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InternalMed_Harrison. LDCT screening for lung cancer comes with known risks including a high rate of false-positive results, false-negative results, potential for unnecessary follow-up testing, radiation exposure, overdiagnosis, changes in anxiety and quality of life, and substantial financial costs. By far the biggest challenge confronting the use of CT screening is the high false-positive rate. False positives can have a substantial impact on patients through the expense and risk of unneeded further evaluation and emotional stress. The management of these patients usually consists of serial CT scans over time to see if the nodules grow, attempted fine-needle aspirates, or surgical resection. At $300 per scan (NCI estimated cost), the outlay for initial LDCT alone could run into the billions of dollars annually, an expense that only further escalates when factoring in various downstream expenditures an individual might incur in the assessment of positive findings. A formal cost-effectiveness analysis of


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InternalMed_Harrison. an expense that only further escalates when factoring in various downstream expenditures an individual might incur in the assessment of positive findings. A formal cost-effectiveness analysis of the NLST is expected soon that should help resolve this crucial concern.


InternalMed_Harrison

InternalMed_Harrison. Despite the aforementioned caveats, screening of individuals who meet the NLST criteria for lung cancer risk (or in some cases, modified versions of these criteria) seems warranted, provided comprehensive multidisciplinary coordinated care and follow-up similar to those provided to NLST participants are available. Algorithms to improve candidate selection are under development. When discussing the option of LDCT screening, use of absolute risks rather than relative risks is helpful because studies indicate the public can process absolute terminology more effectively than relative risk projections. A useful guide has been developed by the NCI to help patients and physicians assess the benefits and harms of LDCT screening for lung cancer (Table 107-3). Finally, even a small negative effect of screening on smoking behavior (either lower quit rates or higher recidivism) could easily offset the potential gains in a population. Fortunately no such impact has been reported to date.


InternalMed_Harrison

InternalMed_Harrison. effect of screening on smoking behavior (either lower quit rates or higher recidivism) could easily offset the potential gains in a population. Fortunately no such impact has been reported to date. Nonetheless, smoking cessation must be included as an indispensable component of any screening program.


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InternalMed_Harrison. Benefits: How Did CT Scans Help Compared To CXR? Harms: What Problems Did CT Scans Cause Compared to CXR? Abbreviations: CXR, chest x-ray; LDCT, low-dose computed tomography; NLST, National Lung Screening Trial. Source: Modified from S Woloshin et al: N Engl J Med 367:1677, 2012.


InternalMed_Harrison

InternalMed_Harrison. Over half of all patients diagnosed with lung cancer present with locally advanced or metastatic disease at the time of diagnosis. The majority of patients present with signs, symptoms, or laboratory abnormalities that can be attributed to the primary lesion, local tumor growth, invasion or obstruction of adjacent structures, growth at distant metastatic sites, or a paraneoplastic syndrome (Tables 107-4 and 107-5). The prototypical lung cancer patient is a current or former smoker of either sex, usually in the seventh decade of life. A history of chronic cough with or without hemoptysis in a current or former smoker with chronic obstructive pulmonary disease (COPD) age 40 years or older should prompt a thorough investigation for lung cancer even in the face of a normal CXR. A persistent pneumonia without constitutional symptoms and unresponsive to repeated courses of antibiotics also should prompt an evaluation for the underlying cause. Lung cancer arising in a lifetime never smoker


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InternalMed_Harrison. pneumonia without constitutional symptoms and unresponsive to repeated courses of antibiotics also should prompt an evaluation for the underlying cause. Lung cancer arising in a lifetime never smoker is more common in women and East Asians. Such patients also tend to be younger than their smoking counterparts at the time of diagnosis. The clinical presentation of lung cancer in never smokers tends to mirror that of current and former smokers.


InternalMed_Harrison

InternalMed_Harrison. Patients with central or endobronchial growth of the primary tumor may present with cough, hemoptysis, wheeze, stridor, dyspnea, or postobstructive pneumonitis. Peripheral growth of the primary tumor may cause pain from pleural or chest wall involvement, dyspnea on a restrictive basis, and symptoms of a lung abscess resulting from tumor cavitation. Regional spread of tumor in the thorax (by contiguous growth or by metastasis to regional lymph nodes) may cause tracheal obstruction, esophageal compression with dysphagia, recurrent laryngeal paralysis with hoarseness, phrenic nerve palsy with elevation of the hemidiaphragm and dyspnea, and sympathetic nerve paralysis with Horner’s syndrome (enophthalmos, ptosis, miosis, and anhydrosis). Malignant pleural effusions can cause pain, dyspnea, or cough. Pancoast (or superior sulcus tumor) syndromes result from local extension of a tumor growing in the apex of the lung with involvement of the eighth cervical and first and second thoracic


InternalMed_Harrison

InternalMed_Harrison. or cough. Pancoast (or superior sulcus tumor) syndromes result from local extension of a tumor growing in the apex of the lung with involvement of the eighth cervical and first and second thoracic nerves, and present with shoulder pain that characteristically radiates in the ulnar


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InternalMed_Harrison. Symptom and Signs Range of Frequency Source: Reproduced with permission from MA Beckles: Chest 123:97-104, 2003. Symptoms elicited in • Constitutional: weight loss >10 lb history • Musculoskeletal: • Neurologic: headaches, syncope, seizures, extremity weakness, recent change in mental status • Hoarseness, neurologic signs, papilledema Routine laboratory tests • Hematocrit, <40% in men; <35% in women • Elevated alkaline phosphatase, GGT, SGOT, and Abbreviations: GGT, gamma-glutamyltransferase; SGOT, serum glutamic-oxaloacetic transaminase. Source: Reproduced with permission from GA Silvestri et al: Chest 123(1 Suppl):147S, 2003.


