2006.
10. Furuse K, Fukuoka M, Kawahara M, et al.: Phase III study of concurrent versus sequential thoracic radiotherapy in combination with mitomycin, vindesine, and cisplatin in unresectable stage III non-small-cell lung cancer. J Clin Oncol 17 (9): 2692-9, 1999.
11. Curran WJ, Scott CB, Langer CJ, et al.: Long-term benefit is observed in a phase III comparison of sequential vs concurrent chemo-radiation for patients with unresected stage III nsclc: RTOG 9410. [Abstract] Proceedings of the American Society of Clinical Oncology 22: A-2499, 2003.
12. Fournel P, Robinet G, Thomas P, et al.: Randomized phase III trial of sequential chemoradiotherapy compared with concurrent chemoradiotherapy in locally advanced non-small-cell lung cancer: Groupe Lyon-Saint-Etienne d'Oncologie Thoracique-Groupe Français de Pneumo-Cancérologie NPC 95-01 Study. J Clin Oncol 23 (25): 5910-7, 2005.
13. Zatloukal P, Petruzelka L, Zemanova M, et al.: Concurrent versus sequential chemoradiotherapy with cisplatin and vinorelbine in locally advanced non-small cell lung cancer: a randomized study. Lung Cancer 46 (1): 87-98, 2004.
14. Cerfolio RJ, Bryant AS, Winokur TS, et al.: Repeat FDG-PET after neoadjuvant therapy is a predictor of pathologic response in patients with non-small cell lung cancer. Ann Thorac Surg 78 (6): 1903-9; discussion 1909, 2004.
15. Pöttgen C, Levegrün S, Theegarten D, et al.: Value of 18F-fluoro-2-deoxy-D-glucose-positron emission tomography/computed tomography in non-small-cell lung cancer for prediction of pathologic response and times to relapse after neoadjuvant chemoradiotherapy. Clin Cancer Res 12 (1): 97-106, 2006.
16. Eschmann SM, Friedel G, Paulsen F, et al.: 18F-FDG PET for assessment of therapy response and preoperative re-evaluation after neoadjuvant radio-chemotherapy in stage III non-small cell lung cancer. Eur J Nucl Med Mol Imaging 34 (4): 463-71, 2007.
17. Hellwig D, Graeter TP, Ukena D, et al.: Value of F-18-fluorodeoxyglucose positron emission tomography after induction therapy of locally advanced bronchogenic carcinoma. J Thorac Cardiovasc Surg 128 (6): 892-9, 2004.
18. Mac Manus MP, Hicks RJ, Matthews JP, et al.: Positron emission tomography is superior to computed tomography scanning for response-assessment after radical radiotherapy or chemoradiotherapy in patients with non-small-cell lung cancer. J Clin Oncol 21 (7): 1285-92, 2003.
19. Cerfolio RJ, Bryant AS: When is it best to repeat a 2-fluoro-2-deoxy-D-glucose positron emission tomography/computed tomography scan on patients with non-small cell lung cancer who have received neoadjuvant chemoradiotherapy? Ann Thorac Surg 84 (4): 1092-7, 2007.
20. Miller JI Jr, Phillips TW: Neodymium:YAG laser and brachytherapy in the management of inoperable bronchogenic carcinoma. Ann Thorac Surg 50 (2): 190-5; discussion 195-6, 1990.
21. Ung YC, Yu E, Falkson C, et al.: The role of high-dose-rate brachytherapy in the palliation of symptoms in patients with non-small-cell lung cancer: a systematic review. Brachytherapy 5 (3): 189-202, 2006 Jul-Sep.
22. Sundstrøm S, Bremnes R, Aasebø U, et al.: Hypofractionated palliative radiotherapy (17 Gy per two fractions) in advanced non-small-cell lung carcinoma is comparable to standard fractionation for symptom control and survival: a national phase III trial. J Clin Oncol 22 (5): 801-10, 2004.
23. Lester JF, Macbeth FR, Toy E, et al.: Palliative radiotherapy regimens for non-small cell lung cancer. Cochrane Database Syst Rev (4): CD002143, 2006.
24. Bezjak A, Dixon P, Brundage M, et al.: Randomized phase III trial of single versus fractionated thoracic radiation in the palliation of patients with lung cancer (NCIC CTG SC.15). Int J Radiat Oncol Biol Phys 54 (3): 719-28, 2002.
25. Erridge SC, Gaze MN, Price A, et al.: Symptom control and quality of life in people with lung cancer: a randomised trial of two palliative radiotherapy fractionation schedules. Clin Oncol (R Coll Radiol) 17 (1): 61-7, 2005.
26. Kramer GW, Wanders SL, Noordijk EM, et al.: Results of the Dutch National study of the palliative effect of irradiation using two different treatment schemes for non-small-cell lung cancer. J Clin Oncol 23 (13): 2962-70, 2005.
27. Senkus-Konefka E, Dziadziuszko R, Bednaruk-Mlynski E, et al.: A prospective, randomised study to compare two palliative radiotherapy schedules for non-small-cell lung cancer (NSCLC). Br J Cancer 92 (6): 1038-45, 2005.

Stage IV Non-Small Cell Lung Cancer

Note: Some citations in the text of this section are followed by a level of evidence. The PDQ editorial boards use a formal ranking system to help the reader judge the strength of evidence linked to the reported results of a therapeutic strategy. (Refer to the PDQ summary on Levels of Evidence for more information.)

Stage IV non-small cell lung cancer (NSCLC) is defined by the following clinical stage grouping:

  • Any T, any N, M1

Forty percent of patients with newly diagnosed NSCLC have stage IV disease. Randomized controlled trials of patients with stage IV disease and stage IIIB disease with malignant pleural effusions and good performance status (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 carboplatin. The role of chemotherapy in patients with poor PS was less certain. Second-line chemotherapy with docetaxel, pemetrexed, or erlotinib also improves survival patients with good PS.[1][Level of evidence: 1iiA]

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:

1. 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.
2. Cisplatin and carboplatinum yield similar improvements in outcome, although 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.
3. Nonplatinum combinations offer no advantage to platinum-based chemotherapy, and some studies demonstrate inferiority.
4. Three-drug combinations of the commonly used chemotherapy drugs do not result in superior survival and are more toxic than two-drug combinations.
5. Certain three-drug combinations that add so-called targeted agents may result in superior survival.

