Val Adams and Justin Balko
LEARNING OBJECTIVES
Upon completion of the chapter, the reader will be able to:
1. Identify major risk factors for the development of lung cancer.
2. Explain the pathologic progression of lung cancer and its relationship with signs and symptoms of the disease.
3. Make appropriate recommendations for screening or preventative measures in high-risk patients.
4. Understand staging of lung cancer patients and how it influences treatment decisions.
5. List the rationale, advantages, disadvantages, and place in therapy for adjuvant and neoadjuvant chemotherapy.
6. Identify the chemotherapeutic regimens of choice for limited and extensive small cell lung carcinoma, as well as local, locally advanced, and advanced nonsmall cell lung carcinoma.
7. Monitor patients for chemotherapy-associated toxicity, and recommend appropriate management.
8. Distinguish the treatment goals of palliative care versus those of first-line treatment.
KEY CONCEPTS
The most important risk factor for the development of lung cancer is smoking, and the most effective way for high-risk patients to reduce their risk is to stop smoking. Additional recommendations should include an increase in dietary intake of fruits and vegetables.
The signs and symptoms of lung cancer can be classified as pulmonary, extrapulmonary, and paraneoplastic. These classifications relate to disease progression.
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.
The performance status (PS) of the patient represents an important aspect of chemotherapy treatment decisions. Patients with a PS of 0 to 1 may be treated with chemotherapy. Patients with a PS of 2 may be treated with less aggressive regimens that have a decreased risk of major toxicities, whereas patients with a PS 3 and 4 should be treated with supportive care only.
Surgical resection of the tumor is the mainstay of treatment in early-stage nonsmall cell lung cancer and produces the longest survival rates.
Doublet chemotherapy regimens offer superior response rates compared 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.
Knowing when and how to treat adverse events from chemotherapy is an important aspect of patient care. Unmanaged events may cause delays in chemotherapy administration and reduced chemotherapy doses, and may contribute to treatment failure.
While some evidence suggests that the use of a colony-stimulating factor reduces the number of neutropenic fever episodes, hospital stay, and antibiotic administration in certain subsets of lung cancer patients, routine front-line (prophylactic) use of a colony-stimulating factor is not recommended owing to lack of a survival benefit.
INTRODUCTION
Lung cancer has a major health impact both in the United States and worldwide. Prior to 1930, lung cancer was a relatively rare disease, but a sharp incline in industrialization and smoking in the early 1900s has bred an epidemic. Lung cancer has a high mortality rate, and although treatment can cure selected patients, most therapies only prolong survival for months. Recent advances in lung cancer research provide good reason for optimism. However, in spite of the emergence of new therapies, antismoking campaigns still appear to offer the best opportunity to reduce lung cancer incidence and mortality.
EPIDEMIOLOGY AND ETIOLOGY
Incidence and Mortality
Cancer is the second leading cause of death in the United States. Cancers of the lung and bronchus rank first in cancer-related mortality, comprising over 28% of cancer-related deaths.1 In 2008, over 215,000 new cases of lung cancer were diagnosed. A close correlation exists between incidence and mortality of lung cancer, reflecting the reality that approximately 85% of lung cancer patients ultimately die of the disease.
Gender
Lung cancer incidence and mortality are slightly higher in males, but the rate in females is expected to match that of males in future years owing to changes in smoking patterns.2 Typically, women with lung cancer are diagnosed at an earlier age, which has raised the question that there may be inherent genetic differences between males and females in susceptibility to lung cancer. Furthermore, there are differences in the prevalence of histological subtypes of tumors. Interestingly, historical studies have shown improved prognosis and survival times for women diagnosed with lung cancer.3
Race
While no significant difference is noted in incidence or mortality between black and white females, black males have a markedly higher incidence and mortality rate than white males. Proposed contributions to this gap include differences in smoking habits, such as increased menthol cigarette use.2 Black Americans also have a significantly lower 5-year survival rate than white Americans regardless of gender. They present with more advanced disease and are less likely to be treated, which suggests that genetic, psychosocial, and socioeconomic components contribute to this disparity. Although it remains a significant health care issue, Asians, Hispanics, and Native Americans have lower rates of lung cancer than both Caucasians and African Americans.2,4,5
Clinical Risk Factors
Smoking
The most important risk factor for the development of lung cancer is smoking. One of the most predictive factors on lung cancer epidemiology is trends in population cigarette smoking. Because lung cancer is a fatal disease in most cases, both incidence and mortality strongly reflect the smoking trends of the population on a 20- to 30-year lag. In other words, decreases in tobacco use now would be expected to affect lung cancer incidence in 2030. With this knowledge, the current expectation is that lung cancer incidence and mortality will decrease steadily until 2020, reflecting decreases in cigarette smoking between 1970 and 1990. Because smoking has continued at a steady rate since 1990, lung cancer incidence is expected to plateau.2 Correlation between smoking and lung cancer continues to drive antismoking campaigns and should be considered an investment in the future health care of the nation. Furthermore, smoking cessation plays an important role in reducing lung cancer risk on a patient-to-patient basis, and appropriately guiding such therapy is a crucial part of treating at-risk patients.6 Total smoke exposure, as well as current use, correlates with the individual’s risk of developing malignancy. The risk of lung cancer decreases to near-normal levels 10 to 15 years following successful smoking cessation. Total smoke exposure is reported as pack-years. One pack-year is the equivalent of smoking 1 pack per day for 1 year. A patient who smokes 40 cigarettes per day (2 packs) for 5 years would have a 10 pack-year history (2 packs/day for 5 years).
Other Air-Related Risks
In addition to direct inhalation of cigarette smoke, other environmental factors have been identified as risks for the development of primary lung tumors. Environmental tobacco smoke (ETS) presents a significant occupational hazard for nonsmokers working in environments that have a high-smoking population, such as bars or restaurants. Some states have instituted laws banning public smoking in order to protect individuals working in these locations. Each year approximately 3,000 cases of lung cancer in nonsmokers are due to ETS. Other environmental factors linked to lung cancer include radon, arsenic, nickel, and chloromethyl ethers. Those who live in an urban environment are also at an increased risk for lung cancer owing to exposure to high concentrations of combustion fumes.4 Asbestos exposure increases the risk of developing a distinct type of lung cancer called mesothelioma, which is rare and beyond the scope of this chapter.
Nutrition
Diet and nutrition have long been suspected to play a role in cancer susceptibility, and many studies have sought to define specific foods or nutrients that influence cancer risk. Because not all heavy smokers develop lung cancer, it is thought that nutritional factors may explain part of this variation. Epidemiologic studies focusing on diet and nutrition in lung cancer have shown reduced rates of lung cancer in individuals who report higher fruit and vegetable consumption. However, studies attempting to identify specific chemical components of fruits and vegetables that are responsible for this effect have not been successful.7 
Recommendations to patients who are at risk owing to smoking or other factors or those who are simply interested in reducing their risk of cancer should include an increase in dietary intake of fruits and vegetables.