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InternalMed_Harrison. distribution of the arm, often with radiologic destruction of the first and second ribs. Often Horner’s syndrome and Pancoast syndrome coexist. Other problems of regional spread include superior vena cava syndrome from vascular obstruction; pericardial and cardiac extension with resultant tamponade, arrhythmia, or cardiac failure; lymphatic obstruction with resultant pleural effusion; and lymphangitic spread through the lungs with hypoxemia and dyspnea. In addition, lung cancer can spread transbronchially, producing tumor growth along multiple alveolar surfaces with impairment of gas exchange, respiratory insufficiency, dyspnea, hypoxemia, and sputum production. Constitutional symptoms may include anorexia, weight loss, weakness, fever, and night sweats. Apart from the brevity of symptom duration, these parameters fail to clearly distinguish SCLC from NSCLC or even from neoplasms metastatic to lungs.


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InternalMed_Harrison. Extrathoracic metastatic disease is found at autopsy in more than 50% of patients with squamous carcinoma, 80% of patients with adenocarcinoma and large-cell carcinoma, and greater than 95% of patients with SCLC. Approximately one-third of patients present with symptoms as a result of distant metastases. Lung cancer metastases may occur in virtually every organ system, and the site of metastatic involvement largely determines other symptoms. Patients with brain metastases may present with headache, nausea and vomiting, seizures, or neurologic deficits. Patients with bone metastases may present with pain, pathologic fractures, or cord compression. The latter may also occur with epidural metastases. Individuals with bone marrow invasion may present with cytopenias or leukoerythroblastosis. Those with liver metastases may present with hepatomegaly, right upper quadrant pain, fever, anorexia, and weight loss. Liver dysfunction and biliary obstructions are rare. Adrenal metastases are


InternalMed_Harrison

InternalMed_Harrison. Those with liver metastases may present with hepatomegaly, right upper quadrant pain, fever, anorexia, and weight loss. Liver dysfunction and biliary obstructions are rare. Adrenal metastases are common but rarely cause pain or adrenal insufficiency unless they are large.


InternalMed_Harrison

InternalMed_Harrison. Paraneoplastic syndromes are common in patients with lung cancer, especially those with SCLC, and may be the presenting finding or the first sign of recurrence. In addition, paraneoplastic syndromes may mimic metastatic disease and, unless detected, lead to inappropriate palliative rather than curative treatment. Often the paraneoplastic syndrome may be relieved with successful treatment of the tumor. In some cases, the pathophysiology of the paraneoplastic syndrome is known, particularly when a hormone with biological activity is secreted by a tumor. However, in many cases, the pathophysiology is unknown. Systemic symptoms of anorexia, cachexia, weight loss (seen in 30% of patients), fever, and suppressed immunity are paraneoplastic syndromes of unknown etiology or at least not well defined. Weight loss greater than 10% of total body weight is considered a bad prognostic sign. Endocrine syndromes are seen in 12% of patients; hypercalcemia resulting from ectopic production of


InternalMed_Harrison

InternalMed_Harrison. defined. Weight loss greater than 10% of total body weight is considered a bad prognostic sign. Endocrine syndromes are seen in 12% of patients; hypercalcemia resulting from ectopic production of parathyroid hormone (PTH), or more commonly, PTH-related peptide, is the most common life-threatening metabolic complication of malignancy, primarily occurring with squamous cell carcinomas of the lung. Clinical symptoms include nausea, vomiting, abdominal pain, constipation, polyuria, 511 thirst, and altered mental status.


InternalMed_Harrison

InternalMed_Harrison. Hyponatremia may be caused by the syndrome of inappropriate secretion of antidiuretic hormone (SIADH) or possibly atrial natriuretic peptide (ANP). SIADH resolves within 1-4 weeks of initiating chemotherapy in the vast majority of cases. During this period, serum sodium can usually be managed and maintained above 128 mEq/L via fluid restriction. Demeclocycline can be a useful adjunctive measure when fluid restriction alone is insufficient. Vasopressin receptor antagonists like tolvaptan also have been used in the management of SIADH. However, there are significant limitations to the use of tolvaptan including liver injury and overly rapid correction of the hyponatremia, which can lead to irreversible neurologic injury. Likewise, the cost of tolvaptan may be prohibitive (as high as $300 per tablet in some areas). Of note, patients with ectopic ANP may have worsening hyponatremia if sodium intake is not concomitantly increased. Accordingly, if hyponatremia fails to improve or worsens


InternalMed_Harrison

InternalMed_Harrison. per tablet in some areas). Of note, patients with ectopic ANP may have worsening hyponatremia if sodium intake is not concomitantly increased. Accordingly, if hyponatremia fails to improve or worsens after 3–4 days of adequate fluid restriction, plasma levels of ANP should be measured to determine the causative syndrome.


InternalMed_Harrison

InternalMed_Harrison. Ectopic secretion of ACTH by SCLC and pulmonary carcinoids usually results in additional electrolyte disturbances, especially hypokalemia, rather than the changes in body habitus that occur in Cushing’s syndrome from a pituitary adenoma. Treatment with standard medications, such as metyrapone and ketoconazole, is largely ineffective due to extremely high cortisol levels. The most effective strategy for management of the Cushing’s syndrome is effective treatment of the underlying SCLC. Bilateral adrenalectomy may be consid ered in extreme cases.