In a randomized study of 878 patients with recurrent or advanced stage IIIB or stage IV NSCLC, 444 received paclitaxel and carboplatin alone, and 434 patients received paclitaxel and carboplatin plus bevacizumab.[2] Chemotherapy was administered every 3 weeks for six cycles, and bevacizumab was administered every 3 weeks until disease progression was evident or toxic effects were intolerable. Patients with squamous cell tumors, brain metastases, clinically significant hemoptysis, or inadequate organ function or PS (ECOG PS >1) were excluded. The median survival was 12.3 months in the group assigned to chemotherapy plus bevacizumab, as compared with 10.3 months in the chemotherapy-alone group (hazard ratio [HR] for death, 0.79; P = .003). The median progression-free survival in the two groups was 6.2 months and 4.5 months, respectively (HR for disease progression, 0.66; P < .001), with corresponding response rates of 35% and 15% (P < .001). Rates of clinically significant bleeding were 4.4% and 0.7%, respectively (P < .001). There were 15 treatment-related deaths in the chemotherapy-plus-bevacizumab group, including five from pulmonary hemorrhage. For this subgroup of patients with NSCLC, the addition of bevacizumab to paclitaxel and carboplatin may provide survival benefit.[2][Level of evidence: 1iiA]

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. The Cochrane Collaboration group reviewed data from all randomized controlled trials published between January 1980 and June 2006, comparing a doublet regimen with a single-agent regimen or comparing a triplet regimen with a doublet regimen in patients with advanced NSCLC.[3] Sixty-five trials (13,601 patients) were identified. In the trials comparing a doublet regimen with a single-agent regimen, a significant increase was observed in tumor response (OR = 0.42; 95% confidence interval [CI], 0.37– 0.47, P < .001) and 1-year survival (OR = 0.80; 95% CI, 0.70–0.91, P < .001) in favor of the doublet regimen. The absolute benefit in 1-year survival was 5%, which corresponds to an increase in 1-year survival from 30% with a single-agent regimen to 35% with a doublet regimen. The rates of grades 3 and 4 toxic effects caused by doublet regimens were statistically increased compared with rates following single-agent therapy, with ORs ranging from 1.2 to 6.2. There was no increase in infection rates in doublet regimens. There was no increase in 1-year survival (OR = 1.01; 95% CI, 0.85–1.21; P = .88) for triplet regimens versus doublet regimens. The median survival ratio was 1.00 (95% CI, 0.94–1.06, P = .97).

Several meta-analyses have evaluated whether cisplatin or carboplatin regimens are superior with variable results.[4,5,6] One meta-analysis reported individual patient data for 2,968 patients entered in nine randomized trials.[4] The objective response rate was higher for patients treated with cisplatin than for patients treated with carboplatin (30% vs. 24%, respectively; OR = 1.37; 95% CI, 1.16–1.61; P < .001). Carboplatin treatment was associated with a nonstatistically significant increase in the hazard of mortality relative to treatment with cisplatin (HR = 1.07; 95% CI, 0.99–1.15; P = .100). In patients with nonsquamous tumors and those treated with third-generation chemotherapy, carboplatin-based chemotherapy was associated with a statistically significant increase in mortality (HR = 1.12; 95% CI, 1.01–1.23 and HR = 1.11; 95% CI, 1.01–1.21, respectively). Treatment-related toxic effects were also assessed in the meta-analysis. More thrombocytopenia was seen with carboplatin than with cisplatin (12% vs. 6%; OR = 2.27; 95% CI, 1.71–3.01; P < .001), while cisplatin caused more nausea and vomiting (8% vs. 18%; OR = 0.42; 95% CI, 0.33–0.53; P < .001) and renal toxic effects (0.5% vs. 1.5%; OR = 0.37; 95% CI, 0.15–0.88; P = .018). The authors concluded that treatment with cisplatin was not associated with a substantial increase in the overall risk of severe toxic effects. This comprehensive individual-patient meta-analysis is consistent with the conclusions of other meta-analyses, which were based on essentially the same clinical trials but which used only published data.

Three literature-based meta-analyses have trials comparing platinum to nonplatinum combinations.[7,8,9] The first meta-analysis identified 37 assessable trials that included 7,633 patients.[7] A 62% increase in the OR for response was attributable to platinum-based therapy (OR = 1.62; 95% CI, 1.46–1.8; P < .001). The 1-year survival rate was increased by 5% with platinum-based regimens (34% vs. 29%; OR = 1.21; 95% CI, 1.09–1.35; P = .003). No statistically significant increase in 1-year survival was found when platinum therapies were compared to third-generation-based combination regimens (OR = 1.11; 95% CI, 0.96–1.28; P = .17). The toxic effects of platinum-based regimens was significantly higher for hematologic toxic effects, nephrotoxic effects, and nausea and vomiting, but not for neurologic toxic effects, febrile neutropenia rate, or toxic death rate. These results are consistent with the second literature-based meta-analysis.

The second meta-analysis identified 17 trials that included 4,920 patients.[8] The use of platinum-based doublet regimens was associated with a slightly higher survival at 1 year (RR = 1.08; 95% CI, 1.01–1.16, P = .03), better partial response (RR = 1.11, 95% CI, 1.02–1.21; P = .02), with a higher risk of anemia, nausea, and neurologic toxic effects. However, in subanalyses, cisplatin-based doublet regimens improved survival at 1 year (RR = 1.16; 95% CI, 1.06–1.27; P = .001), complete response (RR = 2.29; 95% CI, 1.08–4.88; P = .03), partial response (RR = 1.19; 95% CI, 1.07–1.32; P = .002) with an increased risk of anemia, neutropenia, neurologic toxic effects, and nausea. Conversely, carboplatin-based doublet regimens did not increase survival at 1 year (RR = 0.95; 95% CI, 0.85–1.07; P = .43).

