Non-Small Cell Lung Cancer Treatment (PDQ®)–Health Professional Version

Treatment Option Overview for NSCLC

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 potentially the most curative therapeutic option for this disease. Postoperative chemotherapy may provide an additional benefit to patients with resected NSCLC. Radiation therapy combined with chemotherapy can produce a cure in a small number of patients and can provide palliation in most patients. Prophylactic cranial irradiation may reduce the incidence of brain metastases, but there is no evidence of a survival benefit and the effect of prophylactic cranial irradiation on quality of life is not known.[1,2] In patients with advanced-stage disease, chemotherapy or epidermal growth factor receptor (EGFR) kinase inhibitors offer modest improvements in median survival, although overall survival is poor.[3,4]

Chemotherapy has produced short-term improvement in disease-related symptoms in patients with advanced NSCLC. Several clinical trials have attempted to assess the impact of chemotherapy on tumor-related symptoms and quality of life. In total, these studies suggest that tumor-related symptoms may be controlled by chemotherapy without adversely affecting overall quality of life;[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.

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

The standard treatment options for each stage of NSCLC are presented in Table 7.

Table 7. Standard Treatment Options for NSCLC

Stage (TNM Staging Criteria)		Standard Treatment Options
ALK = anaplastic lymphoma kinase; BRAF = v-raf murine sarcoma viral oncogene homolog B1; EGFR = epidermal growth factor receptor; MEK = MAPK kinase 1; NSCLC = non-small cell lung cancer; PD-L1 = programmed death-ligand 1; TKI = tyrosine kinase inhibitors; TNM = T, size of tumor and any spread of cancer into nearby tissue; N, spread of cancer to nearby lymph nodes; M, metastasis or spread of cancer to other parts of body.
Occult NSCLC		Surgery
Stage 0 NSCLC		Surgery
Stage 0 NSCLC		Endobronchial therapies
Stages IA and IB NSCLC		Surgery
Stages IA and IB NSCLC		Radiation therapy
Stages IIA and IIB NSCLC		Surgery
		Adjuvant chemotherapy
		Neoadjuvant chemotherapy
		Radiation therapy
Stage IIIA NSCLC	Resected or resectable disease	Surgery
		Neoadjuvant therapy
		Adjuvant therapy
	Unresectable disease	Radiation therapy
	Unresectable disease	Chemoradiation therapy
	Superior sulcus tumors	Radiation therapy alone
		Surgery
		Chemoradiation therapy followed by surgery
	Tumors that invade the chest wall	Surgery
		Surgery and radiation therapy
		Radiation therapy alone
		Chemotherapy combined with radiation therapy and/or surgery
Stages IIIB and IIIC NSCLC		Sequential or concurrent chemotherapy and radiation therapy
		Radiation therapy dose escalation for concurrent chemoradiation
		Additional systemic therapy before or after concurrent chemotherapy and radiation therapy
		Radiation therapy alone
Newly Diagnosed Stage IV, Relapsed, and Recurrent NSCLC		Cytotoxic combination chemotherapy
		Combination chemotherapy with monoclonal antibodies
		Maintenance therapy following first-line chemotherapy (for patients with stable or responding disease after four cycles of platinum-based combination chemotherapy)
		EGFR tyrosine kinase inhibitors (for patients with EGFR mutations)
		ALK inhibitors (for patients with ALKtranslocations)
		ROS1 inhibitors (for patients with ROS1rearrangements)
		BRAFV600E and MEK inhibitors (for patients with BRAFV600E mutations
		Immune checkpoint inhibitor for PD-L1 expressing NSCLC.
		Local therapies and special considerations
Progressive Stage IV, Relapsed, and Recurrent NSCLC		Chemotherapy
		EGFR-directed therapy
		ALK-directed TKI
		ROS1-directed therapy
		BRAFV600E and MEK inhibitors (for patients with BRAFV600E mutations)
		Immunotherapy

In addition to the standard treatment options presented in Table 7, treatment options under clinical evaluation include the following:

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

Follow-Up

Several small series have reported that reduction in fluorine F 18-fludeoxyglucose positron emission tomography (18F-FDG PET) after chemotherapy, radiation therapy, or chemoradiation therapy correlates with pathological complete response and favorable prognosis.[8-15] Studies have used different timing of assessments, 18F-FDG PET parameters, and cutpoints to define 18F-FDG PET response. Reduction in maximum standardized uptake value (SUV) of higher than 80% predicted for complete pathological response with a sensitivity of 90%, specificity of 100%, and accuracy of 96%.[16] Median survival after resection was longer for patients with tumor SUV values of lower than 4 (56 months vs. 19 months).[15] Patients with complete metabolic response following radiation therapy were reported to have median survivals of 31 months versus 11 months.[17]

18F-FDG PET may be more sensitive and specific than computed tomography (CT) scan in assessing response to induction therapy. Optimal timing of imaging remains to be defined; however, one study suggested that greater sensitivity and specificity of 18F-FDG PET is achieved if repeat imaging is delayed until 30 days after radiation therapy.[16]

There is no clear role for routine posttreatment PET-CT scans.[18][Level of evidence: 3iiA]

Evidence (surveillance imaging after radiation therapy with or without chemotherapy):

A prospective multicenter trial led by the American College of Radiology Imaging Network (ACRIN) and the Radiation Therapy Oncology Group (RTOG) cooperative group (ACRIN 6668/RTOG 0235 [NCT00083083]) studied the role of posttreatment PET-CT at approximately 14 weeks (range, 12–16 weeks) to predict overall survival (OS) after standard-of-care concurrent chemotherapy and radiation therapy in 173 patients with stage III disease.
- The primary endpoint was to determine the relationship between SUVpeak at a prespecified binary cutoff of SUVpeak 3.5 with OS.
- The study demonstrated no association between OS and SUVpeak of 3.5 or lower compared with SUVpeak higher than 3.5 with 2-year OS estimates of 51% vs. 37% (P = 0.29).
- Exploratory analyses showed associations between OS and SUVpeak as a continuous variable, and binary cutoffs of SUVpeak 5.0 and 7.0.

Current Clinical Trials

Use our advanced clinical trial search to find NCI-supported cancer clinical trials that are now enrolling patients. The search can be narrowed by location of the trial, type of treatment, name of the drug, and other criteria. General information about clinical trials is also available.

References

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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. [PUBMED Abstract]
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Pao W, Girard N: New driver mutations in non-small-cell lung cancer. Lancet Oncol 12 (2): 175-80, 2011. [PUBMED Abstract]
Curran WJ Jr, Paulus R, Langer CJ, et al.: Sequential vs. concurrent chemoradiation for stage III non-small cell lung cancer: randomized phase III trial RTOG 9410. J Natl Cancer Inst 103 (19): 1452-60, 2011. [PUBMED Abstract]
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. [PUBMED Abstract]
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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. [PUBMED Abstract]
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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. [PUBMED Abstract]
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. [PUBMED Abstract]
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. [PUBMED Abstract]
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. [PUBMED Abstract]
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