InternalMed_Harrison

InternalMed_Harrison. Skeletal–connective tissue syndromes include clubbing in 30% of cases (usually NSCLCs) and hypertrophic primary osteoarthropathy in 1–10% of cases (usually adenocarcinomas). Patients may develop periostitis, causing pain, tenderness, and swelling over the affected bones and a positive bone scan. Neurologic-myopathic syndromes are seen in only 1% of patients but are dramatic and include the myasthenic Eaton-Lambert syndrome and retinal blindness with SCLC, whereas peripheral neuropathies, subacute cerebellar degeneration, cortical degeneration, and polymyositis are seen with all lung cancer types. Many of these are caused by autoimmune responses such as the development of anti-voltage-gated calcium channel antibodies in Eaton-Lambert syndrome. Patients with this disorder present with proximal muscle weakness, usually in the lower extremities, occasional autonomic dysfunction, and rarely, cranial nerve symptoms or involvement of the bulbar or respiratory muscles. Depressed deep tendon


InternalMed_Harrison

InternalMed_Harrison. muscle weakness, usually in the lower extremities, occasional autonomic dysfunction, and rarely, cranial nerve symptoms or involvement of the bulbar or respiratory muscles. Depressed deep tendon reflexes are frequently present. In contrast to patients with myasthenia gravis, strength improves with serial effort. Some patients who respond to chemotherapy will have resolution of the neurologic abnormalities. Thus, chemotherapy is the initial treatment of choice. Paraneoplastic encephalomyelitis and sensory neuropathies, cerebellar degeneration, limbic encephalitis, and brainstem encephalitis occur in SCLC in association with a variety of antineuronal antibodies such as anti-Hu, antiCRMP5, and ANNA-3. Paraneoplastic cerebellar degeneration may be associated with anti-Hu, anti-Yo, or P/Q calcium channel autoantibodies. Coagulation or thrombotic or other hematologic manifestations occur in 1–8% of patients and include migratory venous thrombophlebitis (Trousseau’s syndrome), nonbacterial


InternalMed_Harrison

InternalMed_Harrison. channel autoantibodies. Coagulation or thrombotic or other hematologic manifestations occur in 1–8% of patients and include migratory venous thrombophlebitis (Trousseau’s syndrome), nonbacterial thrombotic (marantic) endocarditis with arterial emboli, and disseminated intravascular coagulation with hemorrhage, anemia, granulocytosis, and leukoerythroblastosis. Thrombotic disease complicating cancer is usually a poor prognostic sign. Cutaneous manifestations such as dermatomyositis and acanthosis nigricans are uncommon (1%), as are the renal manifestations of nephrotic syndrome and glomerulonephritis (≤1%).


InternalMed_Harrison

InternalMed_Harrison. Tissue sampling is required to confirm a diagnosis in all patients with suspected lung cancer. In patients with suspected metastatic disease, a biopsy of the most distant site of disease is preferred for tissue confirmation. Given the greater emphasis placed on molecular testing for NSCLC patients, a core biopsy is preferred to ensure adequate


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InternalMed_Harrison. Neoplasms of the Lung 512 tissue for analysis. Tumor tissue may be obtained via minimally invasive techniques such as bronchial or transbronchial biopsy during fiberoptic bronchoscopy, by fine-needle aspiration or percutaneous biopsy using image guidance, or via endobronchial ultrasound (EBUS) guided biopsy. Depending on the location, lymph node sampling may occur via transesophageal endoscopic ultrasound-guided biopsy (EUS), EBUS, or blind biopsy. In patients with clinically palpable disease such as a lymph node or skin metastasis, a biopsy may be obtained. In patients with suspected metastatic disease, a diagnosis may be confirmed by percutaneous biopsy of a soft tissue mass, lytic bone lesion, bone marrow, pleural or liver lesion, or an adequate cell block obtained from a malignant pleural effusion. In patients with a suspected malignant pleural effusion, if the initial thoracentesis is negative, a repeat thoracentesis is warranted. Although the majority of pleural effusions are


InternalMed_Harrison

InternalMed_Harrison. effusion. In patients with a suspected malignant pleural effusion, if the initial thoracentesis is negative, a repeat thoracentesis is warranted. Although the majority of pleural effusions are due to malignant disease, particularly if they are exudative or bloody, some may be parapneumonic. In the absence of distant disease, such patients should be considered for possible curative treatment. The diagnostic yield of any biopsy depends on several factors including location (accessibility) of the tumor, tumor size, tumor type, and technical aspects of the diagnostic procedure including the experience level of the bronchoscopist and pathologist. In general, central lesions such as squamous cell carcinomas, small-cell carcinomas, or endobronchial lesions such as carcinoid tumors are more readily diagnosed by bronchoscopic examination, whereas peripheral lesions such as adenocarcinomas and large-cell carcinomas are more amenable to transthoracic biopsy. Diagnostic accuracy for SCLC versus


InternalMed_Harrison

InternalMed_Harrison. diagnosed by bronchoscopic examination, whereas peripheral lesions such as adenocarcinomas and large-cell carcinomas are more amenable to transthoracic biopsy. Diagnostic accuracy for SCLC versus NSCLC for most specimens is excellent, with lesser accuracy for subtypes of NSCLC. Bronchoscopic specimens include bronchial brush, bronchial wash, bronchioloalveolar lavage, transbronchial fine-needle aspiration (FNA), and core biopsy. For more accurate histologic classification, mutation analysis, or investigational purposes, reasonable efforts (e.g., a core needle biopsy) should be made to obtain more tissue than what is contained in a routine cytology specimen obtained by FNA. Overall sensitivity for combined use of bronchoscopic methods is approximately 80%, and together with tissue biopsy, the yield increases to 85–90%. Like transbronchial core biopsy specimens, transthoracic core biopsy specimens are also preferred. Sensitivity is highest for larger lesions and peripheral tumors. In


InternalMed_Harrison

InternalMed_Harrison. the yield increases to 85–90%. Like transbronchial core biopsy specimens, transthoracic core biopsy specimens are also preferred. Sensitivity is highest for larger lesions and peripheral tumors. In general, core biopsy specimens, whether transbronchial, transthoracic, or EUS-guided, are superior to other specimen types. This is primarily due to the higher percentage of tumor cells with fewer confounding factors such as obscuring inflammation and reactive nonneoplastic cells.