The third meta-analysis of phase III trials randomizing platinum-based versus nonplatinum combinations as first-line chemotherapy identified 14 trials.[9] Experimental arms were gemcitabine and vinorelbine (n = 4), gemcitabine and taxane (n = 7), gemcitabine and epirubicin (n = 1), paclitaxel and vinorelbine (n = 1), and gemcitabine and ifosfamide (n = 1). This meta-analysis was limited to the set of 11 phase III studies that used a platinum-based doublet (2,298 and 2,304 patients in platinum-based and nonplatinum arms, respectively). Patients treated with a platinum-based regimen benefited from a statically significant reduction in the risk of death at 1 year (odds ratio [OR] = 0.88; 95% CI, 0.78–0.99; P = .044) and a lower risk of being refractory to chemotherapy (OR = 0.87; 0.73–0.99; P = .049). Forty-four (1.9%) and 29 (1.3%) toxic-related deaths were reported for platinum-based and nonplatinum regimens, respectively (OR = 1.53; 0.96–2.49; P = 0.08). An increased risk of grade 3–4 gastrointestinal and hematological toxic effects for patients receiving platinum-based chemotherapy was statistically demonstrated. There was no statistically significant increase in risk of febrile neutropenia (OR=1.23; 0.94–1.60; P = .063).

Among the active combinations, definitive recommendations regarding drug dose and schedule cannot be made. However, there has been one meta-analysis of seven trials that included 2,867 patients to assess the benefit of docetaxel versus vinorelbine.[10] Docetaxel was administered with a platinum agent in three trials, with gemcitabine in two trials, or as monotherapy in two trials. Vinca alkaloid (vinorelbine in six trials and vindesine in one trial) was administered with cisplatin in six trials or alone in one trial. The pooled estimate for OS showed an 11% improvement in favor of docetaxel (HR = 0.89; 95% CI, 0.82–0.96; P = .004). Sensitivity analyses considering only vinorelbine as a comparator or only the doublet regimens showed similar improvements. Grade 3–4 neutropenia and grade 3–4 serious adverse events were less frequent with docetaxel-based regimens versus vinca alkaloid-based regimens (OR = 0.59; 95% CI, 0.38–0.89; P = .013 and OR = 0.68; 95% CI, 0.55–0.84; P < .001, respectively). There have been two randomized trials comparing weekly versus every 3 weeks' dosing of paclitaxel carboplatin, which reported no significant difference in efficacy and better tolerability for weekly administration.[11,12] Although meta-analyses of randomized controlled trials suggest that cisplatin combinations may be superior to carboplatin or nonplatinum combinations, the clinical relevance of the differences in efficacy must be balanced against the anticipated tolerability, logistics of administration, and familiarity of the medical staff for treatment decisions for individual patients.

A large noninferiority, phase III, randomized study compared the overall survival in 1,725 chemotherapy-naive patients with stage IIIB or IV NSCLC and a PS of 0 to 1.[13] Patients received cisplatin 75 mg/m2 on day 1 and gemcitabine 1,250 mg/m2 on days 1 and 8 (n = 863) or cisplatin 75 mg/m2 and pemetrexed 500 mg/m2 on day 1 (n = 862) every 3 weeks for up to six cycles. OS for cisplatin and pemetrexed was noninferior to cisplatin and gemcitabine (median survival, 10.3 mo vs. 10.3 mo, respectively; HR = 0.94; 95% CI, 0.84–1.05). OS was statistically superior for cisplatin and pemetrexed versus cisplatin and gemcitabine in patients with adenocarcinoma (n = 847; 12.6 mo vs. 10.9 mo, respectively) and large-cell carcinoma histology (n = 153; 10.4 mo vs. 6.7 mo, respectively). In contrast, in patients with squamous cell histology, there was a significant improvement in survival with cisplatin and gemcitabine versus cisplatin and pemetrexed (n = 473; 10.8 mo vs. 9.4 mo, respectively). For cisplatin and pemetrexed, rates of grade 3 or 4 neutropenia, anemia, and thrombocytopenia (P = .001); febrile neutropenia (P = .002); and alopecia (P < .001) were significantly lower, whereas grade 3 or 4 nausea (P = .004) was more common. This study suggests that cisplatin and pemtrexed is another alternative doublet for first-line chemotherapy of advanced NSCLC and also suggests that there may be differences in outcome depending on histology.

Platinum-containing combination chemotherapy regimens provide clinical benefit when compared with supportive care or single-agent therapy; however, such treatment may be contraindicated in some older patients because of the age-related reduction in the functional reserve of many organs and/or comorbid conditions. Approximately two-thirds of patients with NSCLC are 65 years or older and approximately 40% are 70 years or older.[14] Surveillance, Epidemiology, and End Results (SEER) data suggest that the percentage of patients who are older than 70 years is closer to 50%. A review of the SEER Medicare data from 1994 to 1999 found a much lower rate of chemotherapy use than expected for the overall population.[15] It also suggested that the elderly may have more comorbidities or a higher rate of functional compromise that would make study participation difficult, if not contraindicated, and lack of clinical trial data may influence decisions to treat individual patients with standard chemotherapy.

Single-agent chemotherapy and combination chemotherapy clearly benefit at least some elderly patients. In the Elderly Lung Cancer Vinorelbine Italian Study, 154 patients who were older than 70 years were randomized to vinorelbine or supportive care.[16] Patients who were treated with vinorelbine had a 1-year survival rate of 32%, compared with 14% for those who were treated with supportive care alone. Quality-of-life parameters were also significantly improved in the chemotherapy arm, and toxic effects were acceptable. A more recent trial from Japan compared single-agent docetaxel with vinorelbine in 180 elderly patients with good PS.[17] Response rates and progression-free survival were significantly better with docetaxel (22% vs. 10%; 5.4 months vs. 3.1 months, respectively), whereas median and 1-year survival rates did not reach statistical significance (14.3 months vs. 9.9 months; 59% vs. 37%, respectively). Retrospective data analyzing and comparing younger (<70 years old) with older (=70 years old) patients who participated in large, randomized trials of doublet combinations have also shown that elderly patients may derive the same survival benefit although with a higher risk of toxic effects in the bone marrow.[18,19,20,21,22,23] Evidence supports that elderly patients with good PS and limited comorbidity may benefit from combination chemotherapy.

In summary, 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 (70–79 years old) to patients who are 80 years or older because only a very small number of patients greater than 80 years of age have been enrolled on clinical trials, and the benefit in this group is uncertain.[18,19]

PS is among the most important prognostic factors for survival of patients with NSCLC.[24] The benefit of therapy for this group of patients has been evaluated through retrospective analyses as well as through prospective clinical trials. The Cancer and Leukemia Group B-9730 trial, CLB-9730, which compared carboplatin and paclitaxel to paclitaxel, enrolled 99 patients with a PS of 2 (18% of the study's population). When compared with patients with a PS of 0 to 1, who had a median survival of 8.8 months and a 1-year survival of 38%, the corresponding figures for patients with a performance status of 2 were 3.0 months and 14%, respectively; this demonstrates the poor prognosis conferred by a lower PS. These differences were statistically significant. When patients with a PS of 2 were analyzed by treatment arm, those who received combination chemotherapy had a significantly higher response rate (24% vs. 10%), longer median survival (4.7 mo vs. 2.4 mo), and superior 1-year survival (18% vs. 10%) compared with those who were treated with single-agent paclitaxel.[22]

A subset analysis of 68 patients with a PS of 2 from a trial that randomly assigned more than 1,200 patients to four platinum-based regimens has been published. Despite a high incidence of adverse events, including five deaths, the final analysis showed that the overall toxic effects experienced by patients with a PS of 2 was not significantly different from that experienced by patients with a PS of 0 to 1. Efficacy analysis demonstrated an overall response rate of 14%, median survival time of 4.1 months, and a 1-year survival rate of 19%; all were substantially inferior to the patients with PS of 0 to 1. A phase II randomized trial (E-1599) of attenuated dosages of cisplatin plus gemcitabine and carboplatin plus paclitaxel included 102 patients with a PS of 2.[25] Response rates were 25% and 16%, median survival times were 6.8 months and 6.1 months, and 1-year survival rates were 25% and 19%, respectively. None of these differences was statistically significant, but the survival figures were longer than expected on the basis of historical controls. Results from two trials suggest that patients with a PS of 2 may experience symptom improvement.[26,27]

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.

Radiation therapy may be effective in palliating symptomatic patients with local involvement, such as tracheal, esophageal, or bronchial compression; pain; vocal cord paralysis; hemoptysis; or superior vena cava syndrome. (Refer to the PDQ summary on Cardiopulmonary Syndromes for more information). In some cases, endobronchial laser therapy and/or brachytherapy has been used to alleviate proximal obstructing lesions.[28] A systematic review identified six randomized trials of high-dose rate brachytherapy (HDREB) alone or with external-beam radiation therapy (EBRT) or laser therapy.[29] Better overall symptom palliation and fewer retreatments were required in previously untreated patients using EBRT alone.[29][Level of evidence: 1iiC] HDREB did provide palliation of symptomatic patients with recurrent endobronchial obstruction previously treated by EBRT, providing it is technically feasible. Although EBRT is frequently proscribed for symptom palliation, there is no consensus on which fractionation scheme should be used. Although different multifraction regimens appear to provide similar symptom relief, [30,31,32,33,34,35] single-fraction radiation may be insufficient for symptom relief compared with hypofractionated or standard regimens, as evidenced in the NCT00003685 trial.[36][Level of evidence: 1iiC] Evidence is available of a modest increase in survival in patients with a better PS given high-dose radiation therapy.[37,38][Level of evidence: 1iiA] In closely observed asymptomatic patients, treatment may often be appropriately deferred until symptoms or signs of a progressive tumor develop.

TREATMENT OPTIONS:

1. EBRT, primarily for palliative relief of local symptomatic tumor growth.[36,37,39]
2. Doublet of chemotherapy with platinum (cisplatin or carboplatin) and paclitaxel, gemcitabine, docetaxel, vinorelbine, irinotecan, and pemetrexed.
3. Paclitaxel, carboplatin, and bevacizumab for patients with non-squamous histology, no brain metastases, or no hemoptysis.
4. Clinical trials evaluating the role of new chemotherapy regimens and other systemic agents.
5. Endobronchial laser therapy and/or brachytherapy for obstructing lesions.[28]

Current Clinical Trials

Check for U.S. clinical trials from NCI's PDQ Cancer Clinical Trials Registry 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.

References:

1. Weick JK, Crowley J, Natale RB, et al.: A randomized trial of five cisplatin-containing treatments in patients with metastatic non-small-cell lung cancer: a Southwest Oncology Group study. J Clin Oncol 9 (7): 1157-62, 1991.
2. Sandler A, Gray R, Perry MC, et al.: Paclitaxel-carboplatin alone or with bevacizumab for non-small-cell lung cancer. N Engl J Med 355 (24): 2542-50, 2006.
3. Delbaldo C, Michiels S, Rolland E, et al.: Second or third additional chemotherapy drug for non-small cell lung cancer in patients with advanced disease. Cochrane Database Syst Rev (4): CD004569, 2007.
4. Ardizzoni A, Boni L, Tiseo M, et al.: Cisplatin- versus carboplatin-based chemotherapy in first-line treatment of advanced non-small-cell lung cancer: an individual patient data meta-analysis. J Natl Cancer Inst 99 (11): 847-57, 2007.
5. Jiang J, Liang X, Zhou X, et al.: A meta-analysis of randomized controlled trials comparing carboplatin-based to cisplatin-based chemotherapy in advanced non-small cell lung cancer. Lung Cancer 57 (3): 348-58, 2007.
6. Hotta K, Matsuo K, Ueoka H, et al.: Meta-analysis of randomized clinical trials comparing Cisplatin to Carboplatin in patients with advanced non-small-cell lung cancer. J Clin Oncol 22 (19): 3852-9, 2004.
7. D'Addario G, Pintilie M, Leighl NB, et al.: Platinum-based versus non-platinum-based chemotherapy in advanced non-small-cell lung cancer: a meta-analysis of the published literature. J Clin Oncol 23 (13): 2926-36, 2005.
8. Rajeswaran A, Trojan A, Burnand B, et al.: Efficacy and side effects of cisplatin- and carboplatin-based doublet chemotherapeutic regimens versus non-platinum-based doublet chemotherapeutic regimens as first line treatment of metastatic non-small cell lung carcinoma: a systematic review of randomized controlled trials. Lung Cancer 59 (1): 1-11, 2008.
9. Pujol JL, Barlesi F, Daurès JP: Should chemotherapy combinations for advanced non-small cell lung cancer be platinum-based? A meta-analysis of phase III randomized trials. Lung Cancer 51 (3): 335-45, 2006.
10. Douillard JY, Laporte S, Fossella F, et al.: Comparison of docetaxel- and vinca alkaloid-based chemotherapy in the first-line treatment of advanced non-small cell lung cancer: a meta-analysis of seven randomized clinical trials. J Thorac Oncol 2 (10): 939-46, 2007.
11. Belani CP, Ramalingam S, Perry MC, et al.: Randomized, phase III study of weekly paclitaxel in combination with carboplatin versus standard every-3-weeks administration of carboplatin and paclitaxel for patients with previously untreated advanced non-small-cell lung cancer. J Clin Oncol 26 (3): 468-73, 2008.
12. Schuette W, Blankenburg T, Guschall W, et al.: Multicenter randomized trial for stage IIIB/IV non-small-cell lung cancer using every-3-week versus weekly paclitaxel/carboplatin. Clin Lung Cancer 7 (5): 338-43, 2006.
13. Scagliotti GV, Parikh P, von Pawel J, et al.: Phase III study comparing cisplatin plus gemcitabine with cisplatin plus pemetrexed in chemotherapy-naive patients with advanced-stage non-small-cell lung cancer. J Clin Oncol 26 (21): 3543-51, 2008.
14. Ries LA: Influence of extent of disease, histology, and demographic factors on lung cancer survival in the SEER population-based data. Semin Surg Oncol 10 (1): 21-30, 1994 Jan-Feb.
15. Ramsey SD, Howlader N, Etzioni RD, et al.: Chemotherapy use, outcomes, and costs for older persons with advanced non-small-cell lung cancer: evidence from surveillance, epidemiology and end results-Medicare. J Clin Oncol 22 (24): 4971-8, 2004.
16. Effects of vinorelbine on quality of life and survival of elderly patients with advanced non-small-cell lung cancer. The Elderly Lung Cancer Vinorelbine Italian Study Group. J Natl Cancer Inst 91 (1): 66-72, 1999.
17. Takeda K, Kudoh S, Nakagawa K, et al.: Randomized phase III study of docetaxel (D) versus vinorelbine (V) for elderly patients (pts) with advanced non-small cell lung cancer (NSCLC): Results of a West Japan Thoracic Oncology Group trial (WJTOG9904). [Abstract] J Clin Oncol 23 (Suppl 16): A-7009, 2005.
18. Langer CJ, Vangel M, Schiller J, et al.: Age-specific subanalysis of ECOG 1594: fit elderly patients (70-80 YRS) with NSCLC do as well as younger pts (<70). [Abstract] Proceedings of the American Society of Clinical Oncology 22: A-2571, 2003.
19. Langer CJ, Manola J, Bernardo P, et al.: Cisplatin-based therapy for elderly patients with advanced non-small-cell lung cancer: implications of Eastern Cooperative Oncology Group 5592, a randomized trial. J Natl Cancer Inst 94 (3): 173-81, 2002.
20. Schiller JH, Harrington D, Belani CP, et al.: Comparison of four chemotherapy regimens for advanced non-small-cell lung cancer. N Engl J Med 346 (2): 92-8, 2002.
21. Belani CP, Fossella F: Elderly subgroup analysis of a randomized phase III study of docetaxel plus platinum combinations versus vinorelbine plus cisplatin for first-line treatment of advanced nonsmall cell lung carcinoma (TAX 326). Cancer 104 (12): 2766-74, 2005.
22. Lilenbaum RC, Herndon JE 2nd, List MA, et al.: Single-agent versus combination chemotherapy in advanced non-small-cell lung cancer: the cancer and leukemia group B (study 9730). J Clin Oncol 23 (1): 190-6, 2005.
23. Hensing TA, Peterman AH, Schell MJ, et al.: The impact of age on toxicity, response rate, quality of life, and survival in patients with advanced, Stage IIIB or IV nonsmall cell lung carcinoma treated with carboplatin and paclitaxel. Cancer 98 (4): 779-88, 2003.
24. Sweeney CJ, Zhu J, Sandler AB, et al.: Outcome of patients with a performance status of 2 in Eastern Cooperative Oncology Group Study E1594: a Phase II trial in patients with metastatic nonsmall cell lung carcinoma . Cancer 92 (10): 2639-47, 2001.
25. Tester WJ, Stephenson P, Langer CJ, et al.: ECOG 1599: randomized phase II study of paclitaxel/carboplatin or gemcitabine/cisplatin in performance status (PS) 2 patients with advanced non-small cell lung cancer (NSCLC). [Abstract] J Clin Oncol 22 (Suppl 14): A-7055, 630s, 2004.
26. Vansteenkiste JF, Vandebroek JE, Nackaerts KL, et al.: Clinical-benefit response in advanced non-small-cell lung cancer: A multicentre prospective randomised phase III study of single agent gemcitabine versus cisplatin-vindesine. Ann Oncol 12 (9): 1221-30, 2001.
27. Hickish TF, Smith IE, O'Brien ME, et al.: Clinical benefit from palliative chemotherapy in non-small-cell lung cancer extends to the elderly and those with poor prognostic factors. Br J Cancer 78 (1): 28-33, 1998.
28. Miller JI Jr, Phillips TW: Neodymium:YAG laser and brachytherapy in the management of inoperable bronchogenic carcinoma. Ann Thorac Surg 50 (2): 190-5; discussion 195-6, 1990.
29. Ung YC, Yu E, Falkson C, et al.: The role of high-dose-rate brachytherapy in the palliation of symptoms in patients with non-small-cell lung cancer: a systematic review. Brachytherapy 5 (3): 189-202, 2006 Jul-Sep.
30. Danson S, Middleton MR, O'Byrne KJ, et al.: Phase III trial of gemcitabine and carboplatin versus mitomycin, ifosfamide, and cisplatin or mitomycin, vinblastine, and cisplatin in patients with advanced nonsmall cell lung carcinoma. Cancer 98 (3): 542-53, 2003.
31. Pfister DG, Johnson DH, Azzoli CG, et al.: American Society of Clinical Oncology treatment of unresectable non-small-cell lung cancer guideline: update 2003. J Clin Oncol 22 (2): 330-53, 2004.
32. Smit EF, van Meerbeeck JP, Lianes P, et al.: Three-arm randomized study of two cisplatin-based regimens and paclitaxel plus gemcitabine in advanced non-small-cell lung cancer: a phase III trial of the European Organization for Research and Treatment of Cancer Lung Cancer Group--EORTC 08975. J Clin Oncol 21 (21): 3909-17, 2003.
33. Kubota K, Watanabe K, Kunitoh H, et al.: Phase III randomized trial of docetaxel plus cisplatin versus vindesine plus cisplatin in patients with stage IV non-small-cell lung cancer: the Japanese Taxotere Lung Cancer Study Group. J Clin Oncol 22 (2): 254-61, 2004.
34. Georgoulias V, Ardavanis A, Agelidou A, et al.: Docetaxel versus docetaxel plus cisplatin as front-line treatment of patients with advanced non-small-cell lung cancer: a randomized, multicenter phase III trial. J Clin Oncol 22 (13): 2602-9, 2004.
35. Sandler AB, Nemunaitis J, Denham C, et al.: Phase III trial of gemcitabine plus cisplatin versus cisplatin alone in patients with locally advanced or metastatic non-small-cell lung cancer. J Clin Oncol 18 (1): 122-30, 2000.
36. Bezjak A, Dixon P, Brundage M, et al.: Randomized phase III trial of single versus fractionated thoracic radiation in the palliation of patients with lung cancer (NCIC CTG SC.15). Int J Radiat Oncol Biol Phys 54 (3): 719-28, 2002.
37. Sundstrøm S, Bremnes R, Aasebø U, et al.: Hypofractionated palliative radiotherapy (17 Gy per two fractions) in advanced non-small-cell lung carcinoma is comparable to standard fractionation for symptom control and survival: a national phase III trial. J Clin Oncol 22 (5): 801-10, 2004.
38. Lester JF, Macbeth FR, Toy E, et al.: Palliative radiotherapy regimens for non-small cell lung cancer. Cochrane Database Syst Rev (4): CD002143, 2006.
39. Macbeth F, Toy E, Coles B, et al.: Palliative radiotherapy regimens for non-small cell lung cancer. Cochrane Database Syst Rev (3): CD002143, 2001.

Recurrent Non-Small Cell Lung Cancer

Note: Some citations in the text of this section are followed by a level of evidence. The PDQ editorial boards use a formal ranking system to help the reader judge the strength of evidence linked to the reported results of a therapeutic strategy. (Refer to the PDQ summary on Levels of Evidence for more information.)

Many patients with recurrent non-small cell lung cancer (NSCLC) are eligible for clinical trials. Radiation therapy may provide excellent palliation of symptoms from a localized tumor mass.

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 disease-free survival with surgical excision of the brain metastasis and postoperative whole-brain radiation therapy (WBRT).[1,2] Unresectable brain metastases in this setting may be treated with radiation surgery.[3] 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.[4] Most patients who are not suitable for surgical resection should receive conventional WBRT. Selected patients with good performance status (PS) and small metastases can be considered for stereotactic radiation surgery.[5]

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.[6] In those selected patients with good PS and without progressive metastases outside of the brain, treatment options include reoperation or stereotactic radiation surgery.[3,6] For most patients, additional radiation therapy can be considered; however, the palliative benefit of this treatment is limited.[7][Level of evidence: 3iiiDiii]

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.[8,9]

The use of chemotherapy has produced objective responses and small improvement in survival for patients with metastatic disease.[10][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.[11,12] Informed patients with good 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. Two prospective randomized studies have shown an improvement in survival with the use of docetaxel compared with vinorelbine, ifosfamide, or best supportive care;[13,14] however, criteria for the selection of appropriate patients for second-line treatment are not well defined.[15] A meta-analysis of five trials of 865 patients assessing the efficacy and safety of docetaxel administered weekly or every 3 weeks has been reported.[16] In that analysis, median survival was 27.4 weeks for patients treated with every 3 weeks and 26.1 weeks for patients treated weekly (P = .24, log-rank test). Significantly less severe and febrile neutropenia was reported with weekly docetaxel (P < .001 for both), whereas no significant differences were observed for anemia, thrombocytopenia, and nonhematologic toxic effects.

A randomized phase III trial of 571 patients designed to demonstrate the noninferiority of pemetrexed compared with docetaxel showed no difference in response rates, progression-free survival (PFS), or overall survival (OS).[17][Level of evidence: 1iiA]

A report of a randomized, placebo-controlled trial indicated that erlotinib prolongs survival and time to deterioration in symptoms in NSCLC patients after first-line or second-line chemotherapy compared with placebo.[18,19] In this trial of 731 patients, 49% had received two prior chemotherapy regimens, and 93% had received platinum-based chemotherapy. OS was 6.7 months and 4.7 months, respectively (hazard ratio (HR) = 0.70; P < .001), in favor of erlotinib.[18][Level of evidence: 1iiA] When used in combination with carboplatin and paclitaxel, [20] or cisplatin and gemcitabine, [21] erlotinib was not found to improve response rates, DFS, or OS in previously untreated patients with advanced or metastatic NSCLC.[20,21][Level of evidence: 1iiA] (For information on cutaneous rash, refer to the Pruritus summary and for information on diarrhea, refer to the Gastrointestinal Complications summary.)

A randomized phase III trial evaluating gefitinib versus placebo in 1,692 previously treated NSCLC patients showed that gefitinib does not improve OS, median survival did not differ significantly between the groups in the overall population (5.6 mo for gefitinib and 5.1 mo for placebo; HR = 0.89; 95% CI, 0.77–1.02], P = .087) or among the 812 patients with adenocarcinoma (6.3 mo vs. 5.4 mo; HR = 0.84; 0.68–1.03] P = .089). Preplanned subgroup analyses showed significantly longer survival in the gefitinib group than in the placebo group for never-smokers (n = 375; 0.67 [0.49–0.92], P = .012; median survival 8.9 mo vs. 6.1 mo) and patients of Asian origin (n = 342; 0.66 [0.48–0.91], P = .01; median survival 9.5 mo vs. 5.5 mo).[22][Level of evidence: 1iiA] In addition, in two randomized trials comparing the addition of gefitinib with standard platinum combination chemotherapy, no improvement in response rates, PFS, or OS was shown.[23,24][Level of evidence: 1iiA]

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.[25,26,27,28,29,30,31] Responses may be associated with sensitizing mutations in the tyrosine kinase domain of the epidermal growth factor receptor (EGFR) [26,27,28,30,31] and with the absence of K-RAS mutations.[29,30,31][Level of evidence: 3iiiDiii] Survival benefit may be greater in patients with EGFR protein expression by immunohistochemistry or increased EGFR gene copy number by FISH,[30,31] although the clinical utility of EGFR testing by immunohistochemistry has been questioned.[32]

TREATMENT OPTIONS:

1. Palliative radiation therapy.[33]
2. Chemotherapy alone.

For patients who have received platinum chemotherapy previously:

  • Docetaxel.[14,17]
  • Pemetrexed.[17]
  • Erlotinib after failure of both platinum-based and docetaxel chemotherapies.[34]
3. Surgical resection of isolated cerebral metastasis (highly selected patients).[6]
4. Laser therapy or interstitial radiation therapy for endobronchial lesions.[35]
5. Stereotactic radiosurgery (highly selected patients).[3,5]

Current Clinical Trials

Check for U.S. clinical trials from NCI's PDQ Cancer Clinical Trials Registry 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.

References:

1. Patchell RA, Tibbs PA, Walsh JW, et al.: A randomized trial of surgery in the treatment of single metastases to the brain. N Engl J Med 322 (8): 494-500, 1990.
2. Mandell L, Hilaris B, Sullivan M, et al.: The treatment of single brain metastasis from non-oat cell lung carcinoma. Surgery and radiation versus radiation therapy alone. Cancer 58 (3): 641-9, 1986.
3. Loeffler JS, Kooy HM, Wen PY, et al.: The treatment of recurrent brain metastases with stereotactic radiosurgery. J Clin Oncol 8 (4): 576-82, 1990.
4. DeAngelis LM, Mandell LR, Thaler HT, et al.: The role of postoperative radiotherapy after resection of single brain metastases. Neurosurgery 24 (6): 798-805, 1989.
5. Alexander E 3rd, Moriarty TM, Davis RB, et al.: Stereotactic radiosurgery for the definitive, noninvasive treatment of brain metastases. J Natl Cancer Inst 87 (1): 34-40, 1995.
6. Arbit E, Wronski M, Burt M, et al.: The treatment of patients with recurrent brain metastases. A retrospective analysis of 109 patients with nonsmall cell lung cancer. Cancer 76 (5): 765-73, 1995.
7. Hazuka MB, Kinzie JJ: Brain metastases: results and effects of re-irradiation. Int J Radiat Oncol Biol Phys 15 (2): 433-7, 1988.
8. Salerno TA, Munro DD, Blundell PE, et al.: Second primary bronchogenic carcinoma: life-table analysis of surgical treatment. Ann Thorac Surg 27 (1): 3-6, 1979.
9. Yellin A, Hill LR, Benfield JR: Bronchogenic carcinoma associated with upper aerodigestive cancers. J Thorac Cardiovasc Surg 91 (5): 674-83, 1986.
10. Souquet PJ, Chauvin F, Boissel JP, et al.: Polychemotherapy in advanced non small cell lung cancer: a meta-analysis. Lancet 342 (8862): 19-21, 1993.
11. Ellis PA, Smith IE, Hardy JR, et al.: Symptom relief with MVP (mitomycin C, vinblastine and cisplatin) chemotherapy in advanced non-small-cell lung cancer. Br J Cancer 71 (2): 366-70, 1995.
12. Girling DJ, et al.: Randomized trial of etoposide cyclophosphamide methotrexate and vincristine versus etoposide and vincristine in the palliative treatment of patients with small-cell lung cancer and poor prognosis. Br J Cancer 67 (Suppl 20): A-4;2, 14, 1993.
13. Fossella FV, DeVore R, Kerr RN, et al.: Randomized phase III trial of docetaxel versus vinorelbine or ifosfamide in patients with advanced non-small-cell lung cancer previously treated with platinum-containing chemotherapy regimens. The TAX 320 Non-Small Cell Lung Cancer Study Group. J Clin Oncol 18 (12): 2354-62, 2000.
14. Shepherd FA, Dancey J, Ramlau R, et al.: Prospective randomized trial of docetaxel versus best supportive care in patients with non-small-cell lung cancer previously treated with platinum-based chemotherapy. J Clin Oncol 18 (10): 2095-103, 2000.
15. Huisman C, Smit EF, Giaccone G, et al.: Second-line chemotherapy in relapsing or refractory non-small-cell lung cancer: a review. J Clin Oncol 18 (21): 3722-30, 2000.
16. Di Maio M, Perrone F, Chiodini P, et al.: Individual patient data meta-analysis of docetaxel administered once every 3 weeks compared with once every week second-line treatment of advanced non-small-cell lung cancer. J Clin Oncol 25 (11): 1377-82, 2007.
17. Hanna N, Shepherd FA, Fossella FV, et al.: Randomized phase III trial of pemetrexed versus docetaxel in patients with non-small-cell lung cancer previously treated with chemotherapy. J Clin Oncol 22 (9): 1589-97, 2004.
18. Shepherd FA, Rodrigues Pereira J, Ciuleanu T, et al.: Erlotinib in previously treated non-small-cell lung cancer. N Engl J Med 353 (2): 123-32, 2005.
19. Bezjak A, Tu D, Seymour L, et al.: Symptom improvement in lung cancer patients treated with erlotinib: quality of life analysis of the National Cancer Institute of Canada Clinical Trials Group Study BR.21. J Clin Oncol 24 (24): 3831-7, 2006.
20. Herbst RS, Prager D, Hermann R, et al.: TRIBUTE - A phase III trial of erlotinib HCI (OSI-774) combined with carboplatin and paclitaxel (CP) chemotherapy in advanced non-small cell lung cancer (NSCLC). [Abstract] J Clin Oncol 22 (Suppl 14): A-7011, 619s, 2004.
21. Gatzemeier U, Pluzanska A, Szczesna A, et al.: Results of a phase III trial of erlotinib (OSI-774) combined with cisplatin and gemcitabine (GC) chemotherapy in advanced non-small cell lung cancer (NSCLC). [Abstract] J Clin Oncol 22 (Suppl 14): A-7010, 619s, 2004.
22. Thatcher N, Chang A, Parikh P, et al.: Gefitinib plus best supportive care in previously treated patients with refractory advanced non-small-cell lung cancer: results from a randomised, placebo-controlled, multicentre study (Iressa Survival Evaluation in Lung Cancer). Lancet 366 (9496): 1527-37, 2005 Oct 29-Nov 4.
23. Herbst RS, Giaccone G, Schiller JH, et al.: Gefitinib in combination with paclitaxel and carboplatin in advanced non-small-cell lung cancer: a phase III trial--INTACT 2. J Clin Oncol 22 (5): 785-94, 2004.
24. Giaccone G, Herbst RS, Manegold C, et al.: Gefitinib in combination with gemcitabine and cisplatin in advanced non-small-cell lung cancer: a phase III trial--INTACT 1. J Clin Oncol 22 (5): 777-84, 2004.
25. Miller VA, Kris MG, Shah N, et al.: Bronchioloalveolar pathologic subtype and smoking history predict sensitivity to gefitinib in advanced non-small-cell lung cancer. J Clin Oncol 22 (6): 1103-9, 2004.
26. Paez JG, Jänne PA, Lee JC, et al.: EGFR mutations in lung cancer: correlation with clinical response to gefitinib therapy. Science 304 (5676): 1497-500, 2004.
27. Lynch TJ, Bell DW, Sordella R, et al.: Activating mutations in the epidermal growth factor receptor underlying responsiveness of non-small-cell lung cancer to gefitinib. N Engl J Med 350 (21): 2129-39, 2004.
28. Pao W, Miller V, Zakowski M, et al.: EGF receptor gene mutations are common in lung cancers from "never smokers" and are associated with sensitivity of tumors to gefitinib and erlotinib. Proc Natl Acad Sci U S A 101 (36): 13306-11, 2004.
29. Pao W, Wang TY, Riely GJ, et al.: KRAS mutations and primary resistance of lung adenocarcinomas to gefitinib or erlotinib. PLoS Med 2 (1): e17, 2005.
30. Tsao MS, Sakurada A, Cutz JC, et al.: Erlotinib in lung cancer - molecular and clinical predictors of outcome. N Engl J Med 353 (2): 133-44, 2005.
31. Hirsch FR, Varella-Garcia M, Bunn PA Jr, et al.: Molecular predictors of outcome with gefitinib in a phase III placebo-controlled study in advanced non-small-cell lung cancer. J Clin Oncol 24 (31): 5034-42, 2006.
32. Clark GM, Zborowski DM, Culbertson JL, et al.: Clinical utility of epidermal growth factor receptor expression for selecting patients with advanced non-small cell lung cancer for treatment with erlotinib. J Thorac Oncol 1 (8): 837-46, 2006.
33. Sundstrøm S, Bremnes R, Aasebø U, et al.: Hypofractionated palliative radiotherapy (17 Gy per two fractions) in advanced non-small-cell lung carcinoma is comparable to standard fractionation for symptom control and survival: a national phase III trial. J Clin Oncol 22 (5): 801-10, 2004.
34. Shepherd FA, Pereira J, Ciuleanu TE, et al.: A randomized placebo-controlled trial of erlotinib in patients with advanced non-small cell lung cancer (NSCLC) following failure of 1st line or 2nd line chemotherapy. A National Cancer Institute of Canada Clinical Trials Group (NCIC CTG) trial. [Abstract] J Clin Oncol 22 (Suppl 14): A-7022, 622s, 2004.
35. Miller JI Jr, Phillips TW: Neodymium:YAG laser and brachytherapy in the management of inoperable bronchogenic carcinoma. Ann Thorac Surg 50 (2): 190-5; discussion 195-6, 1990.

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The NCI Web site provides online access to information on cancer, clinical trials, and other Web sites and organizations that offer support and resources for cancer patients and their families. For a quick search, use the search box in the upper right corner of each Web page. The results for a wide range of search terms will include a list of "Best Bets," editorially chosen Web pages that are most closely related to the search term entered.

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Changes to This Summary (01 / 29 / 2010)

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.

Editorial changes were made to this summary.

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ABOUT PDQ

  • PDQ® - NCI's Comprehensive Cancer Database.
    Full description of the NCI PDQ database.

ADDITIONAL PDQ SUMMARIES

  • PDQ® Cancer Information Summaries: Adult Treatment
    Treatment options for adult cancers.
  • PDQ® Cancer Information Summaries: Pediatric Treatment
    Treatment options for childhood cancers.
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  • PDQ® Cancer Information Summaries: Screening/Detection (Testing for Cancer)
    Tests or procedures that detect specific types of cancer.
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    Risk factors and methods to increase chances of preventing specific types of cancer.
  • PDQ® Cancer Information Summaries: Genetics
    Genetics of specific cancers and inherited cancer syndromes, and ethical, legal, and social concerns.
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    Information about complementary and alternative forms of treatment for patients with cancer.

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Date Last Modified: 2010-01-29

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