Pharmacotherapy A Pathophysiologic Approach, 9th Ed.

106. Lung Cancer

Val R. Adams and Susanne M. Arnold


KEY CONCEPTS

 Images Lung cancer is the leading cause of cancer deaths in both men and women in the United States. The overall 5-year survival rate for all types of lung cancer is about 15%.

 Images Cigarette smoking is responsible for most lung cancers. Smoking cessation should be encouraged, particularly in those receiving curative treatment (i.e., stages I to IIIA non–small cell lung cancer [NSCLC] and limited-stage small cell lung cancer [SCLC]).

 Images NSCLC is diagnosed in most (∼80%) lung cancer patients. NSCLC typically has a slower growth rate and doubling time than SCLC.

 Images Screening test is currently recommended to identify lung cancer in high-risk individuals. However, several studies are evaluating the optimal frequency and duration, as well as the impact of false-positive tests.

 Images Treatment decisions are guided by the stage of disease, which is characterized by tumor size and spread. Patient-specific factors (i.e., performance status, comorbid conditions, etc.) must also be considered when developing a treatment plan.

 Images The treatment goals in lung cancer are cure (early stage disease), prolongation of survival, and maintenance or improvement of quality of life through alleviation of symptoms.

 Images Early stage lung cancer has the highest cure rates when surgical resection of the tumor is used with or without chemotherapy for NSCLC and chemoradiotherapy for SCLC.

 Images Advanced-stage lung cancer is primarily treated with systemic therapy. Doublet chemotherapy regimens are superior in response to single-agent regimens and should be used when the patient can tolerate the associated toxicity. Platinum-containing doublets are first-line treatment in most cases of NSCLC and SCLC.

 Images Optimal patient care needs to include prevention and treatment of adverse events from chemotherapy. Adverse events may cause delays in chemotherapy administration, increase morbidity, and contribute to treatment failure.


Lung cancer is a major cause of morbidity and mortality. It has reached epidemic proportions in many industrialized countries and is the most frequently fatal malignancy in the world. It is estimated that 228,190 new cases of lung cancer were diagnosed in the United States in 2013.1 Despite major advances in the understanding and management of lung cancer, the overall 5-year survival rate for all types of lung cancer remains a dismal 16%. In the United States, lung cancer accounts for about 14% of all newly diagnosed cancer in adults.1 Images It remains the leading cause of cancer death in both adult men and women, with about 159,480 deaths in 2013.1 The incidence and death rate caused by lung cancer are declining, which has been attributed to decreased tobacco use over the last 50 years. In comparison to whites, the incidence and mortality of lung cancer is greater in African American men and slightly lower in African American women.1

The incidence of lung cancer increases with age, with about two thirds of cases diagnosed between 60 and 79 years.1 Early lung cancer screening studies failed to demonstrate a survival advantage, but in November 2010, the largest trial of its kind, the National Lung Screening Trial, demonstrated a 20% reduction in the relative risk of death from lung cancer in moderate- to high-risk individuals (95% confidence interval [CI], 6.8 to 26.7; P = 0.004). Among subjects enrolled in lung cancer screening trials, the rate of malignancy in the pulmonary nodule detected on low-dose chest computed tomography (CT) scan is low, and surgical procedures are not without risk. Consequently, patients who receive scans as part of lung cancer screening or for another purpose should have other criteria or tests done before considering a biopsy to evaluate for malignant pathology.2

Patients with lung cancer may undergo surgery, chemotherapy, radiation, or multimodality therapy, depending on the histologic type of the tumor, its size and location, and the presence of metastases at diagnosis.3 Two leading oncology groups representing leading clinicians in the United States have published clinical practice guidelines for the treatment of lung cancer. The National Comprehensive Cancer Network (NCCN) has developed consensus-based guidelines that provide recommendations regarding the screening, staging, and treatment of both small cell lung cancer (SCLC) and non–small cell lung cancer (NSCLC).4,5 The American Society of Clinical Oncology (ASCO) first published evidence-based guidelines regarding the staging and treatment of NSCLC in 1997, which were subsequently updated in 2003; the stage IV NSCLC guideline was updated in 2011.6

ETIOLOGY

Lung carcinomas arise from normal bronchial epithelial cells that have acquired multiple genetic lesions and are capable of expressing a variety of phenotypes.2 Significant advances have been made recently in understanding the molecular genetic changes involved in lung cancer pathogenesis.3 A large variety of molecular lesions result in abrogation of key cellular regulatory and growth control pathways. Activation of a proto-oncogene, inhibition or mutation of tumor suppressor genes, and production of autocrine (self-stimulatory) growth factors contribute to cellular proliferation and malignant transformation.3 Many of these molecular alterations are common to both SCLC and NSCLC, but certain mutations are found more frequently in specific subtypes of lung cancer and offer more targeted interventions to prevent or treat lung cancer. In autocrine loop abnormalities, SCLC frequently overexpresses C-KIT (a protein tyrosine kinase receptor that is specific for stem cell factor [aka, CD117]), whereas NSCLC frequently overexpresses epidermal growth factor receptor (EGFR).7 EGFR inhibitors, such as erlotinib, are used clinically to treat NSCLC and offer a potential method of lung cancer chemoprevention. Crizotinib, a drug that targets the EML4-ALK gene rearrangement protein, demonstrates the importance of this pathway in a subset of adenocarcinoma lung cancer patients.8

Images Smoking is a major cause of lung cancer, with about 80% of lung cancer deaths in the United States directly attributed to tobacco use. Tobacco smoke contains many substances, including tumor promoters, carcinogens, and cocarcinogens,1,7 which are proven carcinogens. The association between environmental tobacco smoke (ETS; also referred to as passive smoking) and lung cancer risk in nonsmokers is not as clear. Most studies have consistently found that spouses of smokers have higher rates of lung cancer than spouses of nonsmokers (about 25% higher risk). In addition, workplace exposure to environmental smoke increases the risk of lung cancer by about 17%. It is currently estimated that ETS contributes to about 3,000 lung cancers annually. Although many of these studies have methodologic flaws, the data seem consistent and seem to indicate a dose–risk relationship, with no safe level of exposure.9 Smoking cessation is associated with a gradual decrease in the risk, but more than 5 years is necessary before an appreciable decline in risk occurs,1,7 and the risk never returns to that of a nonsmoker. Because of the public health implications, the United States has several, mainly state-led, tobacco control efforts, including antismoking campaigns, increased tobacco taxes, and smoke-free areas in many public areas. Although the prevalence of cigarette smoking has slowly decreased, it remains at about 19% in 2010 and 2011.10

Although most cases of lung cancer are attributable to cigarette smoking, less than 20% of smokers develop lung cancer, which suggests that other risk factors are relevant. An increased risk of lung cancer has been associated with exposure to other environmental respiratory carcinogens (e.g., asbestos, benzene, and arsenic). Genetic risk factors are also important, with an increased risk of lung cancer observed in those with first-degree relatives diagnosed with the disease. Lung cancer risk is associated with polymorphisms that affect the expression and/or function of enzymes regulating metabolism of tobacco carcinogens, DNA repair, or inflammation. Patients with a history of chronic obstructive airway disease and adults with asthma are at an increased risk for lung cancer.1,7,9 Further studies to better identify which patients are at highest risk of developing lung cancer will be key for new lung cancer screening trials and in chemoprevention trials.

HISTOLOGIC CLASSIFICATION

Before treatment begins, it is critical that an experienced lung cancer pathologist reviews the pathologic material because of the different treatment regimens for NSCLC and SCLC. Images NSCLC is diagnosed in most (80%) lung cancer patients. NSCLC typically has a slower growth rate and doubling time than SCLC. The histologic classification of NSCLC is well defined and widely accepted (Table 106-1).11 In the most recent classification, the histologic types, subtypes, and identifiable variants convey information about tumors’ natural behavior and in some cases influence therapeutic decisions.4,5,7,11

TABLE 106-1 Histologic Classification of Non-Small Cell Lung Carcinomas

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Four major cell types of carcinomas (squamous cell, adenocarcinoma, large cell, and small cell) account for more than 90% of all lung tumors. Early studies with localized disease demonstrated that radiation could cure small cell histology, while surgery did not. Studies with the other histologic types demonstrated better outcomes with surgery than with radiation; hence, the general classification of SCLC and NSCLC was created. Historically, systemic treatment for metastatic squamous cell, adenocarcinoma, and large cell carcinomas was the same and resulted in a similar overall prognosis, which again supported a general classification of SCLC and NSCLC. Trials over the last decade with newer agents have shown differences in efficacy and toxicity with regard to NSCLC histologic types and, consequently, knowledge concerning the histology is essential to optimize drug therapy.4,5,7

Squamous cell carcinoma was once the most common histology, but it now represents less than 30% of all lung cancers. Squamous cell carcinomas have a much higher incidence in smokers and among males and appear to have a strong dose–response relationship to tobacco exposure. Most of these tumors occur centrally, but the incidence of peripheral presentation is increasing. Studies describing the natural history of lung cancer in the era of screening with low-dose CT (LDCT) scans have revealed a relatively constant tumor volume doubling time (104 to 122 days), while the other histologies indicate that smaller tumors found with a CT scan are more indolent (e.g., doubling times three to four times longer with CT-discovered tumors).12 Squamous cell tumors are slower to metastasize, but they eventually spread to the hilar and mediastinal lymph nodes, liver, adrenal glands, kidneys, bone, and GI tract.3,11

Adenocarcinoma accounts for about one-half of lung cancers and is increasing in frequency. It is the most common histology in nonsmoking lung cancer patients. The natural history of adenocarcinoma in the lung shows that small tumors discovered with CT screening are relatively slow growing and the tumor doubling time increases as they get larger; volume doubling time of tumors discovered with CT screening is about 576 days, while those found with routine care double every 169 days.12 This information is most important when considering screening and the potential for lead time bias. Patients with adenocarcinoma can present with a single nodule, multifocal nodules, or rapidly progressing, bilateral, diffuse processes. This histology is likely to metastasize from a relatively small tumor (often before the diagnosis of the primary tumor) and spread widely to distant sites, including the contralateral lung, liver, bone, adrenal glands, kidneys, and CNS. As a result, adenocarcinoma has a worse prognosis than squamous cell carcinoma, but the prognosis is similar when controlled for stage.3,4

Table 106-1 shows several subclassifications and variants of adenocarcinoma. The importance of these subtypes to treatment is currently limited, but newer targeted therapies may work best in certain subtypes, thus allowing more individualized treatment selection. For example, erlotinib was approved because it was effective in NSCLC, but it appears more effective in adenocarcinoma, particularly those with a mutation in the EGFR. The 3% to 13% of NSCLC tumors that have an EML4-ALK rearrangement is almost exclusively adenocarcinoma, which is important to know for testing and if positive will impact therapy.4,13

Large cell carcinomas are undifferentiated epithelial tumors, which are often a diagnosis of exclusion. These tumors tend to be large and bulky tumors arising in the periphery of the lung, have a propensity to metastasize in a pattern quite similar to adenocarcinomas, and are associated with a similar poor prognosis.3,4

SCLCs account for about 15% of all lung tumors. Nearly all SCLCs are immunoreactive for keratin, epithelial membrane antigen, and thyroid transcription factor 1, and many stain positively for markers of neuroendocrine differentiation. They are distinguished by a proliferation of neoplastic cells with round to oval nuclei. These tumors occur in both the major bronchi and the periphery of the lung. SCLC is a very aggressive and rapidly growing tumor, with about 60% to 70% of patients initially presenting with disseminated disease outside of the hemithorax. These tumors commonly express neuroendocrine differentiation, which may account for some of the paraneoplastic syndromes frequently associated with this disease. SCLC secretes gastrin-releasing peptide that acts as an autocrine growth factor. Secretion of other peptide hormones, cytogenetic abnormalities, and amplification and increased expression of oncogenes are also common. This disease has a propensity to metastasize to the lymph nodes, opposite lung, liver, adrenal glands and other endocrine organs, bone, bone marrow, and CNS.3,5

Lung can exhibit more than one histologic cell type (e.g., adenosquamous), which may impact therapy. Patients can also occasionally have multiple lung nodules arising in different lobes or the contralateral lung. They can be the same or different histology. This is referred to as synchronous tumors, and the nodules may be of similar or different cell types. This usually worsens the patient’s overall prognosis.3

CLINICAL PRESENTATION

At the time of diagnosis, 15% of lung cancers are localized, 22% have regional spread, and 56% have distant metastases (the remaining were not staged).1 Location and extent of the tumor determine the presenting signs and symptoms. A lesion in the central portion of the bronchial tree is more likely to cause symptoms at an earlier stage as compared with a lesion in the periphery of the lung, which may remain asymptomatic until the lesion is large or has spread to other areas. The most common initial signs and symptoms include cough, dyspnea, and chest pain or discomfort, with or without hemoptysis.3Unfortunately, many patients with lung cancer also have chronic pulmonary and/or cardiovascular diseases (usually related to smoking), and such symptoms may go unnoticed or be attributed to the concomitant disease. Many patients also exhibit systemic symptoms of malignancy such as anorexia, weight loss, and fatigue. Disseminated disease can cause extrapulmonary signs and symptoms such as neurologic deficits resulting from CNS metastases, bone pain or pathological fractures secondary to bone metastases, or liver dysfunction resulting from tumor involvement in the liver.3


CLINICAL PRESENTATION Lung Cancer

Local Signs and Symptoms Associated with Primary Tumor or Regional Spread within the Thorax

    • Cough

    • Hemoptysis

    • Dyspnea

    • Rust-streaked or purulent sputum

    • Chest, shoulder, or arm pain

    • Wheeze and stridor

    • Superior vena cava obstruction

    • Pleural effusion or pneumonitis

    • Dysphagia (secondary to esophageal compression)

    • Hoarseness (secondary to laryngeal nerve paralysis)

    • Horner’s syndrome

    • Phrenic nerve paralysis

    • Pericardial effusion/tamponade

    • Tracheal obstruction

Extrapulmonary Signs and Symptoms Associated with Metastatic Involvement

    • Bone pain and/or pathologic fractures

    • Liver dysfunction

    • Neurologic deficits

    • Spinal cord compression

Paraneoplastic Syndromes

    • Weight loss

    • Cushing’s syndrome

    • Hypercalcemia (most commonly in squamous cell lung cancer)

    • Syndrome of inappropriate secretion of antidiuretic hormone (most commonly in SCLC)

    • Pulmonary hypertrophic osteoarthropathy

    • Clubbing

    • Anemia

    • Eaton-Lambert’s myasthenic syndrome

    • Hypercoagulable state

Paraneoplastic syndromes are signs and symptoms that occur at sites away from the primary tumor or its metastases and are not associated with direct tumor involvement. They may be caused by the production of biologically active substances (e.g., peptide hormones) or antibodies, or by other undefined mechanisms. Paraneoplastic syndromes occur more frequently with lung cancer than with any other tumor, and more frequently with SCLC than with NSCLC. These syndromes may be the first signs of a tumor and may prompt the search for an underlying malignancy.3

SCREENING AND PREVENTION

Images Most lung cancer patients are diagnosed with advanced disease, which is a key factor in the poor prognosis associated with this disease. Surgery (NSCLC) and radiation (SCLC) are the most effective treatment modalities, which generally limit curative intent to patients diagnosed at an early clinical stage.35 Therefore, it is important to diagnose lung cancer earlier, which implies a potential improvement with screening. Several screening techniques, including chest x-ray, CT, and positron emission tomography (PET), scanning have been investigated to detect lung cancer at an earlier stage. The mortality results from screening with a chest x-ray have been negative, but positive results for LDCT scans to screen for lung cancer have been reported. A recent systematic review of the potential benefit and harm from LDCT screening was reported with accompanying recommendations.14 The largest and only positive study was known as the National Lung Cancer Screening trial that enrolled more than 54,000 high-risk smokers. The study reported a decrease in overall (7% vs. 7.5%) and lung cancer–specific (1.3% vs. 1.7%) mortality with LDCT versus control, respectively. The resulting recommendation is to offer annual LDCT screening to individuals aged 55 to 74 years with a 30-pack-year history who are still smoking or have quit for less than 15 years. These recommendations come with a few caveats, including the fact that the most important step is for current smokers to quit. The optimal frequency and duration of screening is unknown and the harm from screening, including frequent false-positive findings, is unknown.14 Consequently, patients interested in screening should be enrolled in a clinical trial so answers to these important questions can be answered.

The term chemoprevention refers to the use of prophylactic medications to prevent the development of cancer. Many studies of potential chemopreventive agents, including nonsteroidal anti-inflammatory drugs (NSAIDs), retinoids, inhaled glucocorticoids, vitamin E, selenium, and green tea extracts, have been conducted, but none have been successful.15 Large randomized clinical trials have evaluated β-carotene as a lung cancer chemopreventive agent in high-risk patients (older smokers). Rather than prevent lung cancer, the trials clearly show that older people who smoke have a higher risk of developing and dying of lung cancer if they take a β-carotene supplement. Nonsmokers do not appear to have an altered risk of lung cancer with β-carotene consumption.16 The impact of selenium and/or vitamin E supplementation was evaluated in older men as part of a large prostate cancer prevention study (Selenium and Vitamin E Cancer Prevention Trial [SELECT]). Unfortunately, no benefit was seen with selenium or vitamin E supplementation.15,16

Because the net benefit of screening is still being defined and chemoprevention trials have not proven to provide a survival benefit, the current recommendation is to avoid smoking and maintain a healthy diet with high amounts of fruits and vegetables.17

DIAGNOSIS

A patient suspected of having lung cancer should undergo a diagnostic evaluation. Diagnosis of lung cancer requires both visualization of the cancerous lesion and tissue sampling for pathologic assessment. All patients must have a thorough history and physical examination with emphasis on detecting signs and symptoms of the primary tumor, regional spread of the tumor, distant metastases, and paraneoplastic syndromes. The patient’s performance status should be assessed to determine whether or not a patient may be able to tolerate surgery and/or chemotherapy.35

Visualization of the suspected tumor provides the clinician with the information necessary to choose the most appropriate sampling technique. Chest radiographs, endobronchial ultrasound, CT scans, and PET scans are among the most valuable diagnostic tests.18 Chest radiography is the primary method of lung cancer detection and may also be used to measure tumor size, establish gross lymph node enlargement, and detect other tumor-related findings, such as pleural effusion, lobar collapse, and metastatic bone involvement of ribs, spine, and shoulders. In addition, CT scans may be helpful in the evaluation of parenchymal lung abnormalities, detection of masses only suspected on the chest radiography, and assessment of mediastinal and hilar lymph nodes. PET scans are more accurate than CT scans in distinguishing malignant from benign lesions, detecting mediastinal lymph node metastases, and identifying metastatic spread. Most recently, the use of integrated CT-PET technology has been reported to improve the diagnostic accuracy in the staging of NSCLC over either CT or PET technology alone.19

Once the tumor has been located, pathologic examination of tumor tissue is necessary to establish the diagnosis of lung cancer. Tissue is typically obtained through the least invasive method likely to result in an adequate sample; methods include sputum cytology, tumor biopsy by bronchoscopy, mediastinoscopy, percutaneous needle biopsy, or open-lung biopsy. The tissue sample not only confirms malignancy but is also necessary to determine the histology (i.e., squamous cell, adenocarcinoma, large cell, or small cell) and to provide adequate tissue for molecular analysis. Once the diagnosis is established, additional radiologic tests may be required to evaluate lymph nodes and potential metastatic sites for accurate staging. Surgical candidates will have additional sampling of their mediastinal nodes to determine those with stage IIIB (N3) disease (Table 106-2).35,19

TABLE 106-2 Tumor (T), Node (N), Metastasis (M) Staging for Non–Small Cell Lung Cancer

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STAGING

Images Once the diagnosis of lung cancer is confirmed, the extent of disease must be determined to estimate prognosis and guide therapy. For NSCLC, tumor growth and spread are staged with the American Joint Committee on Cancer (AJCC) tumor, node, and metastasis (TNM) staging system. SCLC is typically staged with the Veterans Administration Lung Cancer Study Group method.35,19

Non–Small Cell Lung Cancer

Clinical staging of NSCLC with the TNM system evaluates the size of the tumor, extent of nodal involvement, and presence of metastatic sites. The TNM criteria have recently been updated,20 and went into effect in January 2010.4The combination of these three evaluations determines the stage. Clinical stages and associated survival rates are described in Table 106-2. For comparison of various therapeutic modalities, a simpler stage grouping system is used in which stage I refers to tumors confined to the lung without lymphatic spread, stage II refers to large tumors with ipsilateral peribronchial or hilar lymph node involvement, stage III includes other lymph node and regional involvement, and stage IV includes tumor with distant metastases. Local disease is associated with the highest cure and survival rates, whereas those with advanced disease have less than a 10% 5-year survival rate.

Small Cell Lung Cancer

The most commonly used system of staging SCLC was developed originally by the Veterans Administration Lung Cancer Study Group. This system categorizes SCLC into two stages: limited and extensive disease. When evidence of the tumor is confined to a single hemithorax and can be encompassed by a single radiation port, the disease is considered limited. Any progression beyond this point is extensive disease. About 60% to 70% of patients initially present with extensive-stage disease. The initial pretreatment evaluation of an SCLC patient should include a medical history, a clinical examination, and laboratory survey, as well as a CT scan of the chest, abdomen, and head. Typically the approach is to identify tumor spread that would demonstrate extensive stage, at which time the workup can stop. For patients without extrathoracic disease identified by these tests, a bone scan and bone marrow biopsy should be performed to confirm limited-stage disease.3,5

TREATMENT

Desired Outcomes

Images The desired outcomes of lung cancer treatment depend on tumor histology, stage of disease, and patient characteristics such as age, history, and performance status.3 These aspects must be assessed before appropriate treatment can be recommended. In the development of a patient care plan, keep in mind the ultimate goals of therapy. In patients with early stage disease that can tolerate aggressive treatment, a definitive cure is the desired outcome of treatment, although this end point is not always met. With advanced stage disease the desired outcomes of treating lung cancer patients who can tolerate aggressive therapy include prolongation of survival. Regardless of treatment based on survival, all therapies should ultimately improve quality of life through alleviation of symptoms. The goals of treatment must be considered when selecting a therapeutic plan. Delivering aggressive treatment that may prolong survival by a few months but includes a high potential for toxicity that could significantly decrease patient quality of life needs to be considered. Treatment decisions must include both the healthcare team and an informed and well-counseled patient.

Non-Small Cell Lung Cancer

If left untreated, patients with advanced NSCLC will die within 3 to 5 months and those with early stage disease found with routine care will die within 10 to 11 months.12 Surgery, radiation therapy, and systemic therapy with cytotoxic chemotherapy and/or targeted therapies are all used in the management of NSCLC patients. The applications of these treatment modalities are determined by stage and other patient-specific factors (e.g., age, performance status).3,4 Table 106-3 lists commonly used chemotherapy regimens including doses and schedules.4,6

TABLE 106-3 Common Chemotherapy Regimens Used to Treat Lung Cancer

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Local Disease

Images Local disease is associated with a favorable prognosis, and the goal of therapy is cure. Surgery is the mainstay of treatment and may be used alone or in some situations with radiation and/or chemotherapy. Patients who have comorbid conditions preventing them from being surgical candidates can be treated with radiation in place of surgery with curative intent, although the cure rates are lower. Stage IA and IB tumors are treated with surgery alone; when complete resection is achieved, adjuvant therapy is not routinely recommended.21 If surgical margins are positive, re-resection is recommended. Alternatively, patients may receive radiotherapy with or without chemotherapy. Although controversial, patients with IB tumors and high-risk features (poorly differentiated tumors, vascular invasion, wedge resection, minimal margins, tumors >4 cm, or visceral pleural involvement) may also receive adjuvant chemotherapy.3,4,21 Postoperative radiation therapy with older techniques may be detrimental and is not recommended.4,21

Stage IIA and IIB disease is primarily treated with surgery, which should be followed by adjuvant chemotherapy. The adjuvant treatment regimen of choice is not clear, but the positive clinical trials used platinum-based regimens, with arguably the best data coming from cisplatin–vinorelbine (Table 106-4).4,21,22 The absolute benefit in terms of 5-year overall survival in large randomized trials ranges from no benefit to 15%, with a recent systematic review reporting an absolute difference of 5%.4,21 Adjuvant radiation should be avoided in patients who have complete resection and clean margins because it has not demonstrated to be beneficial and can be detrimental. In those with resected lung cancer and N2 nodal disease, radiation is recommended followed by adjuvant chemotherapy. Radiation, or more commonly chemoradiotherapy, is the treatment of choice for stage II patients who are medically inoperable. Concurrent rather than sequential administration of chemotherapy and radiation therapy is preferred. The chemotherapy portion of concurrent chemoradiotherapy is platinum-based, with the preferred regimen being cisplatin and etoposide.4

TABLE 106-4 Adjuvant Chemotherapy for Early Stage Lung Cancer

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Locally Advanced Disease (Stage III)

Images Patients with more advanced local disease have large tumors, multiple tumors, and/or nodal involvement—particularly mediastinal nodal involvement (N2). Collectively this group of patients is heterogeneous and few well-defined large trials are available to guide treatment. Consequently, treatment is best planned by a multimodality team where individual features and patient input are considered. Optimal outcomes are achieved with multimodality therapy that typically includes systemic chemotherapy. Patients with operable disease should be considered for surgery preceded or followed by systemic chemotherapy. Adjuvant chemotherapy after surgery in selected patients improves overall survival (Table 106-4).4,2131 The primary adjuvant trials included patients with stage IIIA disease as well as early stage disease; 5-year survival in these studies improved by about 5%. Chemotherapy administration prior to surgery (i.e., neoadjuvant) should also be considered. Hypothetically, it will treat micrometastatic disease prior to surgery and reduce the tumor size making surgery easier and better tolerated. However, it is possible that the tumor will grow and become inoperable during therapy. Two meta-analyses have reported that neoadjuvant chemotherapy improves 5-year survival by about 5% compared with surgery alone.32,33 Although a randomized trial comparing neoadjuvant and adjuvant therapy has not been reported, it appears that both approaches are roughly equivalent and better than surgery alone.

Radiation may be given in place of surgery as the local treatment modality combined with chemotherapy. Although a large definitive trial has not been performed, this research question has been evaluated in small randomized trials. The largest trial randomized 333 stage IIIA (N2) patients who responded to three cycles of induction chemotherapy to radiation or surgery. No significant difference in median overall survival (17.5 months vs. 16.3 months for radiation and surgery, respectively) or overall 5-year survival was observed.34 This study suggests that surgery could be avoided by administering chemoradiotherapy, although it does not improve survival. Based on the knowledge that dual-modality therapy was better than a single modality, researchers tested trimodal therapy in small studies. None of the studies to date have demonstrated a survival benefit with chemotherapy, radiation, and surgery so it is considered investigational. The results of a randomized trial (SAKK-16/00) addressing this question are scheduled to be reported in the fall of 2013. It is currently recommended that patients with resectable stage IIIA NSCLC be treated with chemotherapy plus either radiation or surgery, depending on individual patient and tumor features.35

Patients with stage IIIA disease who are not surgical candidates or have a tumor that cannot reasonably be resected and nearly all stage IIIB patients are usually treated with both an active platinum-containing regimen and concurrent radiotherapy. Patients with tumors that cannot fit safely in a radiation port may receive induction chemotherapy followed by chemoradiotherapy. Responding patients may then become surgical candidates. Patients who are not surgical candidates should continue treatment with concurrent chemotherapy and radiation. Patients who are not candidates for radiation are treated like stage IV disease as discussed below.4


Clinical Controversy…

Multimodality therapy improves outcomes for patients with stage III disease, but the sequence and use of surgery or radiation remains to be defined for the stage as a whole.

Advanced-Stage Disease (Stage IIIB and IV)

Images About two-thirds of NSCLC patients present with advanced disease (unresectable stage IIIB or IV) at the time of diagnosis.1,3 Most of these advanced tumors are not surgically resectable and have disseminated metastatic disease. A few patients with single metastatic sites may undergo surgical resection of both the primary tumor and the metastatic site.4 For patients who have a tumor that will fit in a tolerable radiation port, chemoradiotherapy should be considered, but systemic therapy is the primary treatment modality for most of these patients.

The intent of first-line chemotherapy is to palliate symptoms, improve quality of life, and increase the duration of survival. Interestingly, the benefits of cytotoxic chemotherapy—as measured by overall survival and quality of life—were not clearly established until the 1990s. The Non–Small Cell Lung Cancer Collaborative Group reported the pivotal results of a large meta-analysis of 52 clinical trials of chemotherapy in the management of NSCLC.36 The results of this meta-analysis showed that chemotherapy, either alone or combined with surgery or radiotherapy, improves median survival for patients with advanced-stage NSCLC by 2 to 4 months and increases the 1-year absolute survival rate from 10% to 20%.36,37 Since chemotherapy became the standard treatment, new agents and targeted therapies have extended these modest gains in survival, while in some cases decreasing toxicity profiles. Current guidelines and experts agree that most patients with advanced-stage disease should receive at least one chemotherapy regimen.3,4,6

Patient selection for treatment of advanced-stage NSCLC depends on patient-specific factors that include age, performance status, and comorbid conditions. The patient’s current performance status (Eastern Cooperative Oncology Group [ECOG] performance status of 0 to 2) appears to be the most consistent predictor of a better response and improved survival after chemotherapy. All patients with a good performance status without significant comorbidities, including elderly patients, should receive first-line therapy. Patients with an ECOG performance status 2 or significant comorbidities should be considered for less intensive therapy (e.g., single-agent chemotherapy). Patients with poor ECOG performance status (≥3) do not respond well to chemotherapy. Patients with an unfavorable prognosis (poor performance status or significant concomitant diseases) should receive best supportive care and palliative radiation when necessary.3,4,6,37

Until the mid-1990s, first-line chemotherapy with etoposide and cisplatin (EP) was regarded as the most active regimen in the treatment of advanced NSCLC. Subsequently, a platinum-based doublet with a newer cytotoxic chemotherapy agent became the standard due to superior response rates or median survival rates.3,38 Each of these newer chemotherapeutic agents had single-agent activity of greater than 20% in NSCLC and included plant alkaloids (i.e., vinorelbine), taxanes (i.e., paclitaxel and docetaxel), antimetabolites (i.e., gemcitabine), antifolates (i.e., pemetrexed), and topoisomerase I inhibitors (i.e., topotecan and irinotecan).39 Results from many published trials combining these new chemotherapy agents with platinum-based regimens suggest improved 1-year survival rates in advanced NSCLC of 30% to 40% versus 15% to 25% with older cisplatin-based combination regimens.38,40,41 A pivotal intergroup study38 compared four of these newer doublet regimens: cisplatin and paclitaxel, gemcitabine and cisplatin, docetaxel and cisplatin, and carboplatin and paclitaxel. Although all of the regimens had overall survival, gemcitabine and cisplatin had the longest time-to-disease progression. When considering all grade 4 and 5 toxic effects, the carboplatin and paclitaxel doublet was lowest at 57%. The investigators concluded that all four regimens are acceptable, but ECOG chose the carboplatin and paclitaxel regimen for future studies due to the lower risk of grade 4 and 5 toxicity.38 Table 106-5 shows the outcomes of this study and other selected phase III trials of chemotherapy in patients with advanced NSCLC.30,38,40,4245 Patients with a contraindication to a platinum agent achieve similar survival results with gemcitabine in combination with paclitaxel or docetaxel.6 Survival with this doublet cytotoxic therapy approach reached a survival plateau that prevailed for about a decade. Then in 2006, bevacizumab was proven to increase the efficacy of first-line carboplatin and paclitaxel.46 Not only did this demonstrate the value of adding a targeted therapy to first-line chemotherapy, it also started a new era where we divide NSCLC in two histologic groups: squamous cell and nonsquamous cell. Although there continues to be multiple acceptable regimens, decision making in the current guidelines depends on classifying advanced-stage NSCLC tumors by their histology (squamous and nonsquamous) as well as genetic mutations or rearrangements.4 Not all targeted agents are associated with additional benefit when added to a platinum doublet. The clinical benefit of adding erlotinib to doublet platinum-based chemotherapy has been studied in two large, randomized controlled trials, with each enrolling more than 1,000 patients.47,48 These studies and others suggest that small molecule tyrosine kinase inhibitors are not synergistic with chemotherapy, while monoclonal antibodies can be synergistic with chemotherapy in lung cancer.