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InternalMed_Harrison. Sputum cytology is inexpensive and noninvasive but has a lower yield than other specimen types due to poor preservation of the cells and more variability in acquiring a good-quality specimen. The yield for sputum cytology is highest for larger and centrally located tumors such as squamous cell carcinoma and small-cell carcinoma histology. The specificity for sputum cytology averages close to 100%, although sensitivity is generally <70%. The accuracy of sputum cytology improves with increased numbers of specimens analyzed. Consequently, analysis of at least three sputum specimens is recommended.


InternalMed_Harrison

InternalMed_Harrison. Lung cancer staging consists of two parts: first, a determination of the location of the tumor and possible metastatic sites (anatomic staging), and second, an assessment of a patient’s ability to withstand various antitumor treatments (physiologic staging). All patients with lung cancer should have a complete history and physical examination, with evaluation of all other medical problems, determination of performance status, and history of weight loss. The most significant dividing line is between those patients who are candidates for surgical resection and those who are inoperable but will benefit from chemotherapy, radiation therapy, or both. Staging with regard to a patient’s potential for surgical resection is principally applicable to NSCLC.


InternalMed_Harrison

InternalMed_Harrison. The accurate staging of patients with NSCLC is essential for determining the appropriate treatment in patients with resectable disease and avoiding unnecessary surgical procedures in patients with advanced disease (Fig. 107-3). All patients with NSCLC should undergo initial Complete history and physical examination Determination of performance status and weight loss Complete blood count with platelet determination Measurement of serum electrolytes, glucose, and calcium; renal and liver function tests PET scan to evaluate mediastinum and detect metastatic disease MRI brain if clinically indicated


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InternalMed_Harrison. Positive for metastatic disease No signs, symptoms, or imaging to suggest metastatic disease Patient has no contraindication to surgery or radiation therapy combined with chemotherapy Refer to surgeon for evaluation of mediastinum and possible resection No surgery Treatment with combined chemoradiation therapy N0 or N1 nodes N2 or N3 nodes Single suspicious lesion detected on imaging Multiple lesions detected on imaging Biopsy lesion See Fig. 107-6 Pulmonary function tests and arterial blood-gas measurements Cardiopulmonary exercise testing if performance status or pulmonary function tests are borderline Coagulation tests Negative for metastatic disease Stage IB <4 cm surgery alone >4 cm surgery followed by adjuvant chemotherapy Stage II or III Surgery followed by adjuvant chemotherapy Stage IA Surgery alone FIGURE 107-3 Algorithm for management of non-small-cell lung cancer. MRI, magnetic resonance imaging; PET, positron emission tomography.


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InternalMed_Harrison. radiographic imaging with CT scan, positron emission tomography (PET), or preferably CT-PET. PET scanning attempts to identify sites of malignancy based on glucose metabolism by measuring the uptake of 18F-fluorodeoxyglucose (FDG). Rapidly dividing cells, presumably in the lung tumors, will preferentially take up 18F-FDG and appear as a “hot spot.” To date, PET has been mostly used for staging and detection of metastases in lung cancer and in the detection of nodules >15 mm in diameter. Combined 18F-FDG PET-CT imaging has been shown to improve the accuracy of staging in NSCLC compared to visual correlation of PET and CT or either study alone. CT-PET has been found to be superior in identifying pathologically enlarged mediastinal lymph nodes and extrathoracic metastases. A standardized uptake value (SUV) of >2.5 on PET is highly suspicious for malignancy. False negatives can be seen in diabetes, in lesions <8 mm, and in slow-growing tumors (e.g., carcinoid tumors or well-differentiated


InternalMed_Harrison

InternalMed_Harrison. value (SUV) of >2.5 on PET is highly suspicious for malignancy. False negatives can be seen in diabetes, in lesions <8 mm, and in slow-growing tumors (e.g., carcinoid tumors or well-differentiated adenocarcinoma). False positives can be seen in certain infections and granulomatous disease (e.g., tuberculosis). Thus, PET should never be used alone to diagnose lung cancer, mediastinal involvement, or metastases. Confirmation with tissue biopsy is required. For brain metastases, magnetic resonance imaging (MRI) is the most effective method. MRI can also be useful in selected circumstances, such as superior sulcus tumors to rule out brachial plexus involvement, but in general, MRI does not play a major role in NSCLC staging.


InternalMed_Harrison

InternalMed_Harrison. In patients with NSCLC, the following are contraindications to potential curative resection: extrathoracic metastases, superior vena cava syndrome, vocal cord and, in most cases, phrenic nerve paralysis, malignant pleural effusion, cardiac tamponade, tumor within 2 cm of the carina (potentially curable with combined chemoradiotherapy), metastasis to the contralateral lung, metastases to supraclavicular lymph nodes, contralateral mediastinal node metastases (potentially curable with combined chemoradiotherapy), and involvement of the main pulmonary artery. In situations where it will make a difference in treatment, abnormal scan findings require tissue confirmation of malignancy so that patients are not precluded from having potentially curative therapy.


