Martin J. Edelman and David R. Gandara
I. EPIDEMIOLOGY AND ETIOLOGY
A. Incidence. Lung cancer is the most common visceral malignancy, accounting for roughly one-third of all cancer deaths, and it is the most common cause of cancer-related death in both men and women. Annually there are approximately 225,000 new cases in the United States. This appears to be an increase, but a revised methodology has been utilized. Although rates for men are decreasing, there is a continued increase for women. Even more disturbing is a possible increase in incidence of non–small cell lung cancer (NSCLC) in patients who never smoked or had a minimal smoking history (i.e., <10 to 15 pack years). Specific mutations, amenable to targeted therapy, have been identified in a large fraction of this emerging population.
B. Etiology
1. Smoking. Cigarette smoking is the cause of 85% to 90% of lung cancer cases; the risk for lung cancer in smokers is 30 times greater than in nonsmokers. Smoking cigars or pipes doubles the risk for lung cancer compared with the risk in nonsmokers. Passive smoking probably increases the risk of lung cancer about twofold, but because a proportion of the risk associated with active inhalation is about 20-fold, the actual risk is small.
a. The risk for lung cancer is related to cumulative dose, which for cigarettes is quantified in “pack-years.” One in seven people who smoke more than two packs per day die from lung cancer. The incidence of death from lung cancer begins to diverge from the nonsmoking population at 10 pack-years.
b. After cessation of smoking, the risk steadily declines, approaching, but not quite reaching, that of nonsmokers after 15 years of abstinence for patients who smoked for <20 years. With the decline in smoking in the United States, a large percentage of new diagnoses of lung cancer occur in former smokers.
c. The risk of the major cell types of lung cancer is increased in smokers. Some adenocarcinomas, especially in women, are unrelated to smoking (see Section I.B.7 below).
d. Small cell lung cancer (SCLC) is almost always associated with smoking. The diagnosis should be questioned in patients who deny a smoking history.
2. Asbestos is causally linked to malignant mesothelioma. Asbestos exposure also increases the risk for lung cancer, especially in smokers (three times greater risk than smoking alone).
3. Radiation exposure may increase the risk for SCLC in both smokers and nonsmokers. Radon has been associated with up to 6% of lung cancer cases.
4. Other substances associated with lung cancer include arsenic, nickel, chromium compounds, chloromethyl ether, and air pollutants.
5. Lung cancer is itself associated with an increased risk for a second lung cancer occurring both synchronously and metachronously. Other cancers of the upper aerodigestive tract (head and neck, esophagus) are associated with an increased risk for lung cancer because of the “field cancerization” effect of cigarette smoking.
6. Other lung diseases. Lung scars and chronic obstructive pulmonary disease are associated with an increased risk for lung cancer.
7. Never and minimal smokers and lung cancer. A substantial portion of the lung cancer population has no obvious toxic exposure. Approximately 10% of patients with NSCLC are never smokers. Many of these cases are associated with mutations of the epidermal growth factor receptor (EGFR). The etiology of these abnormalities is unknown. In addition, EML4/ALK translocations have been described in this population. Patients with EGFR or EML4/ALK mutations may be highly responsive to specific EGFR or ALK-targeted agents, respectively, and have a markedly different prognosis from other patients with lung cancer.
II. PATHOLOGY AND NATURAL HISTORY. Fine-needle aspiration (FNA), through bronchoscopy or transthoracic CT guided biopsy, makes specific histologic classification of lung cancer difficult. Although FNA can usually distinguish between SCLC and NSCLC, it is difficult to distinguish between the histologic subtypes of NSCLC, and this can occasionally result in misdiagnosis of carcinoid as SCLC. A needle core biopsy or paraffin fixation of FNA material is preferable as these allow for better histologic analysis as well as immunohistochemistry or other special diagnostic techniques. These are of increasing importance as targeted therapies for specific subsets of patients are validated.
A. Small cell lung cancer (SCLC; 15% of all lung cancers). SCLC comprises several histologic subtypes: oat cell, polygonal cell, lymphocytic, and spindle cell carcinoma. The natural histories of these subtypes are virtually identical.
1. Location. More often central or hilar (95%) than peripheral (5%)
2. Clinical course. Patients with SCLC often have widespread disease at the time of diagnosis. Rapid clinical deterioration in patients with chest masses often indicates SCLC.
a. Hematogenous metastases commonly involve the brain, bone marrow, or liver. Pleural effusions are common.
b. Relapse after radiation therapy (RT) or chemotherapy occurs in the sites initially affected as well as in previously uninvolved sites.
3. Associated paraneoplastic syndromes include the syndrome of inappropriate antidiuretic hormone (SIADH; most common), hypercoagulable state (common), ectopic adrenocorticotropic hormone (ACTH) syndrome (uncommon), and Eaton–Lambert (myasthenic) syndrome (rarely seen with any other tumor). Hypercalcemia occurs rarely in SCLC, even in the presence of extensive bony metastases.
B. Non–small cell lung cancer (NSCLC; 85% of all lung cancers). Squamous, adenocarcinoma, and large cell lung cancer have been grouped together as NSCLC. Because significant differences in treatment for squamous versus nonsquamous NSCLC have emerged, it is now important to define the actual histologic variant.
1. Squamous cell carcinoma (20% to 25% of NSCLC)
a. Location. Previously, adenocarcinomas were thought to occur in a predominantly peripheral location, whereas squamous cell cancers occurred centrally. Studies indicate a changing radiographic presentation, with the two cell types now having similar patterns of location.
b. Clinical course. Compared with other kinds of lung cancers, squamous cell lung cancers are most likely to remain localized early in the disease and to recur locally after either surgery or RT.
c. Associated paraneoplastic syndromes. Hypercalcemia resulting from ectopic production of parathyroid hormone–related peptide (PTH-RP) is the more frequent syndrome. Hypertrophic osteoarthropathy (occasional), paraneoplastic neutrophilia (sometimes associated with hypercalcemia), prominent joint symptoms (occasional), or hypercoagulability is also seen.
2. Adenocarcinoma (50% to 60% of NSCLC). Adenocarcinoma is the most common cell type occurring in nonsmokers, especially young women. Most cases, however, are smoking associated. The incidence of this histology has increased in recent years.
a. Location. These tumors present as peripheral nodules more commonly than squamous cell carcinoma.
b. Clinical course. More than half of patients with adenocarcinoma, apparently localized as a peripheral nodule, have regional nodal metastases. Adenocarcinomas and large cell carcinomas have similar natural histories and spread widely outside the thorax by hematogenous dissemination, commonly involving the bones, liver, and brain.
c. Associated paraneoplastic syndromes include hypertrophic osteoarthropathy, hypercoagulable state, hypercalcemia due to PTH-RP or cytokines, and gynecomastia (large cell).
d. Despite recent changes to the histologic classification of adenocarcinoma of the lung, bronchioloalveolar carcinoma (BAC) remains a defineable subtype of adenocarcinoma with distinct histologic, biologic, epidemiologic, clinical, and therapeutic characteristics. Pure bronchioloalveolar carcinoma is characterized by a spreading (“lepidic”) pattern within the bronchioles without evidence of invasion. The disease is characterized radiographically by an infiltrative pattern and is frequently multicentric. It is frequently misdiagnosed as pneumonia on initial presentation. The most common type of BAC is adenocarcinoma with a BAC component. This implies invasiveness through the basement membrane. Epidemiologically, it seems to occur more frequently in young, female nonsmokers and reportedly is more responsive than other lung cancer types to the tyrosine kinase inhibitors erlotinib and gefitinib.
3. Large cell and “not otherwise specified” lung cancer. The remainder of NSCLC consists of large cell and other histologies. Large cell NSCLC with neuroendocrine features is increasingly diagnosed on the basis of immunohistochemical features of neuroendocrine differentiation (e.g., chromogrannin, neuron specific enolase).
C. Uncommon tumors of the lung and pleura
1. Bronchial carcinoids may present with local symptoms from airway obstruction, ectopic ACTH production, or carcinoid syndrome (see Chapter 15, Section II). These tumors demonstrate neuroendocrine differentiation and are occasionally confused with SCLC.
2. Cystic adenoid carcinomas (“cylindromas”) are locally invasive cancers. Locoregional recurrence is most common, but they may also metastasize to other areas of the lung and to distant sites (see Chapter 19, Section V).
3. Carcinosarcomas are large lesions that have a tendency to remain localized and are more often resectable than other lung malignancies.
4. Mesotheliomas are caused by exposure to asbestos and occur primarily in the pleura, peritoneum, or tunica vaginalis or albuginea of the testis. A history of asbestos exposure of any duration at any time is prima facieevidence that it caused the mesothelioma.
a. Histopathology. Mesotheliomas consist of several histologic variants: sarcomatous, epithelioid, and others that have the histologic appearance of adenocarcinoma. The latter type can be distinguished from other adenocarcinomas by the absence of mucin staining and the loss of hyaluronic acid staining after digestion by hyaluronidase.
b. Clinical course. The diffuse (usual) form of mesothelioma spreads rapidly over the pleura and encases the lung. It may develop multifocally and invade the lung parenchyma. Distant metastases are not common and usually occur late in the course. If there is a sarcomatous pattern, liver, brain, and bone may be involved.
III. DIAGNOSIS AND FURTHER EVALUATION. The diagnostic evaluation should proceed in an orderly manner to establish an accurate diagnosis and stage of disease. If lung cancer is suspected on the basis of the signs and symptoms described in the following subsections, an initial limited laboratory and radiologic evaluation is indicated. The primary effort should be directed at establishing a histologic diagnosis because this will determine the need for, and type of, additional tests as well as therapeutic options.
If NSCLC is diagnosed, the subsequent staging evaluation is directed to determine which modalities of therapy (surgery, radiotherapy, or chemotherapy) should be employed. In the past, surgery has been the mainstay of therapy for NSCLC and remains the primary mode in early stage (I and II) disease. Therefore, the initial evaluation determines whether the tumor is potentially resectable (the tumor can be surgically removed with clear margins) and operable(the patient is physiologically capable of withstanding such a procedure).
The fundamental question must also be asked: What are the long-term results for surgical resection of any given stage of NSCLC? If surgery is not warranted, then the next question is whether the patient24 is a potential candidate for nonsurgical management with curative intent (i.e., chemoradiotherapy).
If SCLC is diagnosed, the evaluation is directed at determining whether the patient has limited- or extensive-stage disease because stage dictates prognosis and the appropriate therapeutic approach. Generally, the therapeutic approach to SCLC involves chemotherapy with or without radiotherapy. Only occasionally does surgery play a role in this disease.
A. Symptoms and signs
1. Symptoms. The majority of patients present with symptomatic disease. Symptoms may be referable to the primary disease in the chest (new or changing cough, hoarseness, hemoptysis, chest pain, dyspnea, pneumonia), metastatic disease (new nodal masses, bone pain, pathologic fracture, headache, seizure), or paraneoplastic manifestations (anorexia, weight loss, nausea due to hypercalcemia, etc.). These symptoms frequently inspire a smoker to quit just before the diagnosis of lung cancer. Patients may also be completely asymptomatic and present as a consequence of an incidental finding on a radiographic study obtained for another reason. Even asymptomatic patients may have advanced disease.
a. Patients with cancers located in the lung apices or superior sulcus (Pancoast tumor) may have paresthesias and weakness of the arm and hand as well as Horner syndrome (ptosis, miosis, and anhidrosis) caused by involvement of the cervical sympathetic nerves.
b. Evidence of metastatic disease includes bone pain; neurologic changes; jaundice, bowel, and abdominal symptoms with a rapidly enlarging liver; subcutaneous masses; and regional lymphadenopathy.
2. Physical findings. In addition to local findings in the chest and lungs, physical examination should be directed at determining whether there is metastatic disease, which would both provide staging information and, in the case of superficial cutaneous or lymph node involvement, allow for easier biopsy. Particular attention should be paid to the head and neck for concomitant cancers; to lymph node areas in the supraclavicular fossa, neck, and axilla for metastases; and to the abdomen for hepatomegaly.
B. Laboratory studies
1. Radiographs
a. Chest radiograph. If a mass is present, old x-ray films should be obtained for comparison. Persistent infiltrates, particularly in the anterior segments of the upper lobes, are suggestive of cancer.
b. Computed tomography (CT) scan of the chest and abdomen through the level of the adrenal glands. CT of the chest for the staging of lung cancer is clearly superior to chest radiographs and has been reported to have an overall accuracy of 70%. Mediastinal lymph nodes are generally considered abnormal when larger than 1.5 cm in diameter and normal when smaller than 1.0 cm; nodes between these two limits are indeterminate. If 1.5 cm is used to categorize mediastinal lymphadenopathy as abnormal, sensitivity of CT is relatively poor, but specificity is excellent. CT scanning provides information about the extent of invasion of the primary tumor, the presence of pleural effusion, and lymph node status. Magnetic resonance imaging (MRI) rarely adds additional information.
(1) Adrenal masses. Unsuspected adrenal metastases are common in NSCLC and alter management if the patient otherwise appears to have early stage disease. Nonmalignant adrenal masses are also common (adrenal adenomas), however, and care must be taken not to deprive a patient of an otherwise curative procedure based on an isolated adrenal mass. It is sometimes possible to distinguish between metastatic disease and adenomas based on the density characteristics on CT or MRI. If the diagnosis is unclear and the adrenal is the only site of suspected metastases, biopsy is indicated.
(2) Other single areas that are suspect for, but not diagnostic of, malignancy (i.e., liver, brain) warrant a similar approach (see also Section VII.B).
C. Obtaining pathologic proof of lung cancer. Before embarking on other studies, a diagnosis of lung cancer must be proved histologically. Pursuit of the diagnosis should start with the least invasive procedure that gives histologic proof of malignancy.
1. Sputum cytology, which was once routine practice, has been largely replaced by the flexible fiberoptic bronchoscope. Even in the best series, repeated sputum cytology is positive in only 60% to 80% of centrally located NSCLC and 15% to 20% of peripheral NSCLC.
2. Flexible fiberoptic bronchoscopy if symptomatic or radiologic evidence indicates a central and accessible cancer or nodal disease. Most cancers can be directly visualized. Additional tumors are evident only as extrinsic bronchial narrowing, which may be diagnosed through the bronchoscope by transbronchial biopsy in some cases. Inspection of the airways by bronchoscopy also rules out endobronchial lesions from a second bronchogenic carcinoma. Bronchoscopy is unnecessary if histologic or cytologic diagnosis of metastatic lung cancer has already been made.
3. Suspicious cutaneous nodules may undergo biopsy to establish a histologic diagnosis and for staging.
4. Lymph nodes. Enlarged, hard, peripheral lymph nodes represent another potential site for biopsy. Blind biopsy of nonpalpable supraclavicular nodes is positive for cancer in <5% of cases. The finding of granuloma in lymph nodes can be misleading; some patients have cancer concomitant with sarcoidosis or granulomatous infections.
D. Subsequent evaluation. After the histologic diagnosis of lung cancer, the evaluation should focus on determining whether disease is confined to the chest and may therefore be treated with curative intent (limited-stage SCLC and stages I to III NSCLC) or whether the patient has distant disease. In appropriately selected patients, the following diagnostic studies may assist in making this determination. In the absence of abnormalities evident from history, physical examination, and routine blood studies, these studies are likely to be normal.
1. Positron emission tomography (PET). PET scanning is an established technology based on the differential uptake of radiolabeled glucose (fluorodeoxyglucose [FDG]) by neoplastic tissues compared with normal tissue. Although PET scanning has demonstrated superiority to CT scanning and is complementary to mediastinoscopy in the evaluation of mediastinal nodes, it is most useful in excluding distant occult metastases. PET may also be useful in restaging after a preoperative therapy (i.e., chemotherapy or chemoradiotherapy) or in follow-up. The precise criteria for what constitutes a “response” by PET scan are in evolution. PET-CT scanners are now becoming available and may further improve the ability to accurately stage patients. False-positive PET scans may occur in the setting of infection, inflammation, or after chemoradiotherapy. False-negative scans are frequently seen in well-differentiated adenocarcinoma with BAC features.
2. Spinal MRI for patients who have suspected epidural metastases in the spinal canal or suspected lung cancer with back pain or brachial plexopathy. In patients with back pain and suspected lung (or any other) cancer, the workup should be performed on an urgent or emergent basis to allow for rapid therapeutic intervention with steroids, RT, or surgery.
3. Brain CT or MRI should be obtained as part of routine staging for patients with SCLC, which is associated with a 10% incidence of neurologically asymptomatic brain metastases. These studies are not recommended for staging most patients with stage I or II NSCLC in the absence of clinical signs. For patients with histologies characterized by frequent spread to the central nervous system (CNS; e.g., large cell with neuroendocrine differentiation or adenocarcinoma), CNS imaging for localized disease should be considered. Patients with stage III and IV NSCLC who are under consideration for aggressive multimodality therapy or chemotherapy should undergo CNS scanning.
4. Mediastinoscopy is useful in the following circumstances:
a. For routine preoperative staging of NSCLC (radiologic assessment alone of the mediastinum is inadequate)
b. In patients with mediastinal masses, negative sputum cytology, and negative bronchoscopy
c. To evaluate mediastinal lymphadenopathy. Hyperplastic nodes related to postobstructive infection are common. Mediastinoscopy may permit the patient to be considered for curative resection if enlarged nodes on CT scan are demonstrated to be pathologically negative.
d. Restaging after preoperative chemotherapy or chemoradiotherapy in patients with stage III NSCLC based on pathologic documentation of N2 positive lymph nodes.
5. Percutaneous and transbronchial needle biopsy are frequently used to diagnose lung cancer. Some argue that if NSCLC is found by these techniques and medical resectability is assumed, mediastinoscopy or thoracotomy inevitably follows in the absence of evidence of metastatic disease, and therefore the procedure is unnecessary. Furthermore, if cancer is suspected and the needle biopsy reveals a granuloma, the cancer may have been missed. If the diagnosis is SCLC, however, thoracotomy may be avoided. Additionally, medically inoperable patients with negative bronchoscopy still require a tissue diagnosis.
6. Bone scans have largely been supplanted by PET. However, the bone scan offers complementary information regarding bone disease to PET and is substantially less expensive. There may be value for obtaining a bone scan in a patient with known metastatic disease in whom new bone involvement is suspected.
7. Bone radiographs (plain films) of painful areas
8. Bone marrow aspiration and biopsy. Bone marrow examination remains a standard part of the evaluation for patients with apparently limited-stage SCLC because of the relatively high incidence of subclinical involvement. Some believe that it is unnecessary if the patient has a normal lactate dehydrogenase level. It is rarely indicated in NSCLC.
E. Evaluation of the solitary pulmonary nodule requires a diagnostic strategy that maximizes the chance of detecting cancer and minimizes the chance of performing a needless thoracotomy if the nodule is benign. The diagnostic approach must be individualized. Facts that should be considered include
1. Characteristics that define a solitary pulmonary nodule are as follows:
a. A peripheral lung mass measuring <6 cm in diameter
b. The nodule is asymptomatic.
c. Physical examination is normal.
d. CBC and LFTs are normal.
2. Calcification of the nodules has little bearing on the diagnostic approach. Calcified nodules are more likely to be malignant unless the pattern is circular, crescentic, or completely and densely calcified.
3. Risk that a solitary pulmonary nodule is malignant
a. According to age
(1) Younger than 35 years of age: <2%
(2) 35 to 45 years of age: 15%
(3) Older than 45 years of age: 30% to 50%
b. According to tumor volume doubling time (DT)
(1) DT of 30 days or less: <1%
(2) DT of 30 to 400 days: 30% to 50%
(3) DT of >400 days: <1%
c. According to smoking history. The risk of a solitary nodule being cancerous in a smoker compared with a nonsmoker is not known. The incidence is generally higher for smokers in the older age group.
4. Needle biopsies of solitary nodules are falsely negative in 15% of cases. In a patient with a high likelihood of cancer (e.g., a smoker who is older than 40 years of age), who is also a good surgical candidate, proceeding directly to thoracotomy without a tissue diagnosis is reasonable.
5. PET scanning has recently demonstrated considerable value in the diagnostic evaluation of the solitary pulmonary nodules, with sensitivity and specificity exceeding all other diagnostic modalities short of thoracotomy.
IV. STAGING SYSTEM AND PROGNOSTIC FACTORS
A. Staging system. The “TNM” system is applied primarily to NSCLC. Table 8.1.A presents the 7th edition (2010) of AJCC Cancer Staging Manual, based on the recommendations of the staging committee of the International Association for Lung Cancer (IASLC) and review of >67,000 lung cancer cases. This system provides for additional cutoffs for tumor size, reassigns the category for pulmonary nodules in some locations, and reclassifies effusions as substage M when compared to the system that was published in the 6th edition (2002). Table 8.1.B. shows the anatomic stage/prognostic groups for the current TNM system.
Table 8.1.A TNM Staging System for Lung Cancera
aAdapted from the AJCC Cancer Staging Manual, 7th edition, 2010, Springer. Changes of descriptors from the 6th edition of the AJCC Cancer Staging Manual (2002) are shown in italics.
Table 8.1.B Stage Groupings for Non–Small Cell Lung Cancera
aAdapted from the AJCC Cancer Staging Manual, 7th edition, 2010, Springer.
Because the older system is still commonly referred to and is necessary to understand when interpreting recent trials. Table 8.1.C shows the new stage groupings related to the older system; bolded stages indicate changes from the last edition. In the new system, stages IA to IIIA represent disease for which a surgical approach (in physiologically appropriate patients) should be considered in the management plan.
Table 8.1.C Stage Groupings for Lung Cancer: Comparison of the 6th and 7th Editions of the AJCC Cancer Staging Manuala
Bold print indicates a change from the 6th edition for a particular TNM category.
aReprinted from Goldstraw P, Crowley J, Chansky K, et al. The IASLC Lung Cancer Staging Project: proposals for the revision of the TNM Stage Groupings in the forthcoming (seventh) edition of the TNM classification for malignant tumours. J Thor Oncol 2007;2:706–714, with permission.
AJCC, American Joint Committee on Cancer.
B. Performance status (PS) has direct bearing on patient survival and should be accounted for in studies evaluating treatment modalities for lung cancer. Criteria for assessment of functional PS are described on the inside of the back cover. Patients who feel well and have few symptoms of disease (PS of 0 to 1) survive longer than ill patients (PS of 2 or more) and are more likely to tolerate chemotherapy, independent of other prognostic factors.
C. Weight loss. Involuntary weight loss of 5% or more is an independent and negative prognostic factor.
D. Tumor histology. Survival is not greatly influenced by cell type if PS and extent of disease are taken into account. In NSCLC, specific histology appears to be of importance in the selection of specific chemotherapy regimens on the basis of both patterns of toxicity and efficacy. Patients with SCLC, however, have debility and extensive disease more often than those with the other cell types.
E. Molecular prognostic factors. Suppressor oncogene alterations are common in NSCLC and are associated with a poor prognosis; mutated p53 (17p) oncogene occurs in half of patients with NSCLC and in almost all patients with SCLC. Dominant oncogene overexpression (c-myc, K-ras, erb-B2) is associated with a poor prognosis.
1. EGFR mutations are increasingly recognized as important features of lung cancer. EGFR mutations appear to be associated with a better overall prognosis as well as to be predictive for benefit from anti-EGFR therapies, notably the tyrosine kinase inhibitors (TKIs) erlotinib and gefitinib. Numerous abnormalities that predict benefit to the EGFR TKIs (“sensitizing mutations”) have been described between exons 18 and 21 of the gene. The most common are deletions in exon 19 and missense mutations in exon 21. Other mutations, most notably on exon 20 (e.g., T790M) predict for resistance to EGFR TKIs.
2. EML4/ALK translocations. Patients with this abnormality are demographically similar to those with EGFR mutations (never/scant smokers, adenocarcinoma). A new agent, crizotinib, is highly active in this setting. Crizotinib has been approved by the FDA for NSCLC with EML4-ALK translocation as defined by a fluorescence in situ hybridization (FISH) assay; however, immunohistochemistry or RT-PCR may define additional ALK positive patients who benefit from crizotinib.
3. ERCC1, a component of the nucleotide excision and repair system, has prognostic value and also may be useful in identifying patients who can benefit from platinum agents. Overexpression of ERCC1, as determined by mRNA expression levels by RT-PCR or by immunohistochemistry, may be associated with lack of benefit from platinum agents. A prospective biomarker validation trial (EPIC) is in development.
V. PREVENTION AND EARLY DETECTION
A. Prevention is the best way to reduce the death rate from lung cancer. More than 90% of patients with lung cancer would not have developed the disease if they had not smoked. Every smoking patient should be advised of the enormous risks. Several ongoing studies are evaluating the role of retinoids and other compounds in preventing secondary tumors. Trials of vitamin A analog supplementation and beta-carotene have failed to demonstrate benefit. Epidemiologically, aspirin use in individuals who have quit smoking has been associated with reduced risk of developing lung cancer.
B. Early detection of lung cancer by screening high-risk populations with chest radiographs and sputum cytology has not been clearly demonstrated to improve survival rates. The role of chest radiography is being re-evaluated. New antibody tests and fluorescent bronchoscopy are also under study.
Spiral CT scan can increase the number of cancers detected. However, this increased rate of detection has not yet been demonstrated to reduce the overall or lung cancer–specific death rate. It is therefore not established as an effective screening tool.
The National Lung Screening Trial (NLST) has completed accrual of 50,000 subjects considered to be at high risk for lung cancer on the basis of age and smoking history. This study compared 3 years of screening with CT versus CXR. The preliminary results of this study were reported by the National Cancer Institute in late 2010. The use of spiral CT scans was associated with a 20% reduction in risk of death from lung cancer as well as reduction in all cause mortality. However, false-positive screening results occurred in approximately 25% of patients due to the prevalence of lung abnormalities in patients at risk for lung cancer. Because the value of a screening test is dependent on the prevalence of a disease in a population, the determination that smokers with minimal degrees of obstructive disease are at substantially higher risk for lung cancer may improve the sensitivity and specificity of screening tests.
VI. MANAGEMENT
A. NSCLC. Surgery, the previous mainstay of management, is still the primary mode of therapy in stage I and II disease. Stage III disease (characterized by mediastinal nodal disease or involvement of major structures) is frequently resectable but almost invariably relapses, resulting in the patient’s death within 5 years (90% to 95%) when managed by surgery alone. Therefore, multimodality therapy is increasingly employed in this large subset (about 40,000 patients per year). Patients with only a single mediastinal nodal “station” positive for disease or with incidentally discovered stage III disease (i.e., patients who undergo surgery for stage I or II disease and who are found to have microscopic mediastinal nodal disease) fare substantially better than other stage III patients.
After histologic proof of NSCLC is obtained, resectability is determined by the extent of the tumor and operability according to the overall medical condition of the patient. About half of patients with NSCLC are potentially operable. About half of tumors in operable patients are resectable (25% of all patients), and about half of patients with resectable tumors survive 5 years (12% of all patients or 25% of operable patients).
The following recommendations are consistent with those of the American Thoracic Society and the European Respiratory Society.
1. Determinants of resectability. Signs of unresectable NSCLC are as follows:
a. Distant metastases, including metastases to the opposite lung. If solitary adrenal, hepatic, or other masses are detected by scans, these areas should be evaluated by biopsy because there is a significant incidence of benign masses that masquerade as tumor (see also Section VII.B).
b. Persistent pleural effusion with malignant cells. Cytologic examination of 50 to 100 mL of fluid is positive for malignant cells in about 65% of patients. Repeat thoracentesis may provide the diagnosis in most of the remaining patients. In the event of negative cytology and in the absence of other contraindications to surgery, thoracoscopy should be undertaken at the time of surgery. Pleural involvement with malignant cells would preclude surgery. Transudative and parapneumonic effusions that clear do not contraindicate surgery. Most exudative effusions in the absence of pneumonia are malignant, regardless of cytologic findings.
c. Superior vena cava obstruction
d. Involvement of the following structures:
(1) Supraclavicular or neck lymph nodes (proved histologically)
(2) Contralateral mediastinal lymph nodes (proved histologically)
(3) Recurrent laryngeal nerve
(4) Tracheal wall
(5) Main-stem bronchus <2 cm from the carina (resectable by sleeve resection technique)
2. Determinants of operability
a. Age and mental illness per se are not factors in deciding operability. Elderly patients, arbitrarily defined as individuals >70 years of age, experience the same degree of benefit from therapy as younger patients provided that they have adequate nutritional and performance status. Clear distinction should be made between the “fit” elderly and those who have multiple comorbidities. The appropriate treatment of the “frail elderly” is unclear.
b. Cardiac status. The presence of uncontrolled cardiac failure, uncontrolled arrhythmia, or a recent myocardial infarction (within 6 months) makes the patient inoperable.
c. Pulmonary status. The patient’s ability to tolerate resection of part or all of a lung must be determined. The presence of pulmonary hypertension or inadequate pulmonary reserve makes the patient inoperable. It is critical that any patient for whom surgery is contemplated stop smoking for at least several weeks before the operation.
(1) Routine pulmonary function tests (PFT). Arterial blood gases and spirometry should be obtained in all patients before surgery. PFTs must be interpreted in the light of optimal medical management of pulmonary disease and patient cooperation. The patient with PFT abnormalities should receive a trial of bronchodilators, antibiotics, chest percussion, and postural drainage before inoperability is concluded. The following results suggest inoperability:
(a) A Paco2 that is >45 mm Hg (that cannot be corrected) or a Pao2 that is <60 mm Hg, or
(b) Forced vital capacity (FVC) <40% of predicted value, or
(c) Forced expired volume at 1 second (FEV1) ≤1 L. Patients with an FEV1 of >2 L or >60% of predicted value can tolerate pneumonectomy.
(2) Special PFTs
(a) The quantitative perfusion lung scan is done when patients with impaired pulmonary function are suspected of not being able to tolerate excision of lung tissue. The FEV1 is measured before the scan. The percentage of blood flow to each lung is calculated from the results of the scan. The percentage of flow in the noncancerous lung is multiplied by the FEV1, giving a measure of the anticipated postoperative FEV1. Pneumonectomy is contraindicated if the calculated postoperative FEV1 is 700 mL because the patient is likely to develop refractory cor pulmonale and respiratory insufficiency.
(b) Exercise testing. If maximal oxygen consumption is >20 mL/kg, perioperative morbidity is low; if it is <10 mL/kg, morbidity and mortality are high.
B. NSCLC: Management of stage I and II disease
1. Surgery. Surgical resection of the primary tumor is the treatment of choice for patients who can tolerate surgery and who have stage I or II NSCLC. The selection of the operative procedure varies with the surgeon’s criteria for patient selection, the extent of disease, and the patient’s ventilatory function.
Definition of nodal involvement during surgical resection is mandatory to determine prognosis and to evaluate the results of treatment; the anatomic boundaries of 13 nodal stations have been described. Although considered technically resectable, most patients with stage IIIa disease (predominantly N2 disease) do poorly (see Section VI.C). An exception is the patient with malignant involvement of a single mediastinal nodal station.
a. Incomplete resections are rarely, if ever, indicated.
b. Lobectomy is the procedure of choice in patients whose lung function permits it. Conservative resection (segmentectomy) has been associated with a significantly worse disease-free survival and an increased local recurrence rate.
c. Bilobectomy, sleeve lobectomy, or pneumonectomy with or without lymph node dissection are used in other clinical presentations.
d. Video-assisted thoracoscopic surgery (VATS) is increasingly employed in thoracic surgery. Its utilization for resection of lung cancer is associated with results comparable to open procedures.
e. Surgical mortality. A multicenter study of contemporary operative mortality due to lung surgery documented the following death rates within 30 days of operation: pneumonectomy, 7.7%; lobectomy, 3.3%; and segmentectomy or wedge resection, 1.4%. Advanced age, weight loss, coexisting disease, reduced FEV1, and more extensive resection are significant risk factors.
2. Pancoast tumor. Historically, RT has been employed as the preliminary treatment for Pancoast tumors (T3 N0 M0, stage IIb) before surgical resection of the primary tumor and involved chest wall. Mature results from a national intergroup trial using preoperative chemotherapy and RT (chemoradiotherapy) in the treatment of this disease entity, however, demonstrated a median survival of 37 months and 5-year survival of 42%, far exceeding the historical approach of radiation followed by surgery. Given the relative rarity of this entity, the use of preoperative chemoradiotherapy can now be considered the standard of care.
3. Adjuvant chemotherapy. The majority of patients undergoing complete resections for NSCLC relapse and die within 3 years of resection. Adjuvant therapy failed to improve outcome in early studies, but they were flawed by the use of ineffective chemotherapy or poor trial design.
Platinum-based adjuvant chemotherapy has now been unequivocally established on the basis of large randomized trials in Europe and North America. Patients were randomized to adjuvant chemotherapy or observation. The International Adjuvant Lung Trial (IALT) detected a 4% to 5% absolute benefit in long-term survival for patients treated with adjuvant platinum-based chemotherapy. Although this trial was characterized by heterogeneous chemotherapy regimens and premature closure, it was the largest trial ever performed studying this question. The results of this trial have now been confirmed by the North American Intergroup trial (JBR-10) and another European trial (ANITA). The latter two studies employed cisplatin/vinorelbine as the adjuvant regimen and demonstrated an approximately 10% absolute reduction in mortality. This level of benefit is comparable to the degree of benefit seen in breast and colon adjuvant studies. Routine use of adjuvant therapy with a cisplatin-based, two-drug regimen is now recommended for patients with resected stage IIa, IIb, and IIIa disease.
The role of adjuvant chemotherapy in patients with resected stage Ib is controversial. Only one trial has specifically addressed this issue, and although it demonstrated improved disease-free survival, overall survival was not significantly improved. Retrospective analysis indicates that patients with tumors >4 cm may enjoy a benefit comparable to that of stage II and III patients, but this is not established. Adjuvant therapy should be discussed on an individual basis with patients with stage Ib disease. Preoperative chemotherapy in localized NSCLC is an alternative approach.
4. Adjuvant RT has also been frequently employed in the treatment of resected stage I, II, and III disease. Its use clearly results in improved local control. As documented in a recent meta-analysis, however, improved local control may come at the expense of diminished survival. Hence, the routine use of adjuvant RT in completely resected NSCLC cannot be recommended.
5. Resectable but inoperable.
a. Definitive RT should be the primary treatment for medically inoperable but resectable patients. The overall survival rate at 5 years is about 20%, depending on the size of the primary tumor and associated comorbidities. The sterilization rate for small tumors ranges from 25% to 50%.
b. Stereotactic body radiotherapy (SBRT) has been recently demonstrated to provide a degree of local control comparable to surgical resection for small (<3 cm) tumors. Due to the potential for complications, at this time, the use of SBRT is restricted to more peripheral lesions. Currently, studies are in progress to determine the relative merits of SBRT versus surgery (wedge resection) for small tumors in patients with marginal cardiopulmonary status as well as to explore the value of chemotherapy after SBRT.
c. Chemoradiotherapy may also be considered for these patients, particularly those with N1 disease, for whom the outcome is very poor with RT alone.
C. NSCLC: Management of stages IIIa and IIIb
1. Combined-modality therapy. In the past, the standard treatment for most of these patients was RT or surgery alone, with modest evidence of survival benefit over supportive care alone. Historical data suggest that RT results in a median survival of 9 months, a 2-year survival rate of 10% to 15%, and a 5-year survival rate of 5% (worse for stage IIIb). Clinical trials indicate a survival advantage at 1 to 3 years with the use of chemoradiotherapy in this setting (with or without surgery); the 2-year survival rate has been reported to be 25% to 40%. Several randomized trials have demonstrated that the use of concurrent chemoradiotherapy is superior to sequential therapy.
a. Conceptually, there are two major approaches: “systemic full dose chemotherapy” with concurrent radiotherapy and “radiosensitizing” chemotherapy concurrent with radiation and followed by consolidative chemotherapy. For the former approach, the most mature data utilize cisplatin/etoposide and concurrent radiation to 61 Gy. For the latter, the most commonly utilized approach combines weekly low doses of carboplatin (AUC 2) and paclitaxel (45 to 50 mg/m2) concurrent with 61 Gy followed by full doses of carboplatin/paclitaxel. These regimens are detailed in Table 8.2. A recent intergroup trial (RTOG 0617) investigating chemoradiotherapy showed no benefit for increasing the total radiation dose to 70 Gy.
Table 8.2 First-Line Chemotherapy Regimens for Advanced Non–Small Cell Lung Cancer
aAUC, area under the curve.
aRestricted to non-squamous histology
b. Most chemoradiotherapy trials entered patients with good PS, minimal weight loss, and little comorbid illness. The use of chemoradiotherapy is also appropriate, however, in many poor-risk patients, defined by weight loss and other medical problems. A multicenter study demonstrated a median survival of 13 months in these patients, comparable to that of more favorable patients. These sicker patients, not surprisingly, do not experience the same long-term survival.
c. An emerging problem in stage III–disease patients treated with combined modality therapy is the occurrence of CNS metastases, which may be the sole site of relapse in 10% to 20% of patients. The role of prophylactic cranial irradiation for patients with stage III disease treated with chemoradiotherapy has been addressed in a multicenter trial. Though the study failed to reach its anticipated accrual, over 350 patients were randomized. The results demonstrate a significant decrease in CNS metastases, but no change in overall survival (see Section VII.B).
2. Preoperative “neoadjuvant” chemotherapy (with or without RT) for patients with locally advanced disease may down-stage the malignancy and make it resectable. Adjuvant surgical resection after chemoradiotherapy was compared with chemoradiotherapy alone in stage IIIa (N2), which was addressed in a North American Intergroup trial. This study demonstrated that an increase in early mortality in the surgical group, primarily in patients undergoing pneumonectomy, offsets a possible long-term advantage from surgery. There was an unusually high rate of pneumonectomy on the trial. At this time, the role of surgical resection after chemoradiotherapy remains to be established and should not be done outside of centers with substantial expertise in this approach.
3. Technical aspects of RT are important, both as a single modality and in combination with chemotherapy. Issues of dose, schedule, and fields are crucial. Evidence indicates that hyperfractionated accelerated RT (two or three times a day) may be superior to conventional, daily fractionation when used alone. A randomized trial failed to demonstrate an advantage for twice-a-day fractions when combined with chemotherapy over standard chemoradiotherapy. Additionally, the use of three-dimensional conformal techniques may reduce or prevent toxicity to normal lung within the radiation field and allow dose escalation.
4. Concurrent versus sequential treatment. Several randomized controlled trials in the United States, Europe, and Japan have demonstrated the superiority of concurrent chemoradiotherapy over sequential therapy. A Japanese study utilized mitomycin, vindesine, and cisplatin concurrent with RT. A trial by the Radiation Therapy Oncology Group used cisplatin and vinblastine concurrent with 6,100 cGy of RT administered over 6 weeks. Significant differences in median survival times (17 vs. 14 months) and in survival at 2 and 3 years strongly favored concurrent treatment.
5. Specific management recommendations should be individualized. In the absence of a clinical trial, patients with documented N2 or N3 disease should receive concurrent chemoradiotherapy. Patients with T4 N0 disease may be considered for induction chemotherapy with or without RT followed by surgery.
6. Radiographic responses. In all cases, patients treated with multimodality therapy may have variable radiographic responses. Except for those who demonstrate progressive disease (and consequently have a dire prognosis), there is no correlation between degree of radiographic response (complete response, partial response, or stable disease) and outcome. It is unclear that PET scanning improves the ability to assess these patients noninvasively.
D. NSCLC: Management of stage IV disease
1. Fully ambulatory patients have increased survival, and symptoms are often palliated by the use of platinum-containing (cisplatin or carboplatin) chemotherapy. A clear advantage for the use of chemotherapy has now been conclusively demonstrated in patients with stage IV disease and PS of 0 to 1. The median survival of such patients is 4 months, and the 1-year survival rate is 10% with best supportive care. With platinum-based chemotherapy (either as single agents or combined with etoposide, vinblastine, vindesine, or mitomycin), these survivals are improved to about 6 to 8 months and 20% to 25%, respectively. Newer regimens (carboplatin plus paclitaxel, cisplatin plus vinorelbine, cisplatin plus gemcitabine, cisplatin plus pemetrexed) have resulted in median survivals of 9 to 10 months and 1-year survival rates of 30% to 40% in large multicenter randomized trials. Economic analysis has demonstrated that it is more cost-effective to treat patients with chemotherapy because of the reduced need for hospitalization, RT, and other interventions.
Pemetrexed-platinum regimens, while highly active, have been restricted to non-squamous cell histologies of NSCLC by the FDA due to the results of a prospective randomized phase III trial and retrospective review of other pemetrexed studies in NSCLC. These results may relate to thymidylate synthetase (TS), which is a molecular target of pemetrexed and generally higher in squamous cell cancers of the lung. In phase III trials of advanced NSCLC, cisplatin/pemetrexed demonstrated superiority over cisplatin/gemcitabine. In second line therapy, pemetrexed was superior to docetaxel in nonsquamous histologies.
Bevacizumab, an antibody to the vascular endothelial growth factor (VEGF), has been demonstrated to result in superior survival in selected patients with advanced NSCLC. Bevacizumab is contraindicated in squamous carcinomadue to toxicity. Studies with bevacizumab have also excluded patients with bleeding disorders, significant cardiovascular or thrombotic disease, CNS metastases, or cavitary lesions. The approved dose is 15 mg/kg every 21 days. A European trial has reported that bevacizumab, in addition to cisplatin/gemcitabine, improved progression-free survival but not overall survival. The role of newer inhibitors of the VEGF receptor tyrosine kinase domain (including agents approved for other indications, such as sorafenib and sunitinib) are under active investigation.
2. Patients who are less than fully ambulatory (PS of ≥2) have poor outcomes. Emerging evidence indicates that such patients do benefit from therapy. The best current evidence indicates that carboplatin-based two-drug therapy is superior to single-agent treatment and to best supportive care. However, management must be individualized, and options are ultimately dependent on the presence of comorbid disease and the patient’s wishes.
3. Patients who have progressed after initial chemotherapy and who have good PS (0 to 1) may respond to second-line therapy with docetaxel (75 mg/m2 IV over 1 hour q 21 days). Two multicenter randomized trials have demonstrated an advantage for docetaxel in this setting (compared with best supportive care in one study and with either ifosfamide or vinorelbine in the other). Pemetrexed (Alimta, 500 mg/m2 q 21 days) was demonstrated to have similar efficacy to docetaxel (retrospectively for nonsquamous histology) with a favorable toxicity profile in a randomized phase III trial.
It is important to recognize that most of the benefit for second line therapy with docetaxel or pemetrexed occurs in patients who had at least some benefit from initial chemotherapy. Individuals who progress rapidly on initial chemotherapy are unlikely to experience benefit from subsequent therapy (in the absence of sensitizing mutations).
4. Erlotinib (Tarceva), 150 mg PO daily, has been approved for second- and third-line therapy of NSCLC. Recent evidence indicates that this agent is likely the preferred choice for first-line treatment in patients with EGFR mutations (deletions in exon 19 and missense in exon 21, see above), which occur in 10% to 15% of NSCLC patients in the United States. These patients tend to be those with minimal (<15 pack-years), never, or distant smokers (quit >20 years earlier). Some patients with reportedly wild type EGFR may benefit, likely as a result of the presence of undetected rare mutations.
The use of an EGFR TKI such as erlotinib as first-line therapy based upon clinical factors (e.g., nonsmokers, female, Asian ancestry) without evidence of EGFR mutation is discouraged because in a randomized trial, patients with wild type EGFR who received initial treatment with EGFR TKI experienced inferior progression-free survival compared with those treated with platinum-based chemotherapy. For patients in whom EGFR mutation is uncertain, initial use of platinum-based chemotherapy is preferred with a switch to an EGFR TKI when a sensitizing mutation is confirmed.
a. The major toxicities of this therapy are skin rash, diarrhea, and rarely, interstitial pneumonitis. Interstitial pneumonitis is predominantly seen in Asians and may be fatal; the incidence in 1%. Cessation of drug, steroid therapy, and hospitalization (as appropriate) should be undertaken in the patient with worsening dyspnea and radiographic changes consistent with interstitial pneumonitis. It is frequently difficult to distinguish pneumonitis from disease progression.
b. Skin rash is a very common toxicity, and its occurrence may correlate with tumor response. At present, there are no established guidelines in either the dermatologic or ophthalmologic literature for treatment of rash-related side effect from the EGFR inhibitors. The following is an algorithm that was adopted from data on file at Genentech, Inc. Prescriptions for topical 1% or 2.5% hydrocortisone cream and 1% clindamycin gel should be provided at the time of the initial erlotinib prescription so that they may be used at the first sign of rash, which may be before the 2-week follow-up visit.
(1) For mild rash (grade 1), use topical hydrocortisone 1% or 2.5% cream and/or clindamycin 1% gel b.i.d. to affected areas. Make sure to apply the topicals at least 1 hour apart. Continue the EGFR inhibitor at current dose, and monitor for change in severity. If after 2 weeks the reactions do not improve, then proceed to treatment for moderate rash.
(2) For moderate rash (grades 2 or 3), use either hydrocortisone 2.5% cream and/or clindamycin 1% gel or pimecrolimus 1% cream plus doxycycline 100 mg PO b.i.d. or minocycline 100 mg b.i.d. Continue the EGFR inhibitor at the current dose, and monitor for change in severity. If there is no improvement in 2 weeks and symptoms worsen, then treat as above with the addition of a methylprednisolone dose pack. If reaction continues to worsen, then dose interruption or discontinuation may be necessary.
(3) For the patients who report pruritic, dry, erythematous eyes when the onset could be attributed to treatment with EGFR inhibitors, use prednisolone sodium phosphate ophthalmic (0.125%), 1 to 2 drops to the affected eyes b.i.d.–q.i.d. If condition increases in severity, it is recommended that the patient follow up with an ophthalmologist.
c. Diarrhea should be managed with Imodium or Lomotil. If toxicities persist despite adequate management (i.e., > grade I), dose interruption followed by reductions of erlotinib are indicated.
5. Crizotinib (Xalkori) is a new agent that has been recently approved by the FDA. The drug is effective in patients with EML4/ALK translocations and can result in rapid and sustained benefit in 65% of patients. Resistance mutations have already been identified in patients treated with crizotinib at the time of progressive disease.
6. Duration of therapy. The maximum benefit from any specific chemotherapy regimen is achieved in six cycles. Fewer cycles may be adequate. Two studies have demonstrated equivalent response and survival when three or four cycles of a platinum-based regimen were compared with more cycles of the same regimen.
Maintenance treatment (i.e., continued treatment with either one of the same agents utilized for first-line treatment or with a different agent) is an area of considerable controversy. Two agents, pemetrexed and erlotinib, are FDA approved for this indication. Much, if not all, of the benefit may be a consequence of early initiation of appropriate second-line therapy. An alternative strategy to maintenance therapy is close follow-up with frequent staging and early institution of second-line treatment at the first indication of progressive disease.
7. The choice of which platinum-based chemotherapy regimen to use as first-line therapy can be based on several considerations. As noted above, histology plays an increasing role in the decision as well as the presence or absence of EGFR mutations. In addition to efficacy, the considerations include convenience of administration, cost, and toxicity profiles. Cisplatin-based regimens are less expensive and in one recent randomized trial demonstrated a survival advantage compared with a carboplatin-based treatment. However, these cisplatin regimens are less convenient and cause more nausea, vomiting, renal toxicity, and ototoxicity. Taxane-based regimens universally result in alopecia and may have significant cumulative neurotoxicity. Gemcitabine-platinum regimens are more myelotoxic but usually do not cause alopecia. Bevacizumab has been safely combined with carboplatin/paclitaxel and cisplatin/gemcitabine in large phase III studies. Data regarding the combination of bevacizumab with other commonly utilized regimens (e.g., carboplatin/gemcitabine, carboplatin/docetaxel) are preliminary. This issue can be summarized as a choice of regimens, but no regimen of choice with the exception of cisplatin/pemetrexed for nonsquamous histologies. Table 8.2 provides details of the most commonly utilized regimens for advanced NSCLC.
8. Problems with phase II trials. New chemotherapy agents and combinations are undergoing evaluation. Performance status, age, sex, degree of weight loss, and staging of the patients govern the response to and toxicity of these regimens. Some phase II trials include patients with stage IIIb (without pleural effusion) disease. Additionally, small numbers (25 to 50) of patients are accrued to such trials, as opposed to the hundreds of patients accrued to phase III trials. As a result, early reports of phase II data frequently overstate the activity and underestimate the toxicity of new regimens.
E. Small cell lung carcinoma: Management
1. Limited stage (I, II, III) is confined to one hemithorax, including contralateral supraclavicular adenopathy. Less than 5% of patients with SCLC have stage I or II disease. About one-third, however, has disease that is clinically confined to the hemithorax and draining regional nodes at presentation (stages IIIa and IIIb).
a. Combined-modality therapy. The available data indicate that these patients should receive concurrent chemotherapy and thoracic RT. Sequential chemotherapy followed by RT results in inferior long-term survival and should be discouraged. At this time, the most accepted chemotherapy regimen is cisplatin and etoposide (Table 8.3). RT given twice daily (hyperfractionated) has been demonstrated to be superior to once-daily therapy (4,500 cGy). It is unclear whether conventionally fractionated RT to a higher dose would be equal or superior to hyperfractionated 4,500 cGy treatments. If given concurrently as induction, combined-modality therapy yields a median survival of 23 months and a 5-year survival rate of 25%.
b. Prophylactic cranial irradiation (PCI) decreases the rate of brain metastases. The use of PCI is controversial because the occurrence of synchronous metastases has made it difficult to demonstrate a survival advantage. The best evidence is that the use of PCI results in about a 5% improvement in survival. When PCI is administered in low-dose fractions (≤200 cGy/day, to a dose of 3,000 cGy), the incidence of neurocognitive dysfunction is not increased.
2. Extensive stage (ESCLC). Some effective chemotherapy regimens for ESCLC are shown in Table 8.3. Fully ambulatory patients with ESCLC have good responses to cisplatin and etoposide (PE regimen) or the combination of cyclophosphamide, doxorubicin, and vincristine. Only 15% to 20% of such patients achieve complete response. The median survival of fully ambulatory patients is about 1 year, and the 2-year survival rate is 20%. Survival for 5 years, however, is unusual.
a. A randomized trial from Japan comparing cisplatin/irinotecan with PE demonstrated superior survival for cisplatin/irinotecan. However, a similar study from the U.S. failed to demonstrate an advantage for either regimen. Either PE or cisplatin/irinotecan can be considered an acceptable regimen for the treatment of ESCLC. In elderly or compromised patients, carboplatin is frequently substituted for cisplatin.
b. Topotecan has demonstrated activity as second-line therapy for SCLC. Other agents (paclitaxel, gemcitabine, vinorelbine, and docetaxel) also have activity in ESCLC.
c. Patients with SCLC who are less than fully ambulatory may still be appropriate candidates for chemotherapy. Patients who respond may have significant improvement in performance status.
Table 8.3 Regimens for Small Cell Lung Cancer
aPCI (prophylactic cranial irradiation) is indicated in patients with limited disease who have obtained a good partial response or a complete response after the completion of other therapy. Chest RT and PCI are administered Monday to Friday.
d. PCI has recently been demonstrated to reduce the risk of CNS metastases and improve event-free and overall survival in patients with ESCLC who have had any degree of response (including stable disease) to initial chemotherapy. However, this trial did not require radiographic assessment of the brain prior to treatment and may simply represent the benefits of therapy for asymptomatic CNS disease after initial systemic therapy.
VII. SPECIAL CLINICAL PROBLEMS
A. Positive sputum cytology with a negative chest radiograph (TX N0 M0) and no other evidence of disease is an occasional problem, usually occurring in screening programs. Patients should be examined by CT scan of the chest and fiberoptic bronchoscopy with selective washings. Bronchial washings may not be helpful in localizing the malignancy because multiple sites may have tumors or suspected dysplastic change.
1. When these measures fail to identify a lesion, patients must be informed that the likelihood that they have a cancer too small to be detected is significant. Such patients should be followed with monthly chest radiographs and should be strongly advised to stop smoking. Repeated sputum cytology is not helpful if the original cytology findings were diagnostic of malignancy and laboratory errors were not suspected.
2. The cytologic discovery of an unequivocal small cell cancer in the absence of other findings should be confirmed by repeat sampling and solicitation of a second pathologist’s opinion at another institution. After the diagnosis is confirmed, patients should be treated as described previously.
B. Solitary brain metastasis. Patients with NSCLC who present with a single site of metastatic disease, most commonly in the brain, can be treated with curative intent. There are two situations in which this occurs: patients who have received definitive therapy and relapse with a single CNS metastasis (and no other disease) and those who at initial presentation have chest disease and the CNS as the sole site of metastasis.
For the relapsed patients, resection of the CNS metastasis may lead to long-term survival. For patients with synchronous disease, resection of the primary chest tumor and resection or the use of radiosurgery for the CNS disease is appropriate. If the patient has locally advanced disease (stage IIIa or IIIb), one could consider resection of the CNS disease followed by chemoradiotherapy with or without surgery for the chest disease in selected patients.
1. The use of postoperative whole-brain RT (WBRT) after surgical resection of a solitary metastasis is recommended because of the frequency of occult micrometastases. Although the use of WBRT in patients who have been treated either with surgery or with radiosurgery has failed to demonstrate a survival advantage, the neurologic event-free survival is clearly superior with WBRT. Most patients who do not initially receive WBRT after treatment of a solitary lesion will receive therapy at the time of relapse.
2. If brain metastasis is anatomically unresectable, stereotactic radiosurgery is superior to whole-brain RT alone.
VIII. FOLLOW-UP
A. After primary therapy with curative intent (i.e., surgery or definitive radiotherapy/chemoradiotherapy). Although most cases of SCLC and NSCLC recur, there is little evidence that frequent laboratory or radiologic studies detect disease before the development of symptoms or that early detection improves outcome. In the nonprotocol setting, we recommend history and physical examination every 2 to 3 months and chest radiograph twice yearly for the first few years after resection. The follow-up visit is an excellent opportunity to reinforce the importance of smoking cessation in individuals who continue to abuse tobacco.
B. Radiologic abnormalities. Patients who undergo chemoradiotherapy frequently demonstrate scarring and infiltrates on radiologic studies, which may evolve with time. These abnormalities are frequently misinterpreted as progressive disease. Proper interpretation of these studies requires determination of RT ports and comparison of initial and follow-up studies.
C. Patients undergoing therapy for metastatic disease should have periodic reassessments of the known sites of disease. Progression of disease (>20% increase in the sum of unidimensional measurements of indicator lesions or the appearance of new disease) or deteriorating performance status is a reason to stop therapy and consider second- or third-line treatment. The appearance of new lesions, even if other disease is smaller or has resolved, constitutes progression. The benefits of second and subsequent lines of therapy are primarily confined to patients who maintain reasonable performance status (ECOG ≤2). These patients should be offered additional treatment after appropriate discussion. For more compromised patients, the use of chemotherapy is frequently associated with toxicity and relatively little benefit. An exception is those patients with mutations that predict for benefit from agents such as erlotinib or crizotinib.
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