TABLE 106-5 First-Line Combination Regimens in Stage IIIB or IV Non–Small Cell Lung Cancer

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Squamous Cell Histology Little has changed for patients diagnosed with advanced-stage squamous cell lung cancer since the mid-1990s. The standard of care continues to be a platinum doublet as described above.4 The lack of progress represents the failure or minor improvement of targeted therapies to be safe and effective in this histology. The only regimen with a targeted agent consists of cetuximab, cisplatin, and vinorelbine. Support of this combination as first-line treatment of advanced NSCLC came from the First-Line ErbituX (FLEX) trial. The primary study end point involving 1,125 patients showed that cetuximab prolonged median overall survival by 1.2 months (11.3 months vs. 10.1 months [hazard ratio for death 0.87, 95% CI 0.762 to 0.996; P = 0.044).49 Although the study met the primary end point, some have questioned whether the survival advantage is large enough to justify an expensive drug that has toxicity, especially since the goal of treatment is to improve quality and duration of life.50 Because the available data from this trial and others are generally outdated and enrollment was not restricted to patients with only squamous histology, we rely on overall outcomes and subset analysis to evaluate different regimens. Combination chemotherapy regimens that have consistently reported response rates exceeding 30% have used various combinations of cisplatin, carboplatin, and gemcitabine, paclitaxel, docetaxel, and vinorelbine (see Tables 106-3 and 106-5). Analysis of a trial comparing cisplatin and gemcitabine versus cisplatin and pemetrexed showed that the results depended on histology. Patients with squamous histology had a significant improvement in survival with cisplatin and gemcitabine versus cisplatin and pemetrexed (n = 473; 10.8 months vs. 9.4 months, respectively). Therefore, some clinicians have extrapolated these data and other subset analyses to support cisplatin and gemcitabine as the platinum doublet of choice for squamous histology.51 However, cisplatin and vinorelbine with or without cetuximab, or carboplatin and paclitaxel are also reasonable options.4

A number of trials and meta-analyses have been performed to determine if carboplatin and cisplatin are equally effective or if one is more effective in NSCLC.5255 Individual clinical trials have produced equivocal data; even meta-analyses evaluating both agents disagree.52,54,55 One meta-analysis of doublet regimens reported that cisplatin was slightly superior when combined with a “newer” agent; cisplatin improved survival by 11% (P = 0.039).53Clinical trials comparing the two agents have also demonstrated a different toxicity profile. Cisplatin is associated with more GI (severe nausea and vomiting) and renal toxicity than carboplatin. However, carboplatin is associated with more hematologic toxicity (thrombocytopenia) than cisplatin.54 Although neither is clearly superior to the other, many clinicians have historically used carboplatin because of its more tolerable GI toxicity, but over the past few years the trend has reversed toward increased use of cisplatin, which could be attributed to improved antiemetics (i.e., the neurokinin-1 receptor antagonist aprepitant).

Nonplatinum doublets (e.g., gemcitabine plus paclitaxel or docetaxel) have been evaluated in the setting of first-line therapy of advanced NSCLC. The results of a meta-analysis comparing platinum-based regimens with either the same regimen without the platinum or the platinum replaced by another agent demonstrated that platinum provides a modest benefit.56,57 One meta-analysis evaluated 17 trials with a total of 4,792 patients and found a small but significant 1-year survival benefit with a platinum-based combination regimen compared with nonplatinum combination regimens (relative risk = 1.08, 95% CI 1.01 to 1.16).57 Further analysis of carboplatin regimens and cisplatin regimens demonstrated that benefit was only seen with cisplatin-based regimens. Although platinum-based combination regimens remain the preferred treatment, nonplatinum-based combinations are acceptable and recommended in patients with a contraindication to a platinum agent.

Addition of a third drug to a platinum doublet has been extensively studied. Although combinations of three cytotoxic agents usually increase response rates, they do not consistently prolong overall survival and increase toxicity.58 Because the goal of treatment for advanced-stage disease is to prolong life and improve quality of life, the use of three cytotoxic agents has not become a standard of care.

The duration of first-line therapy has also been studied. The optimal number of cycles remains controversial.59 Response rates and quality of life were not improved with administration of six as compared with three cycles of mitomycin, cisplatin, and vinblastine.60 For those receiving paclitaxel–carboplatin, administration of chemotherapy until disease progression had no clinically significant benefit in survival, response rate, or quality of life, but increased toxicity as compared with administration of four cycles.61 Many large randomized trials have used six cycles as a standard. Current guidelines recommend a total of four to six cycles of first-line platinum-based doublet chemotherapy for advanced squamous cell lung cancer that is stable or responding to chemotherapy.4 The one exception to this recommendation is when cetuximab is added to cisplatin plus vinorelbine, where the chemotherapy portion stops after six cycles, but the cetuximab continues until progress (continuation maintenance).49

Nonsquamous Histology Patients with advanced nonsquamous histology have new treatment options that have improved outcomes. Selecting therapy begins at the time of diagnosis where tumor tissue samples should undergo genetic testing. More specifically, tumor tissue needs to be tested for mutations in the kinase domain of EGFR, exon 19 and mutation of exon 21 (del746-750 and L858R), as well as for the EML4-ALK rearrangement. Tumors that harbor one of these genetic mutations (positive findings) will have a different treatment plan.4

Patients who have a tumor that harbors a mutation in the EGFR receptor should receive first-line erlotinib. A recent trial that compared first-line erlotinib, a relatively nontoxic EGFR tyrosine kinase inhibitor to standard platinum-doublet therapy (EUTRAC trial), found erlotinib to be superior.62 The study was stopped at the interim analysis because of the difference in progression-free survival (9.7 months vs. 5.2 months). As expected the patients receiving erlotinib had less severe adverse events than the patients who received the platinum doublet (6% vs. 20%, respectively). The different toxicities were consistent with prior studies with these regimens; grade 3 to 4 rash occurred in 13% of erlotinib patients and none of the chemotherapy patients, while grade 3 to 4 neutropenia occurred in 22% of platinum doublet patients and none of the erlotinib patients.62 It is also noteworthy that the erlotinib is continued until disease progression or intolerable toxicity.

The NCCN guidelines recommend that patients whose tumors have an ALK rearrangement should be treated with crizotinib, an ALK tyrosine kinase inhibitor.4 FDA approval was based on a single-arm phase II trial because of the very impressive results seen in pretreated patients. The original study reported that more than one half had received two or more prior treatments, and 41% had received three or more prior treatments. The response rate in this heavily pretreated patient population was 57%, and one patient achieved a complete response.63 After its approval, crizotinib has been evaluated in a randomized phase III trial where it was compared with standard second-line chemotherapy (pemetrexed or docetaxel). Patients treated with crizotinib had a higher response rate (65% vs. 20%; P <0.0001) and longer progression-free survival (7.7 months vs. 3 months, P <0.0001). Although first-line crizotinib is currently being evaluated in a phase III trial, the impressive activity in the relapsed setting led the panel to recommend crizotinib as first-line therapy.64 Toxicity was comparable in patients treated with second-line crizotinib and single-agent chemotherapy (59% all grades in both groups), but clearly differed by type of toxicity. Crizotinib toxicity was GI in nature (diarrhea 53%, nausea 52%, vomiting 44%, and elevated liver enzymes 36%), while the chemotherapy had comparable nausea (35%), but more myelosuppression (neutropenia 22%) and alopecia (20%). An additional measure of toxicity is the proportion of patients who discontinued treatment because of toxicity; 6% of crizotinib patients and 10% of chemotherapy patients discontinued treatment because of drug toxicity, which was consistent with crizotinib’s improved quality of life.

For advanced-stage patients whose tumor does not have one of these mutations, better options than the historical four to six cycles of a platinum doublet are available. Bevacizumab was the first targeted agent that improved outcomes compared with a platinum doublet and also started the movement toward individualized therapy based on histology (based on toxicity). A phase II trial randomized 99 chemotherapy-naïve patients with advanced or recurrent NSCLC to carboplatin and paclitaxel, either alone or combined with bevacizumab 7.5 or 15 mg/kg.65 Patients with CNS metastases, nonhealing wounds, significant cardiovascular disease, significant peripheral vascular disease, active secondary malignancy, pregnancy, or major surgery within 4 weeks of starting therapy, and those requiring anticoagulation were excluded from the trial because of concern over excessive toxicity to the angiogenesis inhibitor. An independent review faculty evaluated the data and found a response rate of 40%, 22%, and 31% and a median survival of 17.7, 11.6, and 14.9 months for the high-dose bevacizumab arm, the low-dose bevacizumab arm, and the control arm, respectively. Nineteen patients in the control arm crossed over to bevacizumab monotherapy on disease progression. Five patients had disease stabilization, and 1-year survival was 47% following crossover. Adverse effects of chemotherapy were not statistically different with the addition of bevacizumab. However, leucopenia, diarrhea, fever, headache, rash, and chills were slightly more common in the bevacizumab-containing arms. In addition, several patients in the bevacizumab arms developed hypertension, proteinuria, and bleeding. Bleeding events included minor mucocutaneous hemorrhage (most commonly grade 1 or 2 epistaxis) and major hemoptysis. Four patients died as a result of hemoptysis or hematemesis; two others experienced life-threatening bleeding complications. All six patients had centrally located tumors, five had necrosis of tumors, and four of the patients had squamous cell carcinoma.65 This trial led to a prospective, randomized trial evaluating the addition of bevacizumab 15 mg/kg every 3 weeks until progression to carboplatin and paclitaxel for six cycles compared with carboplatin and paclitaxel alone.46 The bevacizumab was continued until progression or unacceptable toxicity. As a result of bleeding complications seen in the phase II trial, patients with squamous cell carcinoma or brain metastases were excluded. The addition of bevacizumab led to longer progression-free survival from 4.5 to 6.2 months (P <0.001), median survival from 10.3 to 12.3 months (P = 0.003), and 1-year survival from 44% to 51%. The risk of bleeding events was significantly higher in the bevacizumab-containing arm (4.4% vs. 0.7%, P <0.001). Seventeen treatment-related deaths occurred during the study: 2 in the carboplatin and paclitaxel group and 15 in the carboplatin, paclitaxel, and bevacizumab group. Other adverse events seen more frequently in the carboplatin, paclitaxel, and bevacizumab group include hypertension, neutropenia, febrile neutropenia, thrombocytopenia, hyponatremia, rash, and headache (P<0.05).46 NCCN guidelines recommend the addition of bevacizumab to chemotherapy for patients with advanced NSCLC of nonsquamous cell histology, no history of recent significant hemoptysis, no CNS metastasis, and not receiving therapeutic anticoagulation.4 Interestingly, a recently published study that randomized patients to cisplatin and gemcitabine with or without bevacizumab did not find any survival benefit with the addition of bevacizumab.66This trial indicates that bevacizumab is not synergistic with all chemotherapy regimens and consequently should only be used in combination with carboplatin and paclitaxel for lung cancer at this time.

Another study that reported differentiated response by histology was a phase III trial comparing six cycles of cisplatin and either gemcitabine or pemetrexed. Overall survival with cisplatin and pemetrexed was noninferior to cisplatin and gemcitabine in all patients (10.3 months vs. 10.3 months, respectively) and in those with nonsquamous histology (11.8 months vs. 10.4 months, hazard ratio 1.23; 95% CI 1 to 1.51; P = 0.05). The cisplatin and pemetrexed had less neutropenia, anemia, and thrombocytopenia but more nausea than cisplatin and gemcitabine.51 This study supports the concept that pemetrexed has limited activity in squamous cell histology, but is as good as other new agents when combined with a platinum agent.

Several studies demonstrate that continuation or switch maintenance therapy improves survival of NSCLC patients with nonsquamous histology. Continuation maintenance therapy is continuing at least one of the agents used in a combination for four to six cycles until progression. Alternatively, switch maintenance therapy is starting a new agent in responding patients after four to six cycles. Pemetrexed and erlotinib are the agents that have proven survival benefit as maintenance (switch or continuation).4

Two large trials have evaluated pemetrexed as maintenance therapy.67,68 In the largest phase III trial, 663 patients who responded to platinum-doublet therapy were randomized (2:1) to pemetrexed maintenance (switch maintenance) or no further therapy until relapse. The results show that pemetrexed maintenance therapy prolonged median overall survival (13.4 months vs. 10.6 months, P = 0.012).33Interestingly, the benefit was only seen in patients with nonsquamous histology, and the best results occurred in patients with adenocarcinoma (median survival 16.8 months vs. 11.5 months for placebo, hazard ratio 0.73, 95% CI 0.56 to 0.96). This histology specificity is consistent with pemetrexed as first-line therapy in combination with cisplatin and also as second-line monotherapy.67 The second large study enrolled 939 nonsquamous histology patients and treated them with four cycles of cisplatin and pemetrexed. The 539 patients who showed benefit from treatment (responders and stable disease) were randomized to continuation maintenance with pemetrexed or placebo. Continuation maintenance with pemetrexed resulted in a longer median overall survival (13.9 months vs. 11 months) and 1-year survival (58% vs. 45%).68 These two studies clearly established maintenance therapy as standard therapy, but for patients who start a doublet with bevacizumab, it is unclear if both bevacizumab and pemetrexed should be used as continuation maintenance. Initial results from the Alimta/Avastin vs. Avastin Alone (AVAPERL) study show that bevacizumab and pemetrexed are superior than bevacizumab alone based on progression-free survival.69 However, a larger study that compared carboplatin, paclitaxel, and bevacizumab with bevacizumab continued maintenance to carboplatin, pemetrexed, and bevacizumab with bevacizumab and pemetrexed continuation maintenance found no difference in overall survival.70 Results of large ongoing studies will address this important research question.


Clinical Controversy…

The benefit of maintenance pemetrexed and bevacizumab for patients with nonsquamous cell stage IV NSCLC is proven. However, the benefit of bevacizumab and pemetrexed versus pemetrexed alone as maintenance is unknown. Additional clinical trial results to clarify optimal maintenance therapy for patients with nonsquamous stage IV NSCLC are needed.

Another recently reported randomized phase III trial shows that maintenance therapy with erlotinib prolongs disease-free survival versus placebo (Sequential Tarceva in Unresectable NSCLC [SATURN] study).71 A total of 1,949 patients received four cycles of a platinum doublet; the 889 patients without progressive disease were then randomized to erlotinib or placebo. Erlotinib maintenance prolonged survival by 1 month (11 months vs. 12 months), which included all patients (11% with EGFR mutation and 89% EGFR wild type). Interestingly, erlotinib maintenance appeared to be most effective in patients with adenocarcinoma histology and in those with an EGFR mutation. Although this study is compelling, pemetrexed is more commonly used because those with an EGFR mutation should receive first-line erlotinib and continue it until progression.4

Studies evaluating gemcitabine72 and docetaxel73 maintenance therapy have been reported with some compelling data. Both studies demonstrate that maintenance therapy improved progression-free survival, with a nonsignificant trend for improved overall survival. These agents should be considered in patients with a contraindication to pemetrexed and erlotinib.

In summary, patients with advanced-stage nonsquamous histology NSCLC should have their tumor tested for an EGFR mutation or ALK rearrangement. Patients with a positive mutation should receive erlotinib (positive EGFR mutation) or crizotinib (ALK rearrangement). Those patients without a mutation should receive four to six cycles of a platinum doublet with bevacizumab or alternatively cetuximab. For those with a contraindication to bevacizumab, treatment with just a doublet is recommended. For patients who have stable disease after or respond to four to six cycles of doublet therapy with or without bevacizumab, maintenance therapy should be initiated.4

Second-Line Chemotherapy Second-line chemotherapy is usually offered to those patients with an ECOG performance status of 0 to 2 who experience disease progression to or after first-line chemotherapy. Third-line therapy can be offered if disease progression continues in a patient with adequate performance status. Best supportive care is recommended by the NCCN guidelines for those patients with disease progression and ECOG performance status worse than 2.4

Monotherapy with docetaxel, pemetrexed, or erlotinib is an options for second-line therapy in patients with a good performance status who progress during or after first-line chemotherapy.4,6 Docetaxel was the first to receive FDA approval for the treatment of advanced NSCLC after failure of a platinum-based chemotherapy regimen. The initial docetaxel dose of 100 mg/m2 IV over 1 hour every 21 days was decreased to 75 mg/m2 after an interim analysis showed a greater risk of severe neutropenia with the higher dose. Docetaxel, at the 75 mg/m2 dose, was superior to best supportive care in terms of time-to-disease progression (10.6 weeks vs. 6.7 weeks, P = 0.001), median survival (7.5 months vs. 4.6 months; P = 0.047), and 1-year survival (37% vs. 11%; P = 0.003).74 Both doses had a statistically significant improvement in 1-year survival when compared with a control regimen of vinorelbine or ifosfamide (32%, 21%, and 19%, respectively).75

Subsequently, pemetrexed (Alimta) was FDA approved for second-line treatment of advanced NSCLC based on results of a phase III trial.76 In that trial, 571 patients were randomized to receive either pemetrexed 500 mg/m2with folate and cyanocobalamin supplementation or docetaxel 75 mg/m2. No significant differences in overall response rate, stable disease, or median survival between the pemetrexed and docetaxel arms were observed. Docetaxel had significantly more hematologic toxicities as compared with pemetrexed, leading to more hospitalizations and use of hematopoietic growth factors and erythropoiesis-stimulating agents. Patients receiving docetaxel had a significantly higher incidence of alopecia, while patients receiving pemetrexed had a significantly higher elevation of alanine aminotransferase.76

Erlotinib, a relatively nontoxic agent that targets the EGFR, was approved in November 2004 as a single agent for patients with advanced NSCLC whose disease progressed after at least one prior chemotherapy regimen. Its approval was based on an international, multicenter, randomized, double-blind phase III trial (BR.21)77 in 731 patients with locally advanced or metastatic NSCLC who had failed at least one prior chemotherapy regimen. Patients were randomized to receive either erlotinib 150 mg or placebo orally once daily. Patients in the erlotinib group had a significantly higher objective response rate (9% vs. 1%, P <0.001) and longer median progression-free and overall survival (9.9 weeks vs. 7.9 weeks, P <0.001 and 6.7 months vs. 4.7 months [hazard ratio = 0.73], P <0.001, respectively) than those in the placebo group. Patients in the erlotinib group also had significantly improved symptom control, specifically time-to-deterioration of cough, dyspnea, and pain.77 Although these benefits are relatively modest, some individual patients show a profound response. This has led researchers to search for patient and tumor-specific factors (i.e., biomarkers) that can be used to select patients who are likely to respond to an EGFR inhibitor. Patients who have the following characteristics are most likely to respond to EGFR inhibitors: never smokers, women, Asians, and those with adenocarcinoma histology, particularly the bronchial alveolar carcinoma subset of adenocarcinoma. Analysis of predictive biomarkers led to EGFR mutational testing and to the recommendation that patients who have EGFR mutation-positive tumors should receive first-line erlotinib.4,62

In summary, patients with a good performance status should receive second-line therapy, which is determined by histology and first-line treatment. In general, drugs are not repeated, and patients with squamous histology do not receive pemetrexed or erlotinib. Other active agents can be used as monotherapy.

Elderly and Poor-Performance Status Patients Single-agent chemotherapy is an alternative in elderly patients or those with an ECOG performance status of 2.4,6 First-line, single-agent chemotherapy has objective response rates of 5% to 25% with no significant effect on overall survival. Complete responses are rare and responses that do occur are of brief duration (i.e., 2 to 4 months).3,78 Among the most active cytotoxic chemotherapy agents in NSCLC are cisplatin, carboplatin, docetaxel, paclitaxel, etoposide, gemcitabine, ifosfamide, irinotecan, topotecan, mitomycin, vinblastine, vinorelbine, and pemetrexed.4 Erlotinib and crizotinib are also active as a single agent and should be considered in patients with a mutation-positive tumor.

Historically, patients with a ECOG performance status 2 were excluded from NSCLC trials because of excessive toxicity with minimal benefit from combination cytotoxic therapy. A recent randomized phase III trial79 comparing single-agent weekly docetaxel (n = 171) with docetaxel and gemcitabine (n = 174) in elderly or poor performance status (35% of patients) had disappointing results. No survival differences were observed with docetaxel and gemcitabine versus weekly docetaxel in the 122 poor-performance status patients (3.8 months vs. 2.9 months, respectively), and the median survival is short compared with patients with good performance status.79 Another randomized phase III trial80 compared single-agent gemcitabine (n = 85) with gemcitabine/carboplatin (n = 85) in PS-2 patients. The median overall survival was not different between gemcitabine and gemcitabine/carboplatin (5.1 months vs. 6.7 months, respectively). The authors concluded that single-agent therapy is still the standard in this setting.80 The updated ASCO guidelines state that available data support the use of single-agent chemotherapy and data are insufficient to recommend combination therapy.6 A recent meta-analysis shows that patients with performance status 2 benefit from treatment.81

Personalized Pharmacotherapy

The translation of basic science to the clinic has resulted in personalized pharmacotherapy plans. Treatment decisions are influenced by tumor biology and patient characteristics (e.g., comorbidities and performance status). The primary tumor biology issues evolve around new targeted therapies where histology (squamous vs. non-squamous histology) and genetic mutations determine the most effective therapy (EGFR mutation, EML4-ALK rearrangement) and duration of therapy. The histology can also correlate with risk of toxicity, such as major bleeding with bevacizumab-treated squamous cell histology patients.

Treatment guidelines generally apply to patients who are fit and desire aggressive therapy. Patient-specific factors that can alter these recommendations include age and comorbid conditions that serve as a relative or absolute contraindication to aggressive platinum-based doublet therapy and even some targeted therapies such that the risk of toxicity outweighs the benefit. For example, elderly patients or those with an ECOG performance status of 2 have a modest benefit to aggressive platinum-doublet therapy; patients with an ECOG performance status of 3 have little to no benefit and a high risk of toxicity. Other considerations include renal dysfunction and the use of a platinum agent, and history of hemoptysis and the use of bevacizumab. Although these examples appear to provide clear guidance, risk is often a continuum and it is sometimes not clear how to treat individual patients (e.g., a fully functioning 50-year-old with angina and a serum creatinine of 1.7 mg/dL and stage IIIB squamous cell lung cancer).

Evaluation of Therapeutic Outcomes

For patients who have undergone surgical resection with or without chemotherapy, radiation, or both, a physical examination and chest radiography are recommended every 3 to 4 months for the first 2 years, then every 6 months for 3 years, and then annually. In addition, a low-dose spiral chest CT scan is recommended annually to monitor for evidence of local recurrence. Suspicious symptoms or physical findings (e.g., bone pain, visual abnormalities, headache, or elevated liver function tests) should prompt an evaluation to rule out distant metastases.35

Tumor response to chemotherapy is generally evaluated at the end of the second or third cycle and at the end of every second cycle thereafter. Patients with stable disease, with objective response, or with measurable decrease in tumor size (complete or partial response) should continue until four to six cycles have been administered. Patients with nonsquamous histology tumors who respond (i.e., nonprogressive disease) should be considered for maintenance therapy with pemetrexed. Following initial therapy for NSCLC, patients must be monitored for evidence of disease progression.35

Small Cell Lung Cancer

SCLC is a rapidly dividing malignancy that spreads early in the disease course. Consequently, most patients present with extensive-stage disease (about 60% to 70% of new cases). When patients with SCLC are not treated, the disease quickly becomes fatal. Fortunately, small cell carcinomas are very responsive to chemotherapy and radiation. Chemotherapy with or without radiotherapy is the treatment of choice for most patients. Even after a complete response to therapy, the cancer usually recurs within 6 to 8 months, and survival time following recurrence is typically short (about 4 months). With treatment, median survival rates for patients with limited and extensive disease are 14 to 20 and 9 to 11 months, respectively. Treatment planning starts with stage of disease (i.e., limited vs. extensive stage), but must also take into account other factors, including performance status (treatment usually restricted to performance status 0 or 1), patient age, comorbid conditions (e.g., renal failure), and patient desire to receive treatment.3,5

Limited Disease

Images When a single SCLC mass is found, local therapy with radiation or surgery is considered, although the use of surgery in SCLC is limited to solitary nodules, without evidence of metastasis to lymph nodes. One of the factors differentiating SCLC and NSCLC is the fact that radiation is favored for treatment of local disease over surgery. Radiation is always combined with chemotherapy in limited-stage SCLC, and the regimen of choice is EP. Carboplatin may be substituted for cisplatin to reduce nausea and vomiting, nephrotoxicity, or neurotoxicity,82 although increased myelosuppression in the form of thrombocytopenia may result. In European countries, a three-drug combination containing an anthracycline has been the mainstay of therapy, but mounting clinical evidence shows that these regimens are inferior to EP plus concurrent radiation and have more toxicity.83 Consequently, the guidelines recommend that the EP regimen be used with concurrent radiotherapy.5 Because patients with SCLC commonly have a recurrence in the CNS, trials have been performed to evaluate the benefit of prophylactic cranial irradiation (PCI). A pivotal study showed that PCI reduces the incidence of brain metastasis and increases 3-year survival from 15% to 21%.84,85 Therefore, patients who achieve a complete response with treatment should be offered PCI.

Extensive Disease

Images Platinum regimens are also the treatment of choice in extensive disease, and many studies have failed to show superiority to the EP regimen as first-line treatment. A combination of irinotecan and cisplatin in one Japanese study demonstrated an increased median survival time by about 3 months over the EP regimen. This regimen showed a lower incidence of severe neutropenic side effects but exhibited higher rates of moderate- to high-grade diarrhea in an Asian population.86 However, irinotecan and cisplatin failed to improve survival as compared with EP in a study conducted in the United States.87Therefore, EP remains the regimen of choice for treating extensive-stage SCLC in the United States, with irinotecan and cisplatin reserved as an acceptable alternative. Concurrent radiotherapy is not used routinely in extensive disease. However, a recent study that randomized extensive-stage patients responding to chemotherapy to observation or PCI reported that PCI decreased the 1-year risk of brain metastasis (14.6% vs. 40.4%), and prolonged survival (27.1% vs. 13.3% at 1 year).88 This study led to guideline revisions recommending PCI for patients with extensive disease responding to chemotherapy.5

Recurrent Disease

SCLC patients who relapse or progress after first-line chemotherapy have a median survival of 4 to 5 months. Unfortunately, when disease recurs, it is usually less sensitive to chemotherapy. The decision of whether or not to use second-line chemotherapy is often based on the length of time between completion of the induction chemotherapy regimen and relapse. If this interval is less than 3 months, the patient has refractory SCLC and is unlikely to respond to second-line therapy; hence, they should receive best supportive care or be enrolled in a clinical trial. For those with greater than a 3-month time interval between first-line chemotherapy and relapse, the expected response rate to treatment is approximately 25%, and second-line therapy should be considered.3,5 Topotecan (IV and oral) is the only FDA-approved second-line therapy for SCLC. The pivotal trial89 leading to the approval randomized patients to IV topotecan or the cyclophosphamide, doxorubicin, and vincristine (CAV) regimen. The response rates (24% vs. 18%), time-to-disease progression (13 weeks vs. 12 weeks), and overall survival (25 weeks vs. 25 weeks) were not different between groups. Interestingly, the proportion of patients experiencing symptom improvement was higher in the topotecan arm. The hematologic toxicity was similar between arms; there was slightly more neutropenia in the CAV arm and more anemia and thrombocytopenia in the topotecan arm. Nonhematologic toxicity appears to be higher in the CAV arm; 11% of patients required a dose reduction compared with 1% in the topotecan arm.89 Oral topotecan appears to be equally effective and similar in terms of dosing, toxicity, and effectiveness as IV topotecan.90 Based on these studies, topotecan should be considered as the second-line treatment of choice, but because of the modest efficacy other agents warrant consideration. Agents that are recommended in national guidelines5 include single-agent topotecan, irinotecan, gemcitabine, paclitaxel, docetaxel, and vinorelbine; CAV regimen; and participation in a clinical trial.

Personalized Pharmacotherapy

Personalized pharmacotherapy based on tumor biology has not become a standard for SCLC. However, there is a significant push in research to identify targeted drug therapy that will improve the outcomes of all or subpopulations of patients with SCLC. Current trials are looking at drugs that inhibit specific targets including insulin growth factor receptor 1R, PI3K, AKT, mTOR, Hedgehog, and apoptosis. In order to increase the likelihood of success with these agents, trials are enrolling patients where the relevant pathway appears to be active. If a drug inhibiting a specific pathway proves to be beneficial, then optimal treatment may be individualized based on the tumor biology. Until then, we will continue to choose treatment primarily based on stage, comorbid conditions, and performance status. Similar to NSCLC, patients without comorbid conditions and good performance status will typically receive a platinum doublet (cisplatin and etoposide), but elderly patients, those with significant comorbid conditions, or those with an ECOG performance status of 2 may receive less aggressive treatment (a single agent), and those with extensive-stage disease who are bedridden will not be given cytotoxic therapy because of a lack of benefit.

Evaluation of Therapeutic Outcomes

The effectiveness of first-line therapy is evaluated after two to three cycles of treatment. At this point, therapy is continued for four to six cycles of therapy in patients with a complete or partial response or stable disease, and discontinued or changed to a non–cross-resistant regimen in patients demonstrating evidence of progressive disease. In the case of SCLC, those with response benefit from the addition of PCI following initial therapy. After recovery from first-line therapy, followup visits should occur every 3 months for years 1, 2, and 3, then every 4 to 6 months for years 4 and 5, and then annually for patients with either a partial or complete response.5

Complications and Supportive Care

Patients with lung cancer frequently have numerous concurrent medical problems. Such problems may be related to invasion of the primary tumor and its metastases, paraneoplastic syndromes (see Clinical Presentation earlier), chemotherapy and radiotherapy toxicity, or concomitant disease states (e.g., cardiac disease, renal dysfunction, chronic obstructive pulmonary disease, asthma, or diabetes). Depression is also common and sometimes persistent in patients with SCLC and NSCLC and should be treated. Identification, diagnosis, and treatment of the patient as a whole may improve the patient’s overall quality of life and tolerance to cancer treatments.

Images The chemotherapy regimens used in the management of lung cancer are intensive and are associated with a wide variety of toxic effects. Nausea and vomiting may be severe. Cisplatin-containing regimens require the use of aggressive acute and delayed antiemetic regimens containing a serotonin antagonist, dexamethasone, and aprepitant.91 Patients experiencing protracted nausea and vomiting may require IV hydration and nutritional support. Myelosuppression is often the dose-limiting toxicity associated with chemotherapy. Granulocytopenia places patients at a high risk for serious infections. Other toxic effects associated with these chemotherapy regimens include mucositis, anemia, nephrotoxicity, peripheral neuropathies, and ototoxicity.

About 30% to 65% of advanced-stage NSCLC patients will develop bone metastases, which may lead to significant bone pain, pathologic fractures, spinal cord compression, and hypercalcemia.92 Zoledronic acid, an IV administered bisphosphonate, has been shown to reduce skeletal-related events in patients with bone metastases at a dose of 4 mg over 15 minutes infused every 3 weeks. Although the data do not show a significant reduction in skeletal-related events, time to first event is significantly increased (230 days vs. 163 days for placebo, P = 0.023), thereby making zoledronic acid a viable therapy for patients with bone metastases.

Patients receiving radiation therapy may experience complications including severe esophagitis, fatigue, radiation pneumonitis, and cardiac toxicity. These toxicities are usually more common and severe when radiation is combined with chemotherapy. The patient’s baseline performance status and the degree of pulmonary dysfunction (e.g., chronic obstructive pulmonary disease from years of tobacco use) must be considered in decisions concerning radiation dosage and fractionation.

It is readily apparent that many lung cancer patients receive complex pharmacologic regimens that may include chemotherapeutic agents, antiemetics, antibiotics, analgesics, anticoagulants, bronchodilators, corticosteroids, anticonvulsants, and cardiovascular agents. Such regimens necessitate intensive therapeutic monitoring in order to avoid drug-related and radiotherapy-related toxic effects and to optimize therapeutic outcome for individual patients.

ABBREVIATIONS

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REFERENCES

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