InternalMed_Harrison

InternalMed_Harrison. The best predictor of metastatic disease remains a careful history and physical examination. If signs, symptoms, or findings from the physical examination suggest the presence of malignancy, then sequential imaging starting with the most appropriate study should be performed. If the findings from the clinical evaluation are negative, then imaging studies beyond CT-PET are unnecessary and the search for metastatic disease is complete. More controversial is how one should assess patients with known stage III disease. Because these patients are more likely to have asymptomatic occult metastatic disease, current guidelines recommend a more extensive imaging evaluation including imaging of the brain with either CT scan or MRI. In patients in whom distant metastatic disease has been ruled out, lymph node status needs to be assessed via a combination of radiographic imaging and/or minimally invasive techniques such as those mentioned above and/or invasive techniques such as mediastinoscopy,


InternalMed_Harrison

InternalMed_Harrison. lymph node status needs to be assessed via a combination of radiographic imaging and/or minimally invasive techniques such as those mentioned above and/or invasive techniques such as mediastinoscopy, mediastinotomy, thoracoscopy, or thoracotomy. Approximately one-quarter to one-half of patients diagnosed with NSCLC will have mediastinal lymph node metastases at the time of diagnosis. Lymph node sampling is recommended in all patients with enlarged nodes detected by CT or PET scan and in patients with large tumors or tumors occupying the inner third of the lung. The extent of mediastinal lymph node involvement is important in determining the appropriate treatment strategy: surgical resection followed by adjuvant chemotherapy versus combined chemoradiation alone (see below). A standard nomenclature for referring to the location of lymph nodes involved with lung cancer has evolved (Fig. 107-4).


InternalMed_Harrison

InternalMed_Harrison. In SCLC patients, current staging recommendations include a CT scan of the chest and abdomen (because of the high frequency of hepatic and adrenal involvement), MRI of the brain (positive in 10% of asymptomatic patients), and radionuclide bone scan if symptoms or signs suggest disease involvement in these areas (Fig. 107-5). Although there are less data on the use of CT-PET in SCLC, the most recent American College of Chest Physicians Evidence-Based Clinical Practice Guidelines recommend PET scans in patients with clinical stage I SCLC who are being considered for curative intent surgical 513 resection. In addition, invasive mediastinal staging and extrathoracic imaging (head MRI/CT and PET or abdominal CT plus bone scan) is also recommended for patients with clinical stage I SCLC if curative intent surgical resection is contemplated. Some practice guidelines also recommend the use of PET scanning in the staging of SCLC patients who are potential candidates for the addition of


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InternalMed_Harrison. if curative intent surgical resection is contemplated. Some practice guidelines also recommend the use of PET scanning in the staging of SCLC patients who are potential candidates for the addition of thoracic radiotherapy to chemotherapy. Bone marrow biopsies and aspirations are rarely performed now given the low incidence of isolated bone marrow metastases. Confirmation of metastatic disease, ipsilateral or contra-lateral lung nodules, or metastases beyond the mediastinum may be achieved by the same modalities recommended earlier for patients with NSCLC.


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InternalMed_Harrison. If a patient has signs or symptoms of spinal cord compression (pain, weakness, paralysis, urinary retention), a spinal CT or MRI scan and examination of the cerebrospinal fluid cytology should be performed. If metastases are evident on imaging, a neurosurgeon should be consulted for possible palliative surgical resection and/or a radiation oncologist should be consulted for palliative radiotherapy to the site of compression. If signs or symptoms of leptomeningitis develop at any time in a patient with lung cancer, an MRI of the brain and spinal cord should be performed, as well as a spinal tap, for detection of malignant cells. If the spinal tap is negative, a repeat spinal tap should be considered. There is currently no approved therapy for the treatment of leptomeningeal disease.


InternalMed_Harrison

InternalMed_Harrison. The tumor-node-metastasis (TNM) international staging system provides useful prognostic information and is used to stage all patients with NSCLC. The various T (tumor size), N (regional node involvement), and M (presence or absence of distant metastasis) are combined to form different stage groups (Tables 107-6 and 107-7). The previous edition of the TNM staging system for lung cancer was developed based on a relatively small database of patients from a single institution. The latest seventh edition of the TNM staging system went into effect in 2010 and developed using a much more robust database of more than 100,000 patients with lung cancer who were treated in multiple countries between 1990 and 2000. Data from 67,725 patients with NSCLC were then used to reevaluate the prognostic value of the TNM descriptors (Table 107-8). The major distinction between the sixth and seventh editions of the international staging systems is within the T classification; T1 tumors are divided into


InternalMed_Harrison

InternalMed_Harrison. of the TNM descriptors (Table 107-8). The major distinction between the sixth and seventh editions of the international staging systems is within the T classification; T1 tumors are divided into tumors ≤2 cm in size, as these patients were found to have a better prognosis compared to patients with tumors >2 cm but ≤3 cm. T2 tumors are divided into those that are >3 cm but ≤5 cm and those that are >5 cm but ≤7 cm. Tumors that are >7 cm are considered T3 tumors. T3 tumors also include tumors with invasion into local structures such as chest wall and diaphragm and additional nodules in the same lobe. T4 tumors include tumors of any size with invasion into mediastinum, heart, great vessels, trachea, or esophagus or multiple nodules in the ipsilateral lung. No changes have been made to the current classification of lymph node involvement (N). Patients with metastasis may be classified as M1a (malignant pleural or pericardial effusion, pleural nodules, or nodules in the contralateral lung)


InternalMed_Harrison

InternalMed_Harrison. classification of lymph node involvement (N). Patients with metastasis may be classified as M1a (malignant pleural or pericardial effusion, pleural nodules, or nodules in the contralateral lung) or M1b (distant metastasis; e.g., bone, liver, adrenal, or brain metastasis). Based on these data, approximately one-third of patients have localized disease that can be treated with curative attempt (surgery or radiotherapy), one-third have local or regional disease that may or may not be amenable to a curative attempt, and one-third have metastatic disease at the time of diagnosis.


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InternalMed_Harrison. In patients with SCLC, it is now recommended that both the Veterans Administration system and the American Joint Committee on Cancer/ International Union Against Cancer seventh edition system (TNM) be used to classify the tumor stage. The Veterans Administration system is a distinct two-stage system dividing patients into those with limitedor extensive-stage disease. Patients with limited-stage disease (LD) have cancer that is confined to the ipsilateral hemithorax and can be encompassed within a tolerable radiation port. Thus, contralateral Neoplasms of the Lung Brachiocephalic (innominate) a. Azygos v. 12, 13, 14R 11L 10L 9 8 12, 13, 14L 7 Inf.pulm. ligt. L.pulmonary a. 3 6 5 Ao PA Phrenic n. N2 = single digit, ipsilateral N3 = single digit, contralateral or supraclavicular


InternalMed_Harrison

InternalMed_Harrison. Azygos v. 12, 13, 14R 11L 10L 9 8 12, 13, 14L 7 Inf.pulm. ligt. L.pulmonary a. 3 6 5 Ao PA Phrenic n. N2 = single digit, ipsilateral N3 = single digit, contralateral or supraclavicular FIGURE 107-4 Lymph node stations in staging non-small-cell lung cancer. The International Association for the Study of Lung Cancer (IASLC) lymph node map, including the proposed grouping of lymph node stations into “zones” for the purposes of prognostic analyses. a., artery; Ao, aorta; Inf. pulm. ligt., inferior pulmonary ligament; n., nerve; PA, pulmonary artery; v., vein.


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InternalMed_Harrison. supraclavicular nodes, recurrent laryngeal nerve involvement, and superior vena caval obstruction can all be part of LD. Patients with extensive-stage disease (ED) have overt metastatic disease by imaging or physical examination. Cardiac tamponade, malignant pleural effusion, and bilateral pulmonary parenchymal involvement generally qualify disease as ED, because the involved organs cannot be encompassed safely or effectively within a single radiation therapy port. Sixty to 70% of patients are diagnosed with ED at presentation. The TNM staging system is preferred in the rare SCLC patient presenting with what appears to be clinical stage I disease (see above).


InternalMed_Harrison

InternalMed_Harrison. Patients with lung cancer often have other comorbid conditions related to smoking including cardiovascular disease and COPD. To improve their preoperative condition, correctable problems (e.g., anemia, electrolyte and fluid disorders, infections, cardiac disease, and arrhythmias) should be addressed, appropriate chest physical therapy should be instituted, and patients should be encouraged to stop smoking. Because it is not always possible to predict whether a lobectomy or pneumonectomy will be required until the time of operation, a conservative approach is to restrict surgical resection to patients who could potentially tolerate a pneumonectomy. Patients with a forced expiratory volume in 1 s (FEV1) of greater than 2 L or greater than 80% of predicted can tolerate a pneumonectomy, and those with an FEV1 greater than 1.5 L have adequate reserve for a lobectomy. In patients with borderline lung function but a resectable tumor, cardiopulmonary exercise testing could be performed as


InternalMed_Harrison

InternalMed_Harrison. those with an FEV1 greater than 1.5 L have adequate reserve for a lobectomy. In patients with borderline lung function but a resectable tumor, cardiopulmonary exercise testing could be performed as part of the physiologic evaluation. This test allows an estimate of the maximal oxygen consumption (Vo ). A Vo <15 mL/(kg⋅min) predicts for a higher risk of postoperative complications. Patients deemed unable to tolerate lobectomy or pneumonectomy from a pulmonary functional standpoint may be candidates for more limited resections, such as wedge or anatomic segmental resection, although such procedures are associated with significantly higher rates of local


InternalMed_Harrison

InternalMed_Harrison. Complete history and physical examination Determination of performance status and weight loss Complete blood count with platelet determination Measurement of serum electrolytes, glucose, and calcium; renal and liver function tests CT scan of chest abdomen and pelvis to evaluate for metastatic disease MRI of brain Bone scan if clinically indicated


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InternalMed_Harrison. No signs, symptoms, or imaging to suggest metastatic disease Single lesion detected on imaging (For clinical stage I SCLC see “Anatomic Staging of Patients with Lung Cancer”) Multiple lesions detected on imaging Chemotherapy alone and/or radiation therapy for palliation of symptoms Patient has no contraindication to combined chemotherapy and radiation therapy Combined modality treatment with platinum-based therapy and etoposide and radiation therapy Sequential treatment with chemotherapy and radiation therapy Patient has contraindication to combined chemotherapy and radiation therapy Negative for metastatic disease Positive for metastatic disease Biopsy lesion Note: Regardless of disease stage, patients who have a good response to initial therapy should be considered for prophylactic cranial irradiation after therapy is completed. FIGURE 107-5 Algorithm for management of small-cell lung cancer. CT, computed tomography; MRI, magnetic resonance imaging.


InternalMed_Harrison

InternalMed_Harrison. FIGURE 107-5 Algorithm for management of small-cell lung cancer. CT, computed tomography; MRI, magnetic resonance imaging. Neoplasms of the Lung recurrence and a trend toward decreased overall survival. All patients should be assessed for cardiovascular risk using American College of Cardiology and American Heart Association guidelines. A myocardial infarction within the past 3 months is a contraindication to thoracic surgery because 20% of patients will die of reinfarction. An infarction in the past 6 months is a relative contraindication. Other major contraindications include uncontrolled arrhythmias, an FEV1 of less than 1 L, CO2 retention (resting Pco2 >45 mmHg), DLco <40%, and severe pulmonary hypertension. The overall treatment approach to patients with NSCLC is shown in Fig. 107-3.


InternalMed_Harrison

InternalMed_Harrison. The overall treatment approach to patients with NSCLC is shown in Fig. 107-3. Patients with severe atypia on sputum cytology have an increased risk of developing lung cancer compared to those without atypia. In the uncommon circumstance where malignant cells are identified in a sputum or bronchial washing specimen but the chest imaging appears normal (TX tumor stage), the lesion must be localized. More than 90% of tumors can be localized by meticulous examination of the bronchial tree with a fiberoptic bronchoscope under general anesthesia and collection of a series of differential brushings and biopsies. Surgical resection following bronchoscopic localization has been shown to improve survival compared to no treatment. Close follow-up of these patients is indicated because of the high incidence of second primary lung cancers (5% per patient per year).


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InternalMed_Harrison. A solitary pulmonary nodule is defined as an x-ray density completely surrounded by normal aerated lung with circumscribed margins, of any shape, usually 1–6 cm in greatest diameter. The approach to a patient with a solitary pulmonary nodule is based on an estimate of the probability of cancer, determined according to the patient’s smoking history, age, and characteristics on imaging (Table 107-9). Prior CXRs and CT scans should be obtained if available for comparison. A PET scan may be useful if the lesion is greater than 7–8 mm in diameter. If no diagnosis is apparent, Mayo investigators reported that clinical characteristics (age, cigarette smoking status, and prior cancer diagnosis) and three radiologic characteristics (nodule diameter, spiculation, and upper lobe location) were independent predictors of malignancy. At present, only two radiographic criteria are thought to predict the benign nature of a solitary pulmonary nodule: lack of growth over a period >2 years and certain


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InternalMed_Harrison. predictors of malignancy. At present, only two radiographic criteria are thought to predict the benign nature of a solitary pulmonary nodule: lack of growth over a period >2 years and certain characteristic patterns of calcification. Calcification alone, however, does not exclude malignancy; a dense central nidus, multiple punctuate foci, and “bulls eye” (granuloma) and “popcorn ball” (hamartoma) calcifications are highly suggestive of a benign lesion. In contrast, a relatively large lesion, lack of or asymmetric calcification, chest symptoms, associated atelectasis, pneumonitis, or growth of the lesion revealed by comparison with an old x-ray or CT scan or a positive PET scan may be suggestive of a malignant process and warrant further attempts to establish a histologic diagnosis. An algorithm for assessing these lesions is shown in Fig. 107-6.


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InternalMed_Harrison. Since the advent of screening CTs, small “ground-glass” opacities (GGOs) have often been observed, particularly as the increased sensitivity of CTs enables detection of smaller lesions. Many of these GGOs, when biopsied, are found to be atypical adenomatous hyperplasia (AAH), adenocarcinoma in situ (AIS), or minimally invasive adenocarcinoma (MIA). AAH is usually a nodule of <5 mm and is minimally hazy, also called nonsolid or ground glass (i.e., hazy slightly increased attenuation, no solid component, and preservation of bronchial and vascular margins). On thin-section CT, AIS is T1 Tumor ≤3 cm diameter, surrounded by lung or visceral pleura, without invasion more proximal than lobar bronchus T1a Tumor ≤2 cm in diameter T1b Tumor >2 cm but ≤ 3 cm in diameter T2 Tumor >3 cm but ≤7 cm, or tumor with any of the following features: Involves main bronchus, ≥2 cm distal to carina


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InternalMed_Harrison. Invades visceral pleura Associated with atelectasis or obstructive pneumonitis that extends to the hilar region but does not involve the entire lung T2a Tumor >3 cm but ≤5 cm T2b Tumor >5 cm but ≤7 cm T3 Tumor >7 cm or any of the following: Directly invades any of the following: chest wall, diaphragm, phrenic nerve, mediastinal pleura, parietal pericardium, main bronchus <2 cm from carina (without involvement of carina) Atelectasis or obstructive pneumonitis of the entire lung Separate tumor nodules in the same lobe T4 Tumor of any size that invades the mediastinum, heart, great vessels, trachea, recurrent laryngeal nerve, esophagus, vertebral body, carina, or with separate tumor nodules in a different ipsilateral lobe M0 No distant metastasis M1 Distant metastasis M1a Separate tumor nodule(s) in a contralateral lobe; tumor with pleural nodules or malignant pleural or pericardial effusion M1b Distant metastasis (in extrathoracic organs) Abbreviation: TNM, tumor-node-metastasis.


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InternalMed_Harrison. Source: Reproduced with permission from P Goldstraw et al: J Thorac Oncol 2:706, 2007. Stage IIA T1a,T1b,T2a N1 M0 Stage IIIA T1a,T1b,T2a,T2b N2 M0 T3 N1,N2 M0 T4 N0,N1 M0 Stage IIIB T4 N2 M0 Any T N3 M0 Stage IV Any T Any N M1a or M1b Abbreviation: TNM, tumor-node-metastasis. Source: Reproduced with permission from P Goldstraw P et al: J Thorac Oncol 2:706, 2007. Abbreviation: TNM, tumor-node-metastasis. usually a nonsolid nodule and tends to be slightly more opaque than AAH. MIA is mainly solid, usually with a small (<5 mm) central solid component. However, overlap exists among the imaging features of the preinvasive and minimally invasive lesions in the lung adenocarcinoma spectrum. Lepidic adenocarcinomas are usually solid but may be nonsolid. Likewise, the small invasive adenocarcinomas also are usually solid but may exhibit a small nonsolid component.


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InternalMed_Harrison. MANAGEMENT OF STAGES I AND II NSCLC Surgical Resection of Stage I and II NSCLC Surgical resection, ideally by an experienced thoracic surgeon, is the treatment of choice for patients with clinical stage I and II NSCLC who are able to tolerate the procedure. Operative mortality rates for patients resected by thoracic or cardiothoracic surgeons are lower compared to general surgeons. Moreover, survival rates are higher in patients who undergo resection in facilities with a high surgical volume compared to those performing fewer than 70 procedures per year, even though the higher-volume facilities often serve older and less socioeconomic advantaged populations. The improvement in survival is most evident in the immediate postoperative period. The extent of resection is a matter of surgical judgment based on findings at exploration. In patients with stage IA NSCLC, lobectomy is superior to wedge resection with respect to rates of local recurrence. There is also a trend toward improvement


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InternalMed_Harrison. based on findings at exploration. In patients with stage IA NSCLC, lobectomy is superior to wedge resection with respect to rates of local recurrence. There is also a trend toward improvement in overall survival. In patients with comorbidities, compromised pulmonary reserve, and small peripheral lesions, a limited resection, wedge resection, and segmentectomy (potentially by video-assisted thoracoscopic surgery) may be reasonable surgical option. Pneumonectomy is reserved for patients with central tumors and should be performed only in margins Source: Reproduced with permission from D Ost et al: N Engl J Med 348:2535, 2003.


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InternalMed_Harrison. SPN detected on CXR Obtain old films. Assess stability over ˜2 years or benign pattern of calcification Step 1 Solid SPN Negative Positive PET or PET-CT Obtain tissue diagnosis. (TTNA, TBBx, surgical resection)*** Serial CT chest** Neoplasms of the Lung FIGURE 107-6 A. Algorithm for evaluation of solitary pulmonary nodule (SPN). B. Algorithm for evaluation of solid SPN. C. Algorithm for evaluation of semisolid SPN. CT, computed tomography; CXR, chest radiograph; GGN, ground-glass nodule; PET, positron emission tomography; TTBx, transbronchial biopsy; TTNA, transthoracic needle biopsy. (Adapted from VK Patel et al: Chest 143:840, 2013.) No follow-up required Follow-up thin-section CT in 3 months. If nodule is unchanged, consider yearly low-dose CT scans.* If there is change in size or nodule characteristics, surgical resection should be strongly considered *Frequency and duration of follow-up CT scans have yet to be definitively established.


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InternalMed_Harrison. If there is change in size or nodule characteristics, surgical resection should be strongly considered *Frequency and duration of follow-up CT scans have yet to be definitively established. patients with excellent pulmonary reserve. The 5-year survival rates are 60–80% for patients with stage I NSCLC and 40–50% for patients with stage II NSCLC.


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InternalMed_Harrison. Accurate pathologic staging requires adequate segmental, hilar, and mediastinal lymph node sampling. Ideally this includes a mediastinal lymph node dissection. On the right side, mediastinal stations 2R, 4R, 7, 8R, and 9R should be dissected; on the left side, stations 5, 6, 7, 8L, and 9L should be dissected. Hilar lymph nodes are typically resected and sent for pathologic review, although it is helpful to specifically dissect and label level 10 lymph nodes when possible. On the left side, level 2 and sometimes level 4 lymph nodes are generally obscured by the aorta. Although the therapeutic benefit of nodal dissection versus nodal sampling is controversial, a pooled analysis of three trials involving patients with stages I to IIIA NSCLC demonstrated a superior 4-year survival in patients undergoing resection and a complete mediastinal lymph node dissection compared with lymph node sampling. Moreover, complete mediastinal lymphadenectomy added little morbidity to a pulmonary resection


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InternalMed_Harrison. undergoing resection and a complete mediastinal lymph node dissection compared with lymph node sampling. Moreover, complete mediastinal lymphadenectomy added little morbidity to a pulmonary resection for lung cancer when carried out by an experienced thoracic surgeon.


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InternalMed_Harrison. Radiation Therapy in Stages I and II NSCLC There is currently no role for postoperative radiation therapy in patients following resection of stage I or II NSCLC. However, patients with stage I and II disease Follow-up thin-section CT in months. If nodule unchanged and solid component is >8 mm, consider PET-CT. Further recommendations may include surgical resection, nodule biopsy, or serial CT scans. If there is a change in size or nodule characteristics, surgical resection should be strongly considered *Fleischner society guidelines; modified from: H. MacMahon, et al: Radiology 2005; 237;395–400 **ACCP guidelines (see MK Gould et al: Chest 2007;132(suppl 3):108s-130S. ***Consider patient preference, severity of medical comorbidities, center specific expertise prior to tissue diagnosis.


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InternalMed_Harrison. who either refuse or are not suitable candidates for surgery should be considered for radiation therapy with curative intent. Stereotactic body radiation therapy (SBRT) is a relatively new technique used to treat patients with isolated pulmonary nodules (≤5 cm) who are not candidates for or refuse surgical resection. Treatment is typically administered in three to five fractions delivered over 1–2 weeks. In uncontrolled studies, disease control rates are >90%, and 5-year survival rates of up to 60% have been reported with SBRT. By comparison, survival rates typically range from 13 to 39% in patients with stage I or II NSCLC treated with standard external-beam radiotherapy. Cryoablation is another technique occasionally used to treat small, isolated tumors (i.e., ≤3 cm). However, very little data exist on long-term outcomes with this technique.


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InternalMed_Harrison. Chemotherapy in Stages I and II NSCLC Although a landmark meta-analysis of cisplatin-based adjuvant chemotherapy trials in patients with resected stages I to IIIA NSCLC (the Lung Adjuvant Cisplatin Evaluation [LACE] Study) demonstrated a 5.4% improvement in 5-year survival for adjuvant chemotherapy compared to surgery alone, the survival benefit was seