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Overview of the initial evaluation, treatment and prognosis of lung cancer

INITIAL EVALUATION — The main issues to assess in a patient with a suspected lung cancer are to confirm that the lesion is malignant, determine whether the cell type non-small cell lung cancer (NSCLC) or small cell lung cancer (SCLC), assess the stage of disease, and the functional status of the patient. These parameters are essential for appropriate patient management. The initial evaluation of a patient with suspected lung cancer is discussed in detail separately.

 

  • A tissue diagnosis is necessary to determine whether a lung cancer is a NSCLC or an SCLC, as well as to rule out the possibility that disease represents a nonmalignant process or lung metastasis from a primary tumor at another site. This information is critical for treatment planning. (See "Procedures for tissue biopsy in patients with suspected non-small cell lung cancer" and "Diagnostic evaluation and management of the solitary pulmonary nodule".)
  • Staging for NSCLC is critical in determining the appropriate treatment for a patient with resectable disease and avoiding unnecessary and unhelpful surgery in advanced disease [3]. The Tumor, Node, Metastasis (TNM) staging system is used for treatment planning and prognostic purposes in patients with NSCLC. The eighth edition is effective in the United States as of January 1, 2018 (table 1). However, outside of the United States, the Union for International Cancer Control (UICC) has implemented the eighth edition changes as of January 1, 2017. The previous edition of the staging system is discussed elsewhere. (See "Tumor, Node, Metastasis (TNM) staging system for lung cancer".)
  • Staging of SCLC usually uses the Veterans Administration Lung Study Group designations of limited (confined to one hemithorax) or extensive (beyond one hemithorax) disease [4], although the TNM system is sometimes also used (table 1). This distinction is important since treatment algorithms differ for patients with limited versus extensive stage disease. (See "Pathobiology and staging of small cell carcinoma of the lung".)
  • Treatment of lung cancer, whether with surgery, chemotherapy, radiation therapy (RT) or a combination of these, can be associated with substantial toxicity. Patients with significant impairment due to their lung cancer or comorbid conditions may not be able to withstand resection or alternatively aggressive chemoradiotherapy. Performance status can be assessed by a variety of methods including the Karnofsky Performance Status (KPS) and the Eastern Cooperative Oncology Group Performance Scale (ECOG PS) (table 2 and table 3). The KPS was introduced in the 1940s and uses a 100-point scale and 11 measures to describe patient's abilities to pursue activities and perform work [5]. The ECOG PS uses a five-point scale and has been shown in a comparative study to be a better predictor of prognosis [6].

Diagnostic procedures and staging should be carried out simultaneously, even though it may be tempting to simply pursue a diagnosis when an obvious abnormality is present on imaging. As an example, in a patient with a 4 cm lung mass and mediastinal adenopathy on CT, a mediastinal node biopsy may provide a diagnosis and confirm N2 (IIIA) disease (image 1 and picture 1). In contrast, a transthoracic needle aspirate of the mass may provide a tissue diagnosis but does not stage the mediastinum. This can lead to the inappropriate assumption that mediastinal lymph nodes are involved or necessitate a second procedure. (See "Tumor, Node, Metastasis (TNM) staging system for lung cancer".)

NSCLC — Rapid advances in understanding the molecular pathogenesis of NSCLC have demonstrated that NSCLC is a heterogeneous group of diseases. Although the initial treatment of localized disease is the same, the molecular characterization of tumor tissue in patients with NSCLC serves as a guide to treatment both in those who present with metastatic disease and in those who relapse after primary therapy. (See "Personalized, genotype-directed therapy for advanced non-small cell lung cancer".)

Currently defined NSCLC subsets for which specific targeted therapies have been standard therapy include those with mutations in the epidermal growth factor receptor (EGFR), those with the EML4-ALK fusion oncogene, and ROS1 fusions. Other driver mutations, such as BRAF, have also been identified and specific treatments are being developed. (See "Personalized, genotype-directed therapy for advanced non-small cell lung cancer" and "Systemic therapy for advanced non-small cell lung cancer with an activating mutation in the epidermal growth factor receptor" and "Anaplastic lymphoma kinase (ALK) fusion oncogene positive non-small cell lung cancer".)

For those without driver mutations, in whom a high level of programmed death ligand 1 (PD-L1) expression is observed (staining on least 50 percent of tumor cells, regardless of intensity), immunotherapy is available as first-line treatment. (See "Immunotherapy of non-small cell lung cancer with immune checkpoint inhibition", section on 'First-line setting'.)

Treatment — Surgical resection offers the best opportunity for long-term survival and cure in patients with resectable NSCLC (algorithm 1). The appropriateness of surgical resection of candidates with known or suspected NSCLC includes preoperative staging and an assessment of performance status with concurrent comorbidities and pulmonary function to allow prediction of postoperative function.

A patient with lung cancer may be “resectable” by virtue of having a surgically removable NSCLC, but may not be "operable" due to poor pulmonary function or comorbidities. Advances in surgical technique, the role of limited resection, and postoperative care may provide the opportunity for surgical resection in patients who previously might not have been considered candidates for aggressive treatment. (See "Preoperative evaluation for lung resection".)

  • Patients with stage I or II NSCLC should be treated with complete surgical resection whenever possible (picture 2). Postoperative adjuvant chemotherapy improves survival in patients with pathologic stage II disease and may have a role for patients with stage IB disease. (See "Management of stage I and stage II non-small cell lung cancer" and "Adjuvant systemic therapy in resectable non-small cell lung cancer".)
  • Patients with stage I or II disease who are not candidates for surgical resection or who refuse surgery may be candidates for nonsurgical local therapy. Radiation may be applied by stereotactic techniques or conventional methods. Radiofrequency ablation (RFA) and cryoablation are alternatives to radiation. Photodynamic therapy may also be useful as a primary treatment modality in carefully selected patients with superficial airway lesions (picture 2). (See "Management of stage I and stage II non-small cell lung cancer", section on 'Nonsurgical candidates' and "Endobronchial photodynamic therapy in the management of airway disease in adults".)
  • For patients with pathologically proven stage III disease prior to definitive therapy, a combined modality approach using concurrent chemoradiotherapy is generally preferred. The role of surgery following chemoradiotherapy is an area of active investigation. Surgery may also retain a role for carefully selected patients with T3 or T4 lesions and negative mediastinal lymph nodes. (See "Management of stage III non-small cell lung cancer".)
  • In patients with clinical stage I or II disease, in whom tumor involvement of mediastinal lymph nodes (pathologic stage IIIA) is documented in the histologic evaluation of the surgical resection specimen, adjuvant chemotherapy has been shown to improve survival. (See "Adjuvant systemic therapy in resectable non-small cell lung cancer".)
  • Patients with stage IV disease are generally treated with systemic therapy or a symptom-based palliative approach. In appropriately selected patients, chemotherapy, molecularly targeted therapy, and/or immunotherapy may prolong survival without sacrificing quality of life. Therapy in this situation should be guided by the mutation status of the tumor whenever possible. RT and surgery may also be useful for symptom palliation in some patients. (See "Overview of the treatment of advanced non-small cell lung cancer" and "Personalized, genotype-directed therapy for advanced non-small cell lung cancer" and "Immunotherapy of non-small cell lung cancer with immune checkpoint inhibition".)
  • Patients with stage IV disease based upon the presence of an isolated metastasis (eg, brain, adrenal) may benefit from resection of the metastasis as well as aggressive treatment of the primary tumor [7]. (See "Overview of the treatment of brain metastases".)
  • Local palliative measures may be useful in patients with uncontrolled pulmonary disease [8]. Dyspnea due to bulky central airway involvement may be palliated by rigid or flexible bronchoscopic removal of tumor using laser for coagulation or cryotherapy. Stenting may be necessary to maintain airway patency and allow external beam radiation. Brachytherapy can be applied locally by a bronchoscopy-directed catheter placement and may be helpful for recurrent or persistent disease in the airway. This approach is usually pursued after maximal external beam radiation. (See "Clinical presentation, diagnostic evaluation, and management of central airway obstruction in adults".)

Prognosis of NSCLC

Stage of disease — The TNM stage at presentation in patients with NSCLC is the factor that has the greatest impact on prognosis. (See "Tumor, Node, Metastasis (TNM) staging system for lung cancer".)

Survival decreases progressively with more advanced disease, according to both the previous and the eighth edition staging systems (figure 1 and figure 2). (See "Overview of the initial evaluation, diagnosis, and staging of patients with suspected lung cancer" and "Tumor, Node, Metastasis (TNM) staging system for lung cancer".)

Clinical parameters — Other clinical factors that exist at the time of diagnosis that can predict survival independent of the disease stage. Most of these factors were identified in studies that primarily included patients with advanced or inoperable NSCLC:

  • Performance status – Poor performance status and weight loss have been associated with shortened survival [9-14]. Reduced appetite, a precursor of weight loss, also has negative prognostic implications [9].
  • Ethnicity – African American ethnicity does not appear to be an independent predictor of poorer survival. Although some studies suggested that African Americans have a worse prognosis even after correcting for stage and treatment, a multivariate analysis indicated that performance status and weight loss account for these results [10].

Histopathology — Studies of patients with NSCLC have given conflicting results as to whether the distinction between adenocarcinoma and squamous cell carcinoma affects prognosis [15-19]. Other pathologic factors that have been linked to prognosis in some studies include the degree of differentiation [20,21], lymphatic invasion [22-25], occult lymph node metastases [26], and intense tumor lymphocytic infiltration [27]. (See "Pathology of lung malignancies".)

Each histologic subtype can vary in its degree of differentiation. The impact of tumor differentiation on resectable NSCLC is uncertain. Some studies indicate that poorly differentiated tumors have a worse prognosis than better differentiated tumors [20,21]. However, this finding has not been universal [17].

Lymphatic vessel invasion has a negative impact on outcome [22-24,28]. In one study of 244 patients who had resected stage I NSCLC, five-year cancer-free survival was higher among patients without lymphatic vessel invasion (74 versus 54 percent) [23]. The presence of microscopic vascular invasion (MVI) also has a negative impact on survival in patients with resected T1/T2 N0 lesions [29,30]. The importance of this finding was illustrated by a single institution series of 746 patients, in which MVI was present in 257 (34 percent) [29]. On multivariate analysis, the five-year survival rate was significantly increased in those without MVI (65 versus 55 percent).

Occult lymph node metastasis can be detected by immunohistochemistry, and one large study has correlated the presence of such micrometastases with a poorer long-term outcome in patients with stage I disease [26] (see "Adjuvant systemic therapy in resectable non-small cell lung cancer"). The reverse transcriptase polymerase chain reaction (RT-PCR) has also been used to detect tumor markers in lymph nodes from patients with NSCLC [31]. However, such studies are limited by lack of laboratory standardization and reproducibility, although the clinical significance of this finding based upon RT-PCR will remain uncertain until long-term studies are reported.

In a study including almost 1000 patients with resected NSCLC treated with platinum-based adjuvant chemotherapy, intense lymphocytic infiltration was observed in 6 percent of tumors and was associated with improved overall survival (hazard ratio [HR] 0.45, 95% CI 0.23-0.85) and disease-free survival (HR 0.44, 95% CI 0.24-0.78) at a median follow-up of six years [27].

Molecular characterization — Contemporary studies have identified various molecular abnormalities that allow the characterization of particular subsets of patients with NSCLC. This subclassification has important implications for personalizing patient care and may define patient categories with differing prognoses. (See "Personalized, genotype-directed therapy for advanced non-small cell lung cancer".)

Specific targeted therapies are widely used for patients with advanced disease with specific molecular features:

  • Activating mutations in the epidermal growth factor receptor (EGFR) define a subset of patients with adenocarcinoma that more frequently affect patients who are never smokers, women, and/or of Asian ethnicity. These patients are generally highly responsive to EGFR tyrosine kinase inhibitors (erlotinib, gefitinib, afatinib) and have a significantly better prognosis than those without EGFR mutations [32]. (See "Systemic therapy for advanced non-small cell lung cancer with an activating mutation in the epidermal growth factor receptor".)
  • The presence of the ROS1 or EML4-anaplastic lymphoma kinase (ALK) fusion oncogene defines other NSCLC subsets that are more frequent in nonsmokers or former smokers and occurs at a younger age. These patients are highly responsive to crizotinib, an inhibitor of the ALK. (See "Anaplastic lymphoma kinase (ALK) fusion oncogene positive non-small cell lung cancer".)
  • Other less frequent driver mutations in non-small cell lung cancer have been identified, including BRAF, HER2, β-catenin, DDR2, and MEK1. Their potential role in therapy is being defined. Multiplexed and whole genome testing may identify presence of these potential targets. Improved results from therapy targeted to the molecular abnormality are propelling the development of highly specific treatment.
  • Expression of tumor PD-L1 predicts response to certain immunotherapies and can guide choice of treatment in both the first-line and subsequent-line treatment settings. (See "Immunotherapy of non-small cell lung cancer with immune checkpoint inhibition", section on 'Antibodies to PD-1 and PD-L1'.)

PET and PET-CT — Positron emission tomography (PET), alone or integrated with computed tomography (CT), is useful in the initial staging to identify sites of tumor involvement. Integrated PET-CT has been shown to improve staging over PET scanning alone [33]. (See "Imaging of lung cancer", section on 'Positron emission tomography'.)

A tumor's metabolic activity can be measured using the standardized uptake value (SUV) to assess the tumor uptake of fluorodeoxyglucose (FDG). A meta-analysis, based upon 21 retrospective studies that included 2637 patients with stages I to IV NSCLC, found that a high SUV was associated with a poor prognosis [34]. Subsequent multivariate analysis including 1500 patients suggested that SUV was an independent prognostic feature in patients with stage I to III disease, although not for patients with stage IV disease [35]. A second independent meta-analysis, limited to patients with stage I NSCLC, also found that a lower FDG uptake was associated with a better prognosis [36]. PET (or PET-CT) may also be useful in predicting response to chemotherapy [37-39].

Additional studies are needed to establish the role of SUV as a prognostic tool or in predicting the response to treatment.

Recurrence after complete resection — Patients who undergo a complete resection for NSCLC may develop recurrent and/or metastatic disease. Multiple factors influence survival following disease recurrence.

In a series of 1073 patients who underwent a complete resection, recurrent NSCLC was identified in 445 patients (41 percent) [40]. The median time to recurrence following surgery was 11.5 months, and the median survival following recurrence was 8.1 months. Multivariate analysis identified several factors that predicted shorter survival following recurrence. These included poor performance status, disease-free interval of one year or less, prior use of neoadjuvant chemotherapy or adjuvant RT, and distant metastases (as opposed to intrathoracic recurrence alone).

SCLC

Treatment — SCLC is a disseminated disease in most patients at presentation and is very responsive to chemotherapy. Thus systemic chemotherapy is an integral part of the initial treatment.

  • Patients with limited stage disease are primarily treated with a combination of chemotherapy and radiation therapy, since the addition of radiation therapy has been shown to prolong survival compared with chemotherapy therapy alone (See "Limited stage small cell lung cancer: Initial management" and "Extensive stage small cell lung cancer: Initial management".)
  • Surgery is not used except in the rare patient who presents with a solitary pulmonary nodule without distant metastases or regional lymph node involvement. (See "Role of surgery in multimodality therapy for small cell lung cancer".)
  • Prophylactic cranial irradiation decreases the incidence of brain metastases and prolongs survival in patients with limited stage SCLC who respond to their initial treatment. (See "Prophylactic cranial irradiation for patients with small cell lung cancer".)
  • For patients with extensive stage SCLC, chemotherapy alone is used as the initial therapy (algorithm 2). Radiation therapy, including both prophylactic cranial irradiation and thoracic RT, may be beneficial in patients with a complete or partial response to their initial chemotherapy. (See "Extensive stage small cell lung cancer: Initial management".)

Prognosis — The most important prognostic factor in patients with SCLC is the extent of disease (stage) at presentation. For patients with limited stage disease, median survivals range from 15 to 20 months, and the reported five-year survival rate is 10 to 13 percent. By contrast, for patients with extensive-stage disease, the median survival is 8 to 13 months, and the five-year survival rate is 1 to 2 percent. (See "Extensive stage small cell lung cancer: Initial management", section on 'Extensive stage disease'.)

Clinical parameters also have prognostic importance in patients with SCLC [14]. Poor performance status and/or weight loss have been associated with shortened survival.

SIDE EFFECTS OF TREATMENT — Both curative and palliative treatment of lung cancer often involves multimodality approaches that may include surgery, RT, and systemic therapy using cytotoxic chemotherapy or molecularly targeted agents.

The side effects of systemic therapy are often of particular concern, because of their potential negative effects on quality of life both during and after treatment. Toxicities will vary depending upon the therapeutic regimen.

Common toxicities observed in patients being treated for lung cancer include the following:

  • Chemotherapy-induced nausea and vomiting of variable severity may be seen with most chemotherapy regimens (table 4), but can usually be prevented or managed effectively with aggressive therapy. (See "Pathophysiology and prediction of chemotherapy-induced nausea and vomiting" and "Prevention and treatment of chemotherapy-induced nausea and vomiting in adults".)
  • Hematologic toxicity, including in particular anemia and neutropenia with an increased risk of infection, is seen with most cytotoxic chemotherapy regimens. (See "Risk assessment of adults with chemotherapy-induced neutropenia" and "Hematologic complications of malignancy: Anemia and bleeding".)
  • Nephrotoxicity, especially with chemotherapy regimens containing cisplatin, can be severe. Intensive hydration is required to prevent this complication. (See "Cisplatin nephrotoxicity".)
  • Neurotoxicity, which is especially frequent with cisplatin and the taxanes (paclitaxel, docetaxel), is usually at least partially reversible after therapy is discontinued. (See "Overview of neurologic complications of non-platinum cancer chemotherapy" and "Overview of neurologic complications of platinum-based chemotherapy".)
  • Fatigue is frequent and may be due to systemic chemotherapy, radiation therapy, or the cancer itself. (See "Cancer-related fatigue: Prevalence, screening and clinical assessment".)
  • Cutaneous toxicity, manifested as an acneiform rash, is frequent with erlotinib and gefitinib. Although this side effect is troublesome, the presence of a rash is correlated with a response to therapy.
  • Treatment with crizotinib is usually well tolerated; visual disturbances (photophobia, flashes of light, decreased visual acuity, blurred vision) are the most common side effects. (See "Anaplastic lymphoma kinase (ALK) fusion oncogene positive non-small cell lung cancer", section on 'Toxicity'.)
  • Anorexia and weight loss are common in patients with lung cancer, and may be due to the disease or its treatment. (See "Pathogenesis, clinical features, and assessment of cancer cachexia" and "Pharmacologic management of cancer anorexia/cachexia".)

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.)

  • Basics topics (see "Patient education: Lung cancer (The Basics)")
  • Beyond the Basics topics (see "Patient education: Lung cancer risks, symptoms, and diagnosis (Beyond the Basics)")

SUMMARY — Lung cancer is the most common cause of cancer mortality worldwide for both men and women.

  • The initial stage in management is to confirm the diagnosis of a malignancy and to assess whether the patient has a non-small cell lung cancer (NSCLC) or a small cell lung cancer (SCLC), the stage of the disease, and the overall performance status of the patient. (See 'Initial evaluation' above.)
  • For patients with NSCLC, initial management is largely determined by the stage of disease (algorithm 1). For patients with early stage disease, surgical resection offers the best opportunity for cure, while concurrent chemoradiotherapy is preferred for those with more extensive intrathoracic disease. In contrast, patients with advanced disease are managed palliatively with systemic therapy and/or local palliative modalities. (See 'NSCLC' above.)
  • For patients with SCLC, systemic chemotherapy is an important component of treatment, because SCLC is disseminated at presentation in almost all patients (algorithm 2). For those with limited stage disease, thoracic radiation therapy is used in combination with chemotherapy. Prophylactic cranial irradiation is often used to decrease the incidence of brain metastases and prolong survival. Prophylactic cranial irradiation and thoracic radiation may also be beneficial in those with a complete or partial response to initial systemic chemotherapy. (See 'SCLC' above.)
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