Hereditary or Genetic Risk Factors
Although smoking is a key risk factor for lung cancer, the majority of people who smoke never develop lung cancer. Genetic risk factors may predispose certain smokers to lung cancer. After adjustments for age, smoke exposure, occupation, and gender, relatives of a lung cancer patient have approximately a twofold risk of developing lung cancer. The degree of inherited risk inversely correlates with the age of the relative at the time of diagnosis. First-degree relatives of a lung cancer patient diagnosed between the ages of 40 and 59 years have a sixfold relative risk for lung cancer. Familial lung cancer that develops at an early age in nonsmokers fits a Mendelian codominant inheritance model. However, a lung cancer gene has not been identified.
Other genetic links to lung cancer involve metabolic enzymes that process carcinogens. The damaging effects of tobacco smoke are thought be a result of bulky aromatic hydrocarbons that damage DNA. These chemicals are activated by certain phase I metabolic enzymes and are deactivated by phase II conjugating enzymes such as the glutathione-S-transferases. People with elevated cytochrome CYP450 2D6, 1A1, or 1A2 have greater risk of DNA damage and subsequent cancer owing to higher formation rates of active carcinogens. Those with deficient phase II metabolism (GSTM1 or GSTT1) similarly may have increased risk owing to lower clearance of carcinogens.8–10
Chemoprevention
Chemoprevention refers to the use of prophylactic medications to prevent the development of cancer. Many studies of potential chemopreventatives, including nonsteroidal anti-inflammatory drugs, retinoids, inhaled glucocorticoids, vitamin E, selenium, and green tea extracts, have been conducted, but none has been successful. Large randomized clinical trials have evaluated β-carotene and vitamin E as lung cancer chemopreventative agents in high-risk patients (older smokers). Although vitamin E has no influence on lung cancer, the trials 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.11
Screening and Early Detection
Overall 5-year survival in lung cancer is only 15%, whereas those who are diagnosed at a localized stage exhibit a 5-year survival rate of 50%. Currently, over three-quarters of newly diagnosed lung cancers present with locally advanced or metastatic disease, and therefore, very few patients are able to undergo surgical resection.1 In an attempt to identify tumors when they are localized and have higher cure rates, many investigators are evaluating different screening modalities. Effective screening methods have the potential to save thousands of lives. To date, no screening study has demonstrated a benefit in overall survival; however, the use of spiral CT scanning has been shown to be sensitive in detecting small nodules. Unfortunately, spiral CT scanning alone is not likely to be of benefit owing to the high rate of false-positive results (i.e., lack of specificity), leading to excessive patient anxiety and workup, which can have a negative effect on morbidity and mortality. Because lung cancer tumors are hypermetabolic, they can typically be visualized with 5-fluorodeoxyglucose (5-FDG) positron-emission tomographic (PET) scanning. The combination of spiral CT scanning and follow-up PET scanning for positive lesions is currently the most promising method. In a recent study, this combination resulted in 90% specificity and 100% sensitivity for detection of cancer when a 3-month follow-up CT was used after a negative PET scan. Furthermore, 92% of nonsmall cell tumors were diagnosed at stage IA or IB.12 Additional studies evaluating the benefits on mortality of this approach are under way. Spiral CT and PET scanning are currently the most promising screening tools for patients at a high risk for lung cancer. High-risk individuals should be encouraged to enter randomized, controlled trials aimed at demonstrating a survival benefit from screening.
PATHOPHYSIOLOGY
Most lung cancers arise from the epithelium of the airways and are classified as carcinomas. There are four major and several rare histological types of lung cancer. They appear to form through different mutagenic pathways; however, they all appear to undergo transition through a premalignant state. The presence of a transitional state from normal tissue to cancerous tissue is important because the premalignant cells contain damage that is generally thought to be reversible. Researchers are currently trying to develop methods to identify people with premalignant lesions as well as drugs that can reverse the damage.
Continued damage to premalignant cells can lead to cancer. The first appearance of cancer cells that have not yet become invasive is referred to as carcinoma in situ. Patients are rarely diagnosed with this early stage of cancer owing to a lack of symptoms and relatively rapid progression from this state to larger invasive tumors. As the tumor grows, cells may become dislodged from the tumor bulk and enter the hematologic or lymphatic circulatory systems where they can travel to either local or distant parts of the body. Hematologic spread usually results in metastatic sites in the bones, liver, and CNS. Lymphatic spread is more orderly in nature, with the hilar and mediastinal lymph nodes in the pleural cavity commonly being involved. Once the tumor has spread to multiple locations, curative treatment is rare because surgical excision and radiotherapy cannot remove all or nearly all the cancer cells.
Histologic Classification
Histologic classification of lung cancer involves determining the cellular origin of the tumor. Knowing the histology of the tumor influences treatment decisions as well as prognosis. In order to carry out a histologic classification, the pathologist must obtain a tissue sample. Methods of tissue sampling are discussed in Table 90–1.
There are four major histologic types of lung cancer that are divided into two classes based on response to treatment and prognosis: small cell lung cancer (SCLC) and nonsmall cell lung cancer (NSCLC). However, it is important to note that certain other rare malignancies as well as mixed-type carcinomas can be seen. The four major types of lung cancer are outlined by class in Table 90–2.13
CLINICAL PRESENTATION AND DIAGNOSIS
Clinical symptoms are not commonly seen until lung cancer tumors become large and/or have metastasized. This is a key factor in the poor prognosis associated with lung cancer. Patients who are diagnosed at an earlier clinical stage have improved prognosis compared to those diagnosed at later stages. Therefore, diagnosing lung cancer earlier through screening and identification of initial signs and symptoms is important. Several screening techniques including CT and PET scanning are being investigated to detect lung cancer at earlier, curable stages in an attempt to reduce mortality. However, screening is not part of the current recommendations. The current approach is based on identifying lung cancer patients on symptomatic presentation or by follow-up of lesions noted from unrelated radiologic scans.
Patient Encounter, Part 1
A 53-year-old African American man presents at your clinic complaining of new-onset cough. He has had several upper respiratory infections in the last 2 months, with occasional hemoptysis. He has consistently smoked 1.5 packs per day for the last 20 years. He has worked as a bartender at a local restaurant for most of his life.
What risk factors for lung cancer are present?
Calculate this patient’s pack-year history.
Table 90–1 Diagnostic Tools
Table 90–2 Lung Tumor Histopathology
Clinical Presentation and Diagnosis of Lung Cancer
Signs and symptoms of lung cancer can be classified into three subdivisions: pulmonary, extrapulmonary, and paraneoplastic syndromes. Distinguishing between these classes of symptoms is important because it can aid in determining the severity of the disease, guide treatment options, and affect prognosis.
Pulmonary Symptoms
Symptoms owing to the direct effects of the primary tumor are often the first to appear and are the most common. These include:
• Cough
• Chest pain
• SVC obstruction
• Shortness of breath
• Dysphagia
• Hemoptysis
• Pleural effusion
Extrapulmonary Symptoms
Once the tumor invades tissues outside the pleural cavity, it can produce a wide array of symptoms including:
• General bone pain
• Nausea
• Adrenal insufficiency
• Focal neurologic symptoms
• Confusion
• Horner’s syndrome
• Personality changes
• Fatigue
• Enlarged lymph nodes
• Headache
• Weight loss
• Vomiting
• Seizures
• Subcutaneous skin nodules
Paraneoplastic Syndromes
Symptoms that are not a result of the direct effects of the tumor are termed paraneoplastic syndromes. They may be caused by substances secreted by the tumor or in response to the tumor and often occur in tissues far from the site of malignancy. Paraneoplastic syndromes are numerous and affect a wide variety of systems, including the endocrine, neurologic, skeletal, renal, metabolic, vascular, and hematologic systems.
Diagnosis
Diagnosis requires visualization of one or more lesions as well as biopsy of the lesion to confirm malignancy. Both visualization and sampling can be performed by invasive or noninvasive methods. These methods are summarized in Table 90–1.
Diagnosis
Diagnosis of lung cancer requires both visualization of the cancerous lesion and tissue sampling for pathologic assessment. Visualization of the suspected tumor provides the clinician with the information necessary to choose the most appropriate sampling technique. While some lung tumors may be apparent using relatively simple techniques such as a chest x-ray (CXR), many can be too small to detect or may be located in an anatomically difficult area to visualize. Therefore, multiple methods of visualization are often used. Once the tumor has been located, sampling provides tissue to confirm malignancy and to determine the histology (e.g., squamous cell, adenocarcinoma, large cell, or small cell). The advantages and disadvantages of various sampling methods must be weighed carefully so that the procedure performed is the least invasive with a high likelihood of providing an accurate diagnosis. Tools used in the diagnosis of lung cancer are outlined in Table 90–1.
Clinical Staging
Once the diagnosis of lung cancer is confirmed through visualization and biopsy, the extent of disease must be determined. NSCLC is staged using the American Joint Committee on Cancer tumor, node, and metastasis (TNM) staging system. SCLC is typically staged using the Veterans Administration Lung Cancer Study Group method. Clinical staging serves two primary purposes: predicting prognosis and guiding therapy.
Nonsmall Cell Lung Cancer
Clinical staging of NSCLC with the TNM system evaluates the size of the tumor (T), extent of nodal involvement (N), and presence of metastatic sites (M). The combination of these three evaluations determines the stage. Clinical stages and associated survival rates are outlined in Table 90–3. Local disease includes tumors that are confined to a single hemithorax and those cancers that have spread to the ipsalateral hilar lymph nodes. Once malignancy invades the mediastinal lymph nodes or contralateral hilar nodes, the disease becomes locally advanced. When signs of cancer are detected outside the pleural cavity, it is classified as advanced disease. Local disease is associated with the highest cure and survival rates, whereas those with advanced disease have a 5-year survival rate of less than 10%.
Table 90–3 Clinical Stage and Prognosis
Small Cell Lung Cancer
The most common system for staging SCLC was developed originally by the Veterans Administration Lung Cancer Study Group. This system categorizes SCLC into two classifications: limited and extensive disease14:
• Limited disease: Evidence of the tumor is confined to a single hemithorax and can be encompassed by a single radiation port
• Extensive disease: Any progression beyond limited disease
TREATMENT
Desired Outcome and General Approach to Patient
The treatment of lung cancer depends on tumor histology, stage of disease, and patient characteristics such as age, gender, history, and performance status (PS). All of these aspects must be assessed before appropriate treatment can be recommended. The general approach to treatment of lung cancer is outlined in Figure 90–1. In the development of a patient care plan, keep in mind the ultimate goals of therapy. In patients with early-stage disease, a definitive cure is the primary goal of treatment, although this end point is not always met. Additional goals of treating lung cancer patients include prolongation of survival and improvement of quality of life through alleviation of symptoms.The goals of treatment must be considered when selecting a therapeutic plan. Some treatments may prolong survival by a few months, but at the expense of significant decreases in patient’s quality of life. Treatment decisions must include both the health care team and an informed and well-counseled patient.
Patient Encounter, Part 2: Medical History, Physical Examination, and Diagnosis
PMH: Significant for COPD (poorly controlled), GERD (controlled with PPIs), and moderate hypertension
FH: Father died of MI, mother living
Meds: Lisinopril 20 mg daily; Lansoprazole 30 mg daily; Albuterol/ipratropium MDI two puffs twice a day
ROS: (+) light chest pain, shortness of breath, hemoptysis; (-) recent weight loss
PE:
VS: BP 135/69, RR 26, P 80, T 37.2°C (99°F)
CV: RRR
Labs: Slightly elevated ionized calcium and LFTs; all others WNL.
CXR reveals a solitary nodule in right lower lobe.
Fine-needle aspiration confirms adenocarcinoma.
Further evaluation with CT and PET scans reveal a T2N0M0 tumor.
What clinical stage is this patient’s disease?
What is the estimated survival time for this stage of NSCLC?
Does this patient have any factors that may negatively or positively influence survival?
Performance Status
The PS of an individual patient predicts response and likelihood of toxicity to chemotherapy as well as overall survival. The PS scaling system used most frequently was developed by the Eastern Cooperative Oncology Group (ECOG) (see Chap. 88). Categorizing patients by their ECOG PS allows for an objective measure of capability to tolerate systemic therapies that may severely compromise the patient’s health. Patients with a good PS (0–1) are more likely to tolerate intense therapy, whereas patients with a poor PS (3–4) are considered unfit for chemotherapy or surgery. There is some controversy over whether to treat patients with a PS of 2. At this point, treatment is aimed at treating comorbidities to improve the PS or the use of palliative symptomatic therapy. Patients with less advanced disease may be treated more aggressively in this scenario since the intent of treatment is curative.
Nonpharmacologic Therapy
Surgery
Of all treatment modalities, surgical resection of the affected lobe or lung leads to the greatest improvement in survival for patients with early-stage and locally advanced NSCLC (clinical stage IA, IB, or IIA). The candidacy of the tumor for resection should only be determined by an experienced thoracic surgeon who routinely works with cancer patients. During surgery, peripheral lymph nodes may be removed if they are thought to be involved, and mediastinal nodes are often dissected for biopsy to determine their involvement. In patients with advanced disease NSCLC, surgery is not curative and as a general approach does not prolong survival. However, surgery for advanced disease is an important palliative treatment that can improve quality of life in some patients. In this respect, surgery is limited to local sites where the tumor is causing significant morbidity (e.g., spinal cord compression). Patients with small cell carcinomas are rarely treated with surgery because the results of a randomized trial published in 1969 showed that surgery did not result in any 5- or 10-year survivors, whereas radiation produced a 4% survival rate at 5 and 10 years.15 With improved imaging and surgical techniques as well as the use of effective adjuvant therapy, some clinicians believe that surgery does have a role in early-stage SCLC. However, this has yet to be proven in a clinical trial.
FIGURE 90–1. Clinical pathway for nonsmall cell lung cancer. aSee text for specific treatment recommendations. (Chemo, chemotherapy; NSCLC, nonsmall cell lung cancer; PORT, postoperative radiotherapy; TNM, tumor node metastasis.)
Radiotherapy
As mentioned earlier, radiotherapy is the treatment of choice for limited-stage SCLC. Optimal patient outcomes are achieved when radiation is administered concurrently with chemotherapy because of synergy between the two modalities. Limited and extensive stage SCLC patients who respond to therapy should also receive prophylactic cranial irradiation (PCI), which prevents brain metastasis and improves cure rates for limited stage disease. Patients with localized NSCLC are best treated with surgery; however, many of these patients are inoperable because of comorbidities (e.g., lung disease from smoking). In these situations, radiation therapy can be used with curative intent in place of surgery, and the success rate is approximately 50% that of surgery.16 Similar to SCLC, patients with late-stage NSCLC can receive radiation therapy to palliate symptomatic metastases. Although radiation is less invasive than surgery, it can have marked toxicity on normal tissue and patients may experience esophagitis, pneumonitis, cardiac abnormalities, myelopathies, and skin irritation. These adverse events can be decreased by using stereotactic radiation and/or hyperfractionated administration.17
Postoperative radiotherapy (PORT) is thought to eliminate remnants of the resected tumor that might be deposited in nearby tissue. In clinical trials, PORT decreases local recurrence; however, a survival benefit has never been shown. A meta-analysis of investigations evaluating PORT suggested that it may actually be detrimental to patients with stage I or II NSCLC.18 The meta-analysis evaluated older studies that used outdated radiation techniques, and consequently, some argue that the meta-analysis does not apply to current practice. Nonetheless, no studies to date have demonstrated a survival advantage with the use of PORT. In cases where local recurrence is a significant risk, PORT still may be a viable option. In fact, current guidelines recommend that patients with positive surgical margins (i.e., cancerous cells are detected on the surface of the excised tissue) undergo re-resection or systemic chemotherapy or PORT.19 Outside of this recommendation, adjuvant radiotherapy without concurrent chemotherapy is not considered beneficial, especially in early-stage disease.
Patient Encounter, Part 3
The patient’s condition has not interfered with his ability to work, and he is able to complete daily activities.
What is this patients ECOG PS score?
Are there any nonpharmacologic interventions you would suggest?
Pharmacologic Therapy
Chemotherapy
Traditional chemotherapeutic agents interfere with processes during cell division or affect DNA replication in nondividing cells, resulting in cell death. Unfortunately, these agents are not specific for cancer cells, and other tissues in the body often are affected. Rapidly cycling cells, both tumor and normal tissue such as bone marrow, epithelial cells of the GI tract, and hair follicles, are most susceptible to chemotherapy toxicity. Because the dose of traditional chemotherapy agents is determined in phase I studies where the maximum tolerated dose is considered the best dose, toxicity is seen with each of these agents. Preventing and managing chemotherapy toxicity are crucial to optimizing patient outcomes (e.g., curing, prolonging life, or palliating symptoms). The decision to start chemotherapy depends greatly on the overall patient picture, with emphasis on PS and comorbid conditions. Knowledge of the major adverse effects of individual regimens is important for anticipation and prophylaxis of such toxicities. Many regimens require appropriate premedication and hydration. Furthermore, decisions to start chemotherapy must include the full consent and understanding of risks by the patient. Counseling on the chemotherapy and risk of toxicity is imperative before dosing. Lung cancer regimens and their associated toxicities are shown in Table 90–4. (See Chap. 88: Cancer Chemotherapy and Treatment for dosing recommendations in renal and hepatic failure.)
Doublet chemotherapy regimens offer superior response rates compared to single-agent regimens and should be used when the patient can tolerate the increased toxicity. Platinum-containing regimens are the mainstay of multidrug regimens. There are several regimens that contain either cisplatin or carboplatin combined with another chemotherapy agent; these are known as platinum doublets. Cisplatin and carboplatin are structurally related, but have distinct toxicity profiles and it is unclear if they are equally efficacious.
Nonsmall Cell Lung Cancer Both carboplatin and cisplatin show the most pronounced improvements in survival in patients with advanced-stage NSCLC when combined with newer agents such as gemcitabine, vinorelbine, docetaxel, or paclitaxel. Due to reduced neurotoxicity, nephrotoxicity, and GI toxicity, many clinicians favor carboplatin over cisplatin.28 There is also interest in developing nonplatinum-containing doublets. Recent studies suggest that gemcitabine combined with paclitaxel or docetaxel is just as effective in advanced-stage NSCLC as a platinum doublet; however, guidelines maintain that a platinum-containing doublet should be used when feasible.19
Small Cell Lung Cancer In SCLC, a platinum agent combined with an older agent (e.g., etoposide) is the treatment of choice. There are also a number of nonplatinum-containing three-drug anthracycline-containing regimens that are as effective as a platinum doublet, in extensive-stage disease. However, the three-drug regimens are more toxic and are rarely used in the United States. In limited-stage disease, cisplatin and etoposide are superior to the three-drug anthracycline-containing regimens, and provide optimal outcomes when combined with concurrent radiation.29
A direct comparison of etoposide combined with either cisplatin or carboplatin in SCLC found similar results. This leads some clinicians to consider the agents interchangeable; however, this trial primarily enrolled patients with extensive-stage disease. A direct comparison in patients with limited-stage disease has not been performed, and most clinicians consider cisplatin and etoposide to be the treatment of choice because this combination has been used in nearly all the large comparative trials.
Single-Agent Chemotherapy First-line therapy for advanced-stage NSCLC and SCLC is best done with a two-drug regimen. However, patients who have a recurrence after the initial regimen are best treated with a single-agent chemotherapy. Single-agent therapy is also acceptable for patients with poor health and advanced disease because toxicities tend to be lower with one-drug regimens. Chemotherapeutic agents used in monotherapy in lung cancer include pemetrexed, docetaxel, gemcitabine, paclitaxel, topotecan, and vinorelbine (Table 90–4).
Adjuvant Chemotherapy Surgery has a limited role in the treatment of SCLC making adjuvant chemotherapy primarily applicable to NSCLC. The rationale behind adjuvant chemotherapy is to eradicate micrometastases or other tumor cells that may have been missed during removal of the primary tumor. The recent results of five relatively large prospective trials (n = 344–1,867) suggest that there is benefit from adjuvant chemotherapy. The largest study, the International Adjuvant Lung trial,30 led to the conclusion that adjuvant chemotherapy following surgical resection of nonsmall cell tumors results in a 4% improvement in survival. However, the majority of patients in the International Adjuvant Lung (IALT) trial were treated with a cisplatin and etoposide, which has been proven inferior to newer combinations of cisplatin in the advanced disease setting. In support of this criticism, the intergroup JBR-10 study evaluated adjuvant cisplatin-vinorelbine (a current standard regimen for advanced-stage disease) and found a survival advantage of 15%.20 Consequently, adjuvant therapy has become the standard of care in resectable NSCLC and should be offered to patients after resection, particularly those with stage II–III disease. Although the regimen of choice is unclear, cisplatin-vinorelbine appears to be the regimen with the most evidence.
Table 90–4 Chemotherapy Regimens in Lung Cancer and Associated Toxicities
Neoadjuvant Therapy Neoadjuvant or induction therapy refers to the use of chemotherapy regimens or radiotherapy prior to surgery. Again, because surgery has a limited role in SCLC, this section applies primarily to NSCLC. The rationale behind neoadjuvant therapy is to decrease the size of the tumor so that it can be extracted more easily with clean margins, as well as to eliminate distant micrometastases before invasive local treatment. Furthermore, patients with marginally resectable or nonresectable tumors may respond sufficiently to induction therapy that surgery becomes an option. Neoadjuvant chemotherapy has been shown to yield benefits in NSCLC (i.e., increase in median survival and disease-free survival and decreased risk of metastasis) for both local and locally advanced disease.31 One concern is that the toxicity of induction regimens may delay surgery, and if the tumor does not respond to the treatment, there is a risk of disease progression. Nonetheless, current data suggest that over 90% of patients who are treated with neoadjuvant therapy maintain their scheduled surgery.32 This approach is most common in patients with locally advanced tumors (stage III).33 Current studies are aimed at comparing neoadjuvant with adjuvant therapy in earlier-stage NSCLC patients. The benefit of combining adjuvant therapy with induction therapy and surgery is also being investigated, but is of unknown value at this time.
Monoclonal Antibodies
Bevacizumab and cetuximab are IgG monoclonal antibodies that have activity in NSCLC. Bevacizumab targets vascular endothelial-derived growth factor (VEGF), which facilitates angiogenesis, a process contributing to growth and maintenance of the tumor environment. Bevacizumab has been shown to improve survival of advanced stage nonsquamous cell NSCLC patients in a large phase III trial34 and has been incorporated into current guidelines.19Squamous cell carcinoma of the lung should not be treated with bevacizumab due to the increased risk of bleeding events (an adverse event associated with bevacizumab administration) in this histological subtype.
Cetuximab targets epidermal growth factor receptor (EGFR), a cytokine receptor on tumor cells that is frequently involved with tumor survival and proliferation. This monoclonal antibody has a different and less extensive toxicity profile than traditional chemotherapy agents and appears to be synergistic when combined with chemotherapy. Cetuximab has recently been shown to be beneficial in NSCLC when added to cisplatin and vinorelbine in recurrent or metastatic NSCLC (Stages IIIB–IV).35
Tyrosine Kinase Inhibitors
Tyrosine kinase inhibitors (TKIs) work by targeting specific intracellular messenger proteins that transmit growth and survival signals. Two TKIs are currently available for treatment of lung cancer: erlotinib and gefitinib. These agents, like cetuximab, target the EGFR that has been shown to be mutated or overexpressed in some lung tumors. Both gefitinib and erlotinib are structurally related and presumably have the same mechanism of action; however, data show that erlotinib prolongs survival, whereas gefitinib does not in unselected patient populations. Consequently, gefitinib availability is restricted until the FDA determines if there is a predictable way to identify patients who will respond to therapy.
Pharmacogenomics and pharmacogenetics will likely soon play a major role in the selection of NSCLC patients who should receive oral EGFR inhibitors such as gefitinib or erlotinib. Large bodies of preclinical and clinical data demonstrate that certain mutations in the kinase domain of EGFR (L858R and del746–750) are associated with significant responses to such agents.36 The presence of other mutations in EGFR (T790M) are associated with resistance to such inhibitors through decreased drug binding to the receptor. EGFR mutations are more frequent in females, Asians, patients with adenocarcinoma histology, and nonsmokers. Additionally, the presence of activating mutations in KRAS, another oncogene known to play a role in lung cancer, is also associated with clinical resistance to EGFR inhibitors. These findings have prompted clinical guidelines to suggest that assessment of the mutation status of EGFRand/or KRAS may be critical in selecting patients for EGFR kinase inhibitor therapy.19 Patients with mutations in exons 19 or 21 of EGFR demonstrate the greatest likelihood of benefit, whereas those with mutations in exon 20 of EGFR or those with mutations in exons 1 or 2 of KRASdemonstrate the lowest likelihood of benefit. However, use of genotyping KRAS and EGFR has not yet entered into routine use in lung cancer. In addition to erlotinib and gefitinib, several “multitargeted” TKIs that target the EGFR and other cell-signaling cascades are in clinical trials and show promise for the treatment of lung cancer.
Small Cell Lung Cancer
SCLC typically presents as extensive disease (approximately 60–70% of new cases) and progresses very quickly. Small cell carcinomas are very responsive to chemotherapy and radiation, but have a short duration of response. Radiotherapy became the standard in 1969, when a randomized trial showed that it offered the potential for cure, whereas surgery did not.37 In the vast majority of patients, chemotherapy with or without radiotherapy is the treatment of choice. Even after a complete response to therapy, the cancer usually recurs within 6 to 8 months, and survival time following recurrence is typically short (approximately 4 months). This yields a typical survival rate of 14 to 20 months for limited disease and 8 to 13 months for extensive disease.21 Figure 90–2 illustrates the general treatment path of SCLC.
Limited Disease
The regimen of choice for limited-disease SCLC is etoposide-cisplatin (EP). In patients who are able to tolerate combined therapy, concomitant chemoradiotherapy offers the greatest survival benefit. Carboplatin may be substituted for cisplatin in patients who cannot tolerate cisplatin toxicity.38 In European countries, a three-drug combination containing an anthracycline has been the mainstay of therapy; however, mounting clinical evidence shows that these regimens are inferior to EP plus concurrent radiation and have more toxicity. Consequently, the guidelines recommend that the EP regimen be used with concurrent radiotherapy.21
Because patients with SCLC commonly have a recurrence in the CNS, trials have been performed to evaluate the benefit of PCI. A pivotal study showed that PCI reduces the incidence of brain metastasis and increases 3-year survival from 15% to 21%.39 Patients with limited stage SCLC who achieve a complete response with treatment should be offered PCI.
Extensive Disease
Platinum regimens, particularly EP, are the treatment of choice in extensive disease. In one Japanese study, a combination of irinotecan and cisplatin demonstrated an increased median survival time by approximately 3 months over the EP regimen. This irinotecan-cisplatin regimen also had a lower incidence of severe neutropenic side effects but exhibited higher rates of middle- to high-grade diarrhea.22However, this study was repeated in the United States and did not show a similar improvement over the EP regimen.40 Therefore, EP remains the regimen of choice for treating extensive SCLC in the United States. Due to the high sensitivity of treatment-naive SCLC to chemotherapy, it is imperative that these patients be monitored for signs of tumor lysis syndrome and possibly treated with prophylactic therapy.
FIGURE 90–2. Small cell lung cancer treatment overview. (CAV, cyclophosphamide, doxorubicin, vincristine; EC, etoposide carboplatin; EP, etoposide cisplatin; IC, irinotecan, cisplatin.) (From Ref 21.)
Concurrent radiotherapy is not used routinely in extensive disease; however, PCI provides significant benefit in patients responding to chemotherapy. A pivotal study demonstrated that median survival from the time of randomization increased from 5.4 to 6.7 months and 1-year survival rates increased from 13.3% to 27.1% with PCI. An additional benefit was a lower rate of brain metastasis (14.6% versus 40.4%).41
Recurrent Disease
The treatment of recurrent SCLC depends on the time to recurrence. If the time to recurrence is less than 6 months, second-line therapy should be considered if the patient has an acceptable PS (see Patient Care and Monitoring). The most widely accepted second-line therapies in SCLC are topotecan alone or CAV [cyclophosphamide, doxorubicin (Adriamycin), and vincristine]. Relapses occurring more than 6 months after treatment warrant a repeat of the initial regimen. Poor PS patients (3–4) are typically treated with palliative care therapies.
Nonsmall Cell Lung Cancer
The first step in treatment of NSCLC involves confirmation of the clinical stage and determination of resectability of the tumor. This decision should always be made by a thoracic surgeon who routinely performs lung cancer surgery. Treatment options depend on the advancement of disease (i.e., local, locally advanced, or metastatic), PS, and eligibility for resection.
Local Disease (Stages 1A, 1B, and II A)
Local disease encompasses stages IA through IIA and is associated with a favorable prognosis because approximately 40% to 60% of patients are expected to live more than 5 years from diagnosis. Goals of therapy are curative in local disease, and surgery is the mainstay of treatment. Stage IA tumors are rarely seen clinically and may be treated with surgery alone. In this case, neoadjuvant or adjuvant therapy has not been adequately studied to know if it conveys a benefit. If surgical margins are positive, radiotherapy or re-resection is recommended.19 Stages IB, IIA, and locally advanced IIB NSCLC is treated with adjuvant chemotherapy. Patients who have positive or questionable margins may receive radiation therapy, which typically is administered with the adjuvant chemotherapy. The regimen of choice in this setting is not clear; however, clinical trials demonstrating the most benefit used cisplatin-vinorelbine.19,42
Locally Advanced Disease (Stages IIB and I IIA)
Patients with locally advanced disease should also be considered for surgery. Neoadjuvant chemotherapy with concurrent radiotherapy can be used prior to surgery, although this practice varies from institution to institution. Progression of disease during induction therapy may preclude surgery, and the regimen should be altered. If there is a response, surgical resection can be attempted, with or without additional adjuvant chemotherapy. Nonresectable locally advanced disease may be treated with both an active platinum-containing regimen and radiotherapy.
Advanced or Metastatic Disease (Stages IIIB and IV)
Advanced disease is treated with chemotherapy if the patient has an acceptable ECOG PS score (0–1). Platinum-containing doublets have produced the highest overall response rates (25–35%) and survival times (30–40% 1-year survival) in well-performing patients with advanced disease. A number of different platinum doublet treatment regimens have been used in this setting. In some patients with stage IIIB disease, cisplatin and etoposide may be given concurrently with radiotherapy. However, treating unresectable stage III patients with a platinum-containing doublet regimen and omitting the radiation is common. The optimal regimen has yet to be determined. There has been some debate about the equivalence of cisplatin and carboplatin. To address this question, a recent meta-analysis was performed, which indicated that cisplatin was superior to carboplatin when combined with another agent (see below) in advanced-stage NSCLC.43 As with any meta-analysis, the methodology is subject to limitations leaving clinicians to make their own decision. Additionally, two nonplatinum-containing regimens have been shown to have similar response and survival benefits. Both gemcitabine-paclitaxel and gemcitabine-docetaxel produce response durations and survival times similar to the platinum-containing doublet regimens. These regimens may be substituted when patients are unlikely to tolerate the toxicity of platinum regimens owing to comorbidities or other factors. NSCLC chemotherapy doublets that are considered generally equivalent include:
• Paclitaxel–cisplatin
• Paclitaxel–carboplatin
• Cisplatin–gemcitabine
• Cisplatin–docetaxel
• Carboplatin–docetaxel
• Cisplatin–vinorelbine
• Gemcitabine–paclitaxel
• Gemcitabine–docetaxel
• Cisplatin–pemetrexed
A large randomized trial comparing the first four regimens reported similar response rates and survival with all treatments, although there was less life-threatening toxicity and treatment-related death associated with paclitaxel–carboplatin.23 Consequently, one may argue that paclitaxel–carboplatin is the treatment of choice. However, the carboplatin–paclitaxel regimen used in the trial infused paclitaxel over 24 hours, which is uncommon in clinical practice. The most common carboplatin-paclitaxel regimen infuses a higher dose of paclitaxel over 3 hours in the clinic rather than admit patients to the hospital for a 24-hour infusion. It is unfair to extrapolate the toxicity advantage from this trial to the commonly used 3-hour paclitaxel infusion, and consequently, there is not a single best regimen.
Taxanes (docetaxel and paclitaxel) are frequently employed in advanced NSCLC. Albumin-bound paclitaxel may be substituted for docetaxel or paclitaxel in patients who have experienced hypersensitivity reactions to taxanes despite antihypersensitivity premedication. The albumin-bound paclitaxel formulation does not include excipients such as Cremophor-EL that are thought to be the primary cause of frequent taxane-related reactions.
Targeted Agents While it is unclear exactly which combination is the best, new research is being aimed at adding targeted agents to platinum regimens. Adding bevacizumab to the carboplatin–paclitaxel (3-hour infusion) regimen increases response rates and prolongs progression-free survival by 1.7 months and overall survival by 2.3 months.34 Consequently, carboplatin–paclitaxel and bevacizumab are arguably the new standard of care. Based on the inclusion/exclusion criteria for this study, bevacizumab is recommended when the patient meets the following criteria:
• Nonsquamous cell histology (NSCLC only)
• History negative for hemoptysis
• History negative for untreated CNS metastasis
• No concurrent anticoagulation therapy (i.e., enoxaparin, heparin, or warfarin). In clinical trials, low-dose aspirin was permissible.
• Chemotherapy regimen that does not have significant (greater than 10%) risk of thrombocytopenia.
Interestingly, bevacizumab does not show synergy with all regimens; when combined with cisplatin and gemcitabine, no survival advantage is seen. Consequently, it should only be used with carboplatin and paclitaxel.
The anti-EGFR monoclonal antibody cetuximab has been shown to improve survival when combined with cisplatin and vinorelbine. The FLEX trial demonstrated a 1.2-month survival advantage of cetuximab when added to cisplatin and vinorelbine in recurrent or metastatic NSCLC (Stages IIIB-IV).35 The study population consisted of chemotherapy-naive patients with PS 0 to 2 that demonstrated positive tumor staining for EGFR by immunohistochemistry. It is unclear how this regimen compares to bevacizumab plus carboplatin and paclitaxel. Because bevacizumab was proven effective first and the survival advantage appears superior; cisplatin, vinorelbine, and cetuximab will likely only be used in patients with a contraindication to bevacizumab (squamous cell histology). Adding EGFR TKIs (erlotinib or gefitinib) to chemotherapy provides no benefit.
Poorly Performing Patients Treating patients with a PS of 2 is a subject of debate. While PS 2 patients typically have inferior survival rates and higher toxicity to platinum chemotherapy than higher-performing patients, low-toxicity single-agent regimens may offer a survival advantage in this subset. Use of these regimens also presents a method of providing symptomatic care for advanced-stage patients. Agents such as pemetrexed, gemcitabine, and docetaxel may be used in this scenario. In PS 3 or 4 patients, chemotherapy typically results in high rates of toxicity and fails to convey a survival benefit. Consequently, treatment should be aimed at relief of symptoms instead of a definitive cure.
Recurrent and Progressive Disease
Although patients may experience a response to initial therapy, disease recurs in many cases. If the recurrence is localized, surgery options may be assessed. If the patient’s PS remains acceptable (0–1), second-line systemic chemotherapy has been shown to improve survival. Although platinum doublets may be used at this point in care, a single-agent therapy with docetaxel, pemetrexed, or erlotinib is recommended.44 Recurrences in poorly performing patients (3-4) usually are not treated with chemotherapy and are instead treated with supportive care. Additional recurrences (e.g., third-line therapy) may be treated with erlotinib if not used previously. Otherwise, repeat single-agent therapy or administer best supportive care.
PATIENT CARE AND MONITORING
Management of Toxicity
Knowing when and how to treat adverse events from chemotherapy is an important aspect of patient care. Unmanaged events may cause delays in chemotherapy administration and reduced chemotherapy doses may contribute to treatment failure. Given the fatal nature of untreated lung cancer, patients and health care professionals are willing to tolerate high risks of severe and life-threatening side effects, provided that the therapy has been shown to benefit the patient. There are multiple methods of preventing or reducing toxicity from chemotherapeutic agents. These methods usually are agent-specific but commonly include maintenance of adequate hydration, use of appropriate premedications, dose reduction of the causative agent, and use of growth factors to combat toxicities associated with cytopenias.
Grading Toxicity
In order to standardize grading of adverse events, the National Cancer Institute (NCI) has developed the Common Toxicity Criteria (CTC, V3.0) for adverse events (see Chap. 88). In most cases, patients who experience grade 3 or 4 toxicity require a change in therapy with the next cycle of treatment. Common changes include a chemotherapy dose reduction or pharmacologic intervention to prevent or treat the toxicity. The CTC is an invaluable tool to determine what serious toxicity is most likely with a particular regimen, and improves the pharmacist s ability to counsel the patient as well as to determine appropriate toxicity-prevention measures.
Dose Intensity and Growth Factors
The term dose intensity refers to the percent of drug delivered compared with the planned amount as measured by milligrams per meter squared per week. Maintaining dose intensity (i.e., delivering the planned dose, according to the scheduled time course) has been shown to influence survival in some cancers such as breast cancer; however, the importance of dose intensity in lung cancer is not well established. In order to maintain dose intensity, pharmacologic agents are sometimes used to combat serious toxicities that may prohibit or delay administration of subsequent doses.
With most lung cancer chemotherapy regimens, the most common grade 3 or 4 toxicity is neutropenia. Patients who experience grade 3 or 4 neutropenia are at a high risk of developing a severe or life-threatening bacterial infection. Consequently, patients with neutropenia who develop a fever are empirically given broad-spectrum antibiotics. If a patient experiences neutropenic fever, dose reduction, or intervention with growth factors (e.g., pegfilgrastim, filgrastim, or sargramostim) to maintain dose intensity should occur prior to the next cycle of chemotherapy. In lung cancer patients, no survival benefit has been demonstrated by using a colony-stimulating factor to maintain dose intensity. While some evidence suggest that the use of a colony-stimulating factor reduces the number of neutropenic fever episodes, hospital stay, and antibiotic administration in certain subsets of lung cancer patients, routine front-line (prophylactic) use of a colony-stimulating factor is not recommended owing to lack of a survival benefit.45,46
Nausea and Vomiting
Platinum agents are the most active lung cancer agents and historically have very high rates of nausea and vomiting. This is particularly true of high-dose cisplatin, which is used in many regimens. Understanding how to prevent and treat chemotherapy-induced nausea and vomiting (CINV) in lung cancer patients is crucial because nearly all the regimens are highly emetogenic. Although the pathology of CINV is not fully understood, there are three classifications of CINV based on the time of occurrence in relationship to chemotherapy administration: acute CINV (1-24 hours after the dose), delayed (1-5 days after the dose), and anticipatory (before the dose following one or more previous cycles).
Acute CINV appears to be influenced predominantly by serotonin binding to 5-hydroxytryptamine-3 (5-HT3) receptors on the vagal nerve, where it innervates the GI tract. Delayed CINV has been attributed to a variety of mechanisms but appears to be influenced by substance-P stimulation of neurokinin-1 (NK-1) receptors in the CNS, as well as a corticosteroid-responsive element. Anticipatory CINV is thought to be a learned or conditioned behavior. The major influencing factors appear to be prior acute or delayed CINV and anxiety. Anticipatory CINV may be prevented or treated with benzodiazepines such as lorazepam or alprazolam not because they possess antiemetic properties but rather because they contain amnesic and antianxiety properties.
There are three main drug targets that are antagonized to prevent or treat acute and delayed CINV: 5-HT3 receptors, dopamine type 2 receptors (D2), and NK-1 receptors. 5-HT3-receptor antagonists are the most effective agents for preventing acute CINV. However, they are only recommended for moderate-to high-emetogenic-potential regimens, primarily owing to cost (see Table 90–5 for a comparison of agents). Aprepitant is the only available NK-1-receptor antagonist that is approved to prevent CINV. It has modest but additive activity in acute CINV and appears to be highly active in preventing delayed CINV. It was approved for use in highly emetogenic regimens but also works in patients receiving moderately emetogenic chemotherapy. The use of aprepitant is somewhat limited by the cost. D2 receptor antagonists, which are approved for schizophrenia, also have antiemetic activity in both acute and delayed CINV. As a group, these agents do not appear to be as effective as 5-HT3-receptor antagonist in acute CINV or as effective as aprepitant in delayed CINV. Consequently, their use is frequently limited to patients receiving mild or moderate emetogenic chemotherapy as prevention or as treatment following full-dose 5-HT3-receptor antagonist and/or aprepitant. They are attractive owing to their relatively low cost but cause a significant number of side effects. Interestingly, corticosteroids, most commonly dexamethasone, is an active antiemetic agent that can be used as monotherapy to prevent acute CINV in patients receiving mild-to-moderate emetogenic chemotherapy. They are also synergistic with 5-HT3-receptor antagonists, aprepitant, and D2-receptor antagonists in acute and delayed CINV. Although antiemetic choices typically are guided by chemotherapy, patient-specific risk factors that may play a role include the following high-risk features: very young age, very old age, female gender, emesis associated with pregnancy or motion sickness, and those with low alcohol intake.47
Diarrhea
Chemotherapy-induced diarrhea can be of significant toxicity in cancer patients and should be managed pharmacologically when necessary. The most common offending agent in the treatment of lung cancer is irinotecan. Treatment may include loperamide (4 mg at the onset followed by 2 mg every 2 hours until resolution—may use 4 mg every 4 hours during sleep) or octreotide (starting at 100 mcg subcutaneously every 8 hours and titrated to effect). The goals of therapy are resolution of diarrhea and improvement in quality of life.
Surveillance
Following response to surgery or pharmacologic treatment, the patient should be monitored regularly to detect recurrence. National Comprehensive Cancer Network (NCCN) guidelines suggest a physical examination and CXR every 3 to 4 months for 2 years. If no disease is detected during this time, follow-up frequency can be prolonged to every 6 months for 3 years and then annually. Low-dose spiral CT scanning is also recommended annually. Additionally, smoking-cessation counseling with or without pharmacologic treatment should be a priority. While studies have shown that patients who continue to smoke through treatment in NSCLC do not perform more poorly compared to those that quit prior to treatment, those that respond to treatment and continue to smoke probably have increased risk of developing secondary malignancies.48 In contrast to NSCLC, some data suggest that SCLC patients with limited stage disease have poorer outcomes if they continue to smoke during treatment.49
Table 90–5 Pharmacotherapy for CINV
Complications
Cachexia and Anorexia
Cachexia is a severe wasting syndrome that is seen in many cancer patients. Although it is more common in advanced disease, it is often seen in localized disease as well. Cachexia is characterized by a catabolic state that leads to significant loss of body mass, both lean muscle and fat. The causes of cachexia are poorly understood, but it is thought that they involve inflammatory cytokines such as tumor necrosis factor-a (originally described as cachexin). Anorexia is the patient’s loss of appetite or willingness to eat. The presence of anorexia can aggravate cachexia and contribute to morbidity. When anorexia contributes to cachexia, it is important to assess the patient for the underlying cause of the anorexia.
Causes for anorexia in lung cancer patients can be widespread and include CINV, esophagitis, and mucosal irritation from combined radiotherapy and chemotherapy, GI obstruction owing to tumors, constipation from opioid analgesics, and psychological factors such as anxiety or depression. Many of these issues may be improved with pharmacologic treatment of the underlying cause (i.e., antidepressant therapy for psychological factors) or with palliative treatment of the offending tumor.50 Additionally, appetite stimulants such as the cannabinoid dronabinol (2.5 mg twice daily with meals, titrated to a maximum of 20 mg/day) and megesterol acetate (400–800 mg/day orally) can aid in increasing caloric intake.
Cachexia is more difficult to treat, although it may resolve following treatment of the underlying malignancy. Nutritional consultation may be of aid, although cachexia is thought to be more attributable to internal pathophysiologic processes than malnutrition.
Paraneoplastic Syndromes
Paraneoplastic syndromes are clinical syndromes caused by nonmetastatic systemic effects of cancer. Tumors make and secrete biologically active products that can stimulate or inhibit hormone production, autoimmunity, immune complex production, or cause immune suppression. Lung cancer, particularly SCLC, is associated with a high rate of paraneoplastic syndromes. Pharmacologic therapy is necessary when the abnormality causes the patient acute physical or psychological stress or adversely affects his or her health. When possible, therapy should be directed at the primary tumor, and a response often leads to resolution of symptoms.
Patient Encounter, Part 4
On the basis of the information provided, develop a care plan for this patient. Include (a) treatment goals, (b) monitoring parameters for anticipated toxicities, and (c) a follow-up plan to determine response to treatment and surveillance.
Palliative Care
Ultimately, most lung cancer patients succumb to their disease. Palliative care involves management of symptoms and improvement of quality of life when curative treatment options are no longer available. Often, problematic metastases can be removed by surgery (depending on location) or can be treated with radiotherapy to reduce tumor size. In selecting options at this point in treatment, it is important to keep the goals of therapy in mind, those being maximizing the duration and quality of life. Low-toxicity single-agent chemotherapy, targeted therapy, and best supportive care (including fatigue and pain management) are commonly the mainstays of palliative care.
OUTCOME EVALUATION
Following treatment, evaluate the goals of therapy versus the response that was achieved. Was there response to treatment or progression of disease? If the patient is being treated with supportive care, then alleviation of symptoms and improvement in quality of life should be of primary importance. Be sure to document objective evaluations of the outcome in the care plan.
Abbreviations Introduced in This Chapter
Patient Care and Monitoring
1. Review the patient’s medical and social history. Was the patient exposed to clinical risk factors for lung cancer?
2. Verify the histology and clinical stage of disease. Evaluate the patient’s PS. Is the patient a surgical candidate? How does this influence your treatment recommendations?
3. Develop a care plan based on treatment goals. If the goal is palliative care, how does treatment-related toxicity influence therapy?
4. If chemotherapy is the treatment of choice, counsel the patient on risks and benefits of undergoing such therapy. Be sure that the patient understands the issues fully before moving forward.
5. Verify dosing of all agents in the chemotherapy regimen. What are the major expected toxicities?
6. Evaluate toxicity as treatment progresses. Is the toxicity severe enough to warrant dose reduction or pharmacologic treatment? Record graded toxicities according to the NCI CTC V3.0 criteria.
7. Evaluate the response to treatment. Did the patient experience a complete response, partial response, stable disease, or disease progression? How does this change future treatment?
8. If the patient is in remission, develop a monitoring plan. What signs or symptoms denote disease progression?
9. Recommend a smoking-cessation program or other risk-reduction plan for the patient.
Self-assessment questions and answers are available at http://www.mhpharmacotherapy.com/pp.html.
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