Overview of the initial treatment and prognosis of lung cancer

INTRODUCTION — Worldwide, lung cancer caused an estimated 1.8 million deaths in 2020 [1]. In the United States, there are approximately 240,000 new cases of lung cancer and 130,000 deaths annually. However, survival after diagnosis has been improving, likely due to screening and treatment advances (eg, targeted therapy and immunotherapy) [2].

Around 1953, lung cancer became the most common cause of cancer deaths in men. In 1985 it became the leading cause of cancer deaths in women, and now causes approximately 50 percent more deaths than breast cancer [3]. There is good news that lung cancer deaths are declining in males and females, largely due to decreases in smoking. Now, however, an equal number of new cases are occurring in women and men, and nearly one-half of all lung cancer deaths occur in women. (See "Females and lung cancer".)

The term lung cancer, or bronchogenic carcinoma, refers to malignancies that originate in the airways or pulmonary parenchyma. Approximately 95 percent of all lung cancers are classified as either small cell lung cancer (SCLC) or non-small cell lung cancer (NSCLC) based upon histologic examination. Given marked differences in biologic behavior, natural history, and response to treatment, this distinction is required for proper staging, treatment, and prognosis. Other cell types comprise about 5 percent of malignancies arising in the lung. (See "Pathology of lung malignancies".)

This discussion will present an overview of the initial treatment, and prognosis of patients with both NSCLC and SCLC. An overview of the risk factors, pathology, and clinical manifestations of lung cancer is presented separately, as is an overview of the management of patients with advanced NSCLC, and a discussion of issues concerning lung cancer survivors. (See "Clinical manifestations of lung cancer" and "Overview of the initial treatment of advanced non-small cell lung cancer" and "Overview of approach to lung cancer survivors".)

IMPACT OF PATHOLOGY ON TREATMENT SELECTION

●Until more recently, the simple pathologic separation of NSCLC from SCLC along with stage was adequate to make treatment decisions for a new diagnosis of lung cancer. (See "Extensive-stage small cell lung cancer: Initial management" and "Limited-stage small cell lung cancer: Initial management" and "Overview of the initial treatment of advanced non-small cell lung cancer".)

●Since 2008, it has been shown that separation of adenocarcinoma and squamous cell carcinoma is important in determining optimal chemotherapy for stage IV NSCLC. (See "Subsequent line therapy in non-small cell lung cancer lacking a driver mutation".)

●Genotype subtype analysis in NSCLC and the development of targeted therapy for specific gene mutations has resulted in individually tailored therapy. Targeted treatment results in responses that are better than are achieved with standard chemotherapy for certain subtypes of NSCLC including those with epidermal growth factor receptor (EGFR), anaplastic lymphoma kinase (ALK), and c-ROS oncogene 1 (ROS1) mutations, and others [4]. Using multiplexed assays, one group identified driver mutations in over 60 percent of more than 700 patients with adenocarcinomas [5]. (See "Personalized, genotype-directed therapy for advanced non-small cell lung cancer".)

●Expression of programmed cell death ligand 1 in NSCLC influences whether checkpoint inhibitors are used, either alone or in combination with chemotherapy. (See "Initial management of advanced non-small cell lung cancer lacking a driver mutation".)

Tailored treatment based on mutation testing and immune inhibition has implications at the initial evaluation of suspected lung cancer because diagnostic sampling needs to be adequate for each type of testing in advanced-stage adenocarcinoma. Over 90 percent of samples from endobronchial ultrasound-guided needle aspirates, transthoracic needle aspirates, and pleural fluid cytology specimens showing adenocarcinoma are adequate for mutation analysis; however, adequacy rates are lower from bone biopsy aspirates that require decalcification [6,7]. (See "Personalized, genotype-directed therapy for advanced non-small cell lung cancer", section on 'Molecular testing'.)

NSCLC — Rapid advances in understanding the molecular pathogenesis of NSCLC have demonstrated that NSCLC is a heterogeneous group of diseases. The molecular characterization of tumor tissue in patients with NSCLC serves as a guide to treatment in the adjuvant setting, as well as 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) as well as B-Raf proto-oncogene (BRAF), those with the echinoderm microtubule-associated protein-like 4 (EML4)-anaplastic lymphoma kinase (ALK) fusion oncogene, and c-ROS oncogene 1 (ROS1) fusions. Other driver mutations have also been identified and specific targeted 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 cell 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. For those with lower PD-L1 expression, combinations of chemotherapy and immunotherapy are available. (See "Initial management of advanced non-small cell lung cancer lacking a driver mutation", section on 'Factors in choosing initial therapy' and "Initial management of advanced non-small cell lung cancer lacking a driver mutation", section on 'PD-L1 low (<50 percent) or unselected tumors'.)

Treatment — Surgical resection offers the best opportunity for long-term survival and cure in patients with resectable NSCLC. The appropriateness of surgical resection for 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. (See "Overview of the initial evaluation, diagnosis, and staging of patients with suspected lung cancer".)

A patient with lung cancer may be potentially "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. Preoperative exercise for patients undergoing surgery for lung cancer may reduce length of hospital stay and postoperative complications [8]. Preoperative evaluation is discussed elsewhere. (See "Preoperative physiologic pulmonary evaluation for lung resection".)

●Patients with stage I or II NSCLC should be treated with complete surgical resection whenever possible (picture 1). (See "Management of stage I and stage II 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 (RT) may be applied by stereotactic techniques or conventional methods (image 1). Radiofrequency ablation (RFA) and cryoablation are alternatives to RT. Photodynamic therapy may also be useful as a primary treatment modality in carefully selected patients with superficial airway lesions (picture 1). (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, with immunotherapy, subsequently, if there has been no progression. 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".)

●Postoperative adjuvant chemotherapy improves survival in patients with pathologic stage II to IIIA disease and may have a role for patients with stage IB disease. The use of adjuvant osimertinib in patients with EGFR-mutant NSCLC is discussed elsewhere. (See "Management of stage I and stage II non-small cell lung cancer" and "Systemic therapy in resectable non-small cell lung cancer" and "Systemic therapy in resectable non-small cell lung cancer", section on 'EGFR-mutated cancers'.)

●Atezolizumab is approved by the US Food and Drug administration (FDA) as adjuvant treatment following resection and platinum-based chemotherapy for adult patients with stage II to IIIA NSCLC whose tumors have PD-L1 expression on ≥1 percent of tumor cells, as determined by an FDA-approved test. (See "Systemic therapy in resectable non-small cell lung cancer", section on 'Adjuvant immunotherapy'.)

●Patients with stage IV disease are generally treated with palliative systemic therapy, immunotherapy, 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. There are a small percentage of patients that do achieve long-term survival with treatment. 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 initial treatment of advanced non-small cell lung cancer" and "Personalized, genotype-directed therapy for advanced non-small cell lung cancer" and "Initial management of advanced non-small cell lung cancer lacking a driver mutation".)

●Patients with stage IV disease based upon the presence of an isolated metastasis (eg, brain, adrenal gland) may benefit from RT or resection of the metastasis as well as aggressive treatment of the primary tumor [9]. (See "Overview of the treatment of brain metastases".)

●Local palliative measures may be useful in patients with uncontrolled pulmonary disease [10]. 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 RT (EBRT). 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 EBRT (see "Clinical presentation, diagnostic evaluation, and management of malignant central airway obstruction in adults").

Patients with recurrent, symptomatic malignant pleural effusions may benefit from placement of a tunneled pleural catheter for self-controlled drainage (image 2) [11]. (See "Management of malignant pleural effusions".)

Prognosis of NSCLC

Stage of disease — The tumor, node, metastasis (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 [12-17]. Reduced appetite, a precursor of weight loss, also has negative prognostic implications [12].

●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 [13].

Other clinical factors that have been prognostically significant on both univariate and multivariate analyses include age, performance status, and smoking cessation [18].

Histopathology — Studies of patients with NSCLC have given conflicting results as to whether the distinction between adenocarcinoma and squamous cell carcinoma affects prognosis [19-23]. Other pathologic factors that have been linked to prognosis in some studies include the degree of differentiation [24,25], lymphatic invasion [26-29], occult lymph node metastases [30], and intense tumor lymphocytic infiltration [31]. (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 [24,25]. However, this finding has not been universal [21].

Lymphatic vessel invasion has a negative impact on outcome [26-28,32]. 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) [27]. The presence of microscopic vascular invasion (MVI) also has a negative impact on survival in patients with resected T1/T2 N0 lesions [33,34]. The importance of this finding was illustrated by a single institution series of 746 patients, in which MVI was present in 257 (34 percent) [33]. 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 [30] (see "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 [35]. 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 [31].

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 treatment and may also 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 EGFR define a subset of patients with adenocarcinoma that more frequently affect patients who are never smokers, women, and/or people from East Asia. These patients are generally highly responsive to EGFR tyrosine kinase inhibitors (osimertinib, erlotinib, gefitinib, afatinib) and have a significantly better prognosis than those without EGFR mutations [36]. (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-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 inhibitors of 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, human epidermal growth factor receptor 2 (HER2), neurotrophic receptor tyrosine kinase (NTRK), MET, and RET. Multiplexed and whole genome testing may identify presence of these potential targets. Targeted therapies for such genotypes are discussed elsewhere. (See "Personalized, genotype-directed therapy for advanced non-small cell lung cancer".)

●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 "Initial management of advanced non-small cell lung cancer lacking a driver mutation", section on 'Factors in choosing initial therapy'.)

PET and PET-CT — Fluorodeoxyglucose positron emission tomography (FDG-PET), alone or integrated with computed tomography (PET/CT), is useful in the initial staging to identify sites of tumor involvement. Integrated PET/CT has been shown to improve staging accuracy over FDG-PET alone [37].

A tumor's metabolic activity can be measured using the standardized uptake value (SUV) to assess the tumor uptake of 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 [38]. 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 [39]. 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 [40]. PET (or PET-CT) may also be useful in predicting response to chemotherapy [41-43].

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) [44]. 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).

Patients who recur with tumors that have certain targetable driver mutations may have prolonged survival in some circumstances. (See "Anaplastic lymphoma kinase (ALK) fusion oncogene positive non-small cell lung cancer" and "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".)

SCLC

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

●Limited-stage-SCLC is defined as disease that is limited to the ipsilateral hemithorax and regional lymph nodes and can be encompassed in a safe radiotherapy field. Patients with limited-stage disease are primarily treated with a combination of chemotherapy and radiation therapy (RT), since the addition of RT 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 "Limited-stage small cell lung cancer: Initial management", section on 'Surgery'.)

•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 (anything beyond limited stage), chemotherapy is used as the initial therapy, typically with immunotherapy. RT, 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 30 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 'Overview of treatment of extensive-stage disease'.)

Clinical parameters also have prognostic importance in patients with SCLC [17]. 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 1), but can usually be prevented or managed effectively with aggressive therapy. (See "Pathophysiology and prediction of chemotherapy-induced nausea and vomiting" and "Prevention 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 "Causes of anemia in patients with cancer".)

●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 conventional 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".)

●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 "Management of cancer anorexia/cachexia".)

SOCIETY GUIDELINE LINKS — Links to society and government-sponsored guidelines from selected countries and regions around the world are provided separately. (See "Society guideline links: Diagnosis and management of lung cancer" and "Society guideline links: Hemoptysis".)

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 5^th to 6^th 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 10^th to 12^th 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 males and females.

●Non-small cell lung cancer (NSCLC) – For patients with NSCLC, initial management is largely determined by the stage of disease. 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. By contrast, patients with advanced disease are managed palliatively with systemic therapy and/or local palliative modalities. (See 'NSCLC' above.)

●Small cell lung cancer (SCLC) – For patients with extensive-stage SCLC, systemic chemotherapy and immunotherapy are important components of treatment, because SCLC is disseminated at presentation in almost all patients. However, 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 potentially 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.)