INTRODUCTION — Treatment of patients with lung cancer depends upon the cell type (non-small cell lung cancer [NSCLC] versus small cell lung cancer), tumor stage, molecular characteristics, and an assessment of the patient's overall medical condition. (See "Overview of the initial evaluation, treatment and prognosis of lung cancer".)
Patients with stage I, II, or III NSCLC are generally treated with curative intent using surgery, chemotherapy, radiation therapy (RT), or a combined modality approach (table 1). In contrast, palliative systemic therapy is appropriate for patients with metastatic (stage IV) disease. Palliative systemic therapy is also used for patients who have relapsed with advanced disease following prior definitive treatment.
An overview to the approach to systemic therapy for patients who present with advanced NSCLC and for those who relapse after initial definitive therapy is presented here.
Detailed discussions of specific aspects of patient management are presented in the following topics:
INITIAL TREATMENT — Multiple factors influence the choice of treatment for a patient with advanced NSCLC. The initial management of patients with advanced NSCLC depends upon the presence or absence of characteristic molecular abnormalities, as well as the patient's age, functional status, comorbidities, and prior therapy.
CHEMOTHERAPY VERSUS TARGETED THERAPY — Whenever possible, therapy should be individualized based upon molecular and histologic features of the tumor.
If feasible, patients should have tumor tissue assessed for the presence of a somatic mutation in the epidermal growth factor receptor (EGFR), which confers sensitivity to EGFR tyrosine kinase inhibitors, and for the anaplastic lymphoma kinase (ALK) fusion oncogene, which confers sensitivity to crizotinib [1]. (See "Small molecule epidermal growth factor receptor inhibitors for advanced non-small cell lung cancer", section on 'Molecular markers' and "Anaplastic lymphoma kinase (ALK) fusion gene positive advanced non-small cell lung cancer", section on 'Molecular pathogenesis'.)
Patient management is then determined by the results of these molecular studies:
NONELDERLY, GOOD PERFORMANCE STATUS PATIENTS — Advances in the development of contemporary active cytotoxic agents (platinum compounds, taxanes, vinorelbine, gemcitabine, pemetrexed, camptothecins) and targeted agents (epidermal growth factor receptor tyrosine kinase inhibitors [erlotinib, gefitinib], ALK fusion oncogene inhibition [crizotinib], and monoclonal antibodies [bevacizumab, cetuximab]) have provided a wide range of treatment options for patients who are candidates for aggressive therapy.
These approaches have been evaluated in numerous randomized, phase III clinical trials, which largely have been conducted primarily in younger patients, with a good performance status (Eastern Cooperative Oncology Group performance status [PS] 0 or 1, (table 2)).
No EGFR mutation and no ALK fusion oncogene — Cytotoxic chemotherapy is the primary treatment for patients with advanced NSCLC who have neither an activating mutation of EGFR nor an ALK fusion oncogene. In selected patients, chemotherapy may be combined with bevacizumab or cetuximab.
EGFR mutation positive — EGFR tyrosine kinase inhibitors (erlotinib, gefitinib) are indicated as monotherapy in patients whose tumors contain an activating mutation in EGFR. (See 'Chemotherapy versus targeted therapy' above and "Initial systemic therapy for advanced non-small cell lung cancer with a mutation in the epidermal growth factor receptor", section on 'Single agent therapy'.)
However, when combined with platinum-based doublet chemotherapy, these agents have not prolonged survival even when patients were selected for sensitivity to these EGFR tyrosine kinase inhibitors based upon clinical criteria. (See "Initial systemic therapy for advanced non-small cell lung cancer with a mutation in the epidermal growth factor receptor", section on 'EGFR TK inhibitors plus chemotherapy'.)
ALK fusion oncogene positive — The presence of the ALK fusion oncogene is associated with sensitivity to crizotinib, an inhibitor of the anaplastic lymphoma kinase (ALK) tyrosine kinase. (See "Anaplastic lymphoma kinase (ALK) fusion gene positive advanced non-small cell lung cancer" and "Anaplastic lymphoma kinase (ALK) fusion gene positive advanced non-small cell lung cancer", section on 'Molecular pathogenesis'.)
Phase II studies using crizotinib demonstrated an objective response rate over 50 percent in patients selected for treatment based upon the presence of the ALK fusion oncogene, with a median duration of response greater than 40 weeks in responders. Crizotinib is preferred for treatment in this patient subset. (See "Anaplastic lymphoma kinase (ALK) fusion gene positive advanced non-small cell lung cancer", section on 'Crizotinib'.)
Maintenance therapy — Treatment with targeted agents (EGFR tyrosine kinase inhibitors [erlotinib, gefitinib] or crizotinib) is generally continued indefinitely in the absence of significant toxicity.
Chemotherapy is generally limited to approximately four cycles. The role of maintenance therapy with a cytotoxic chemotherapy agent or an EGFR TK inhibitor is evolving and may provide an option for patients with a response or stable disease after their initial course of treatment. (See "Maintenance therapy for patients with advanced non-small cell lung cancer who respond to initial chemotherapy".)
ELDERLY PATIENTS — As with younger patients, the molecular characteristics of the tumor are critical in choosing the appropriate initial therapy for older patients. (See 'Chemotherapy versus targeted therapy' above and "Initial systemic therapy for elderly patients with advanced non-small cell lung cancer".)
No EGFR mutation and no ALK fusion oncogene — Phase III trials established that chemotherapy prolongs survival in appropriately selected elderly patients with NSCLC, although the tolerability of chemotherapy is a common concern. Combination regimens, such as carboplatin plus paclitaxel, appear to be more effective than single agents, although elderly patients with significant comorbidity or a marginal performance status may be candidates for single agent chemotherapy. (See "Initial systemic therapy for elderly patients with advanced non-small cell lung cancer", section on 'No EGFR mutation or ALK fusion oncogene'.)
Factors that may be useful in selecting patients for chemotherapy and determining the appropriate regimen include performance status, comorbidities, and a baseline comprehensive geriatric assessment. (See "Comprehensive geriatric assessment for patients with cancer" and "Systemic chemotherapy for cancer in elderly persons".)
EGFR mutation positive — The oral administration and toxicity profile of EGFR inhibition may offer some special advantage for the initial treatment of advanced NSCLC in the elderly. This approach is recommended in those with an EGFR mutation and is an option for patients who refuse or are deemed ineligible for chemotherapy. (See "Initial systemic therapy for elderly patients with advanced non-small cell lung cancer", section on 'EGFR mutation positive disease' and "Small molecule epidermal growth factor receptor inhibitors for advanced non-small cell lung cancer", section on 'Predictors of responsiveness'.)
ALK fusion oncogene positive — The presence of the ALK fusion oncogene is associated with sensitivity to crizotinib in phase II studies. Data are limited in the elderly population, but this approach is preferred for these patients. (See "Anaplastic lymphoma kinase (ALK) fusion gene positive advanced non-small cell lung cancer".)
POOR PERFORMANCE STATUS PATIENTS — Patients with an Eastern Cooperative Oncology group performance status (PS) ≥2 (table 2) or Karnofsky Performance Status (KPS) ≤70 (table 5) constitute a substantial fraction of patients with advanced NSCLC. However, such patients have been excluded from most clinical trials, and those with PS ≥3 are often managed with best supportive care alone. (See "Systemic therapy for poor performance status patients with advanced non-small cell lung cancer".)
However, some patients with PS2 and wild type EGFR may benefit from systemic therapy. Chemotherapy with either a single agent or attenuated doses of a doublet regimen may prolong survival without worsening quality of life. (See "Systemic therapy for poor performance status patients with advanced non-small cell lung cancer", section on 'No EGFR mutation and no ALK fusion oncogene'.)
For patients with a poor performance status (PS ≥2) and a known sensitivity mutation in the EGFR, single agent therapy with an EGFR tyrosine kinase inhibitor (erlotinib or gefitinib) is generally recommended. (See "Systemic therapy for poor performance status patients with advanced non-small cell lung cancer", section on 'EGFR mutation positive patients'.)
The presence of the ALK fusion oncogene conferred sensitivity to crizotinib in phase II studies. Although only 17 percent of patients in the phase II database were PS 2 or 3, this approach is an appropriate option for these patients. (See "Anaplastic lymphoma kinase (ALK) fusion gene positive advanced non-small cell lung cancer".)
SECOND-LINE THERAPY — Most patients with advanced NSCLC eventually develop progressive disease and require additional treatment. In selected patients, second-line therapy improves both survival and quality of life after failure of a treatment regimen.
Options include cytotoxic chemotherapy and small molecule inhibitors of the epidermal growth factor receptor (EGFR) tyrosine kinase, as well as palliative radiation therapy when symptoms are limited to a single anatomic region. (See "Second-line therapy for patients with previously treated advanced non-small cell lung cancer".)
There are no data to support the use of crizotinib as second line therapy in patients whose tumor does not contain the ALK fusion gene. (See "Anaplastic lymphoma kinase (ALK) fusion gene positive advanced non-small cell lung cancer".)
Chemotherapy — Second-line cytotoxic chemotherapy should be considered only in previously treated patients with a good performance status because of the potential toxicity and low response rates associated with such regimens.
EGFR TK inhibitors — Small molecule epidermal growth factor receptor (EGFR) tyrosine kinase inhibitors were initially developed as second-line therapy after failure with a cytotoxic chemotherapy regimen. (See "Small molecule epidermal growth factor receptor inhibitors for advanced non-small cell lung cancer".)
PALLIATIVE CARE — Early integration of palliative care into the disease-specific therapies for patients with advanced NSCLC may offer a number of benefits [2]. In a trial in which 151 patients were randomly assigned to early palliative care or standard management, a formal program with a palliative care team resulted in improved quality of life and mood [3]. The active intervention arm focused on assessment of physical and psychosocial issues, the establishment of goals for care, decision-making related to treatment, and coordination of care. Although patients had less aggressive care at the end of life, median survival was significantly longer in the active intervention arm (11.6 versus 8.9 months). It is unclear how palliative care would result in improved survival, and the survival benefit should be interpreted with caution.
BONE METASTASES — Bone metastases are a frequent complication in patients with metastatic NSCLC. Bone metastases can impair quality of life by causing pain or pathologic fractures. (See "Radiation therapy for the management of painful bone metastases".)
Bisphosphonate therapy is suggested for patients with NSCLC metastatic to bone based upon results of a phase III trial in which zoledronic acid significantly reduced the number of skeletal-related events (pathologic fracture, spinal cord compression, RT or surgery to bone, hypercalcemia) compared to placebo. Necessary dental work should be completed prior to treatment with bisphosphonates and further dental work should be avoided because of the risk of osteonecrosis of the jaw. (See "Bisphosphonates and denosumab in patients with metastatic cancer", section on 'Lung cancer and other solid cancers' and "Risks of therapy with bone modifying agents in patients with advanced malignancy", section on 'Osteonecrosis of the jaw'.)
CENTRAL NERVOUS SYSTEM METASTASES
Brain metastases — Brain metastases are a frequent complication during the natural history of NSCLC. The prognosis of patients with NSCLC and brain metastases is highly variable. A multivariate analysis of 1833 NSCLC patients identified age, Karnofsky performance status, the presence or absence of extracranial metastases, and the number of brain metastases as factors that independently influenced survival [4]. Median survival ranged from 3 to 15 months in subgroups defined by these parameters (table 6).
Brain metastases in patients whose tumor harbors an EGFR activating mutations are responsive to therapy with gefitinib or erlotinib, and may constitute a favorable subset compared with those whose tumors do not contain such a mutation [5]. (See "Systemic therapy for brain metastases", section on 'Targeted agents'.)
The general management of patients with brain metastases is discussed separately. (See "Overview of the clinical manifestations, diagnosis, and management of patients with brain metastases".)
Leptomeningeal metastases — Leptomeningeal carcinomatosis from NSCLC is associated with a particularly poor prognosis, with a median survival of approximately three months [6]. Standard treatment with whole brain RT and/or intrathecal chemotherapy does not appear to have a significant effect on survival. There is anecdotal evidence that treatment with EGFR inhibitors may be beneficial in patients whose tumors contain an EGFR mutation. (See "Treatment of leptomeningeal metastases (carcinomatous meningitis)", section on 'Other agents'.)
SYMPTOM PALLIATION — Short courses of radiation therapy are useful for patients who require symptom palliation. This may include symptoms arising from progressive intrathoracic disease or disease at other sites (eg, bone, brain). (See "Second-line therapy for patients with previously treated advanced non-small cell lung cancer", section on 'Symptom palliation'.)
In carefully selected patients with symptoms due predominantly to endobronchial recurrence, endobronchial brachytherapy or other interventional techniques may be useful in providing symptom palliation. (See "Endobronchial brachytherapy", section on 'Palliation' and "Airway stents" and "Bronchoscopic laser resection" and "Endobronchial electrocautery" and "Bronchoscopic cryosurgery: Indications, contraindications, and outcomes".)
INFORMATION FOR PATIENTS — UpToDate offers two types of patient education materials, “The Basics” and “Beyond the Basics.” The Basics patient education pieces are written in plain language, at the 5th to 6th grade reading level, and they answer the four or five key questions a patient might have about a given condition. These articles are best for patients who want a general overview and who prefer short, easy-to-read materials. Beyond the Basics patient education pieces are longer, more sophisticated, and more detailed. These articles are written at the 10th to 12th grade reading level and are best for patients who want in-depth information and are comfortable with some medical jargon.
Here are the patient education articles that are relevant to this topic. We encourage you to print or e-mail these topics to your patients. (You can also locate patient education articles on a variety of subjects by searching on “patient info” and the keyword(s) of interest.)
SUMMARY AND RECOMMENDATIONS
Molecular characterization — Whenever possible, therapy should be individualized based upon molecular and histologic features of the tumor. If feasible, patients should have tumor tissue assessed for the presence of a somatic mutation in the epidermal growth factor receptor (EGFR), which confers sensitivity to EGFR tyrosine kinase inhibitors, and for the ALK fusion oncogene, which is associated with sensitivity to crizotinib. (See 'Chemotherapy versus targeted therapy' above.)
Nonelderly, good performance status patients
No EGFR mutation and no ALK fusion oncogene
EGFR mutation positive — For patients whose tumors contain a characteristic mutation of EGFR, we recommend initial therapy with an EGFR inhibitor (erlotinib or gefitinib) rather than cytotoxic chemotherapy (Grade 1A). (See "Initial systemic therapy for advanced non-small cell lung cancer with a mutation in the epidermal growth factor receptor".)
ALK fusion oncogene positive — For patients whose tumors contain the ALK fusion oncogene, we recommend initial therapy with crizotinib (Grade 1B). (See "Anaplastic lymphoma kinase (ALK) fusion gene positive advanced non-small cell lung cancer", section on 'Crizotinib'.)
Elderly patients
Poor performance status patients
Second-line therapy — In selected patients with NSCLC, second-line therapy improves both survival and quality of life after failure of an initial cytotoxic chemotherapy regimen. Options include cytotoxic chemotherapy and small molecule inhibitors of the epidermal growth factor receptor (EGFR) tyrosine kinase (TK). (See "Second-line therapy for patients with previously treated advanced non-small cell lung cancer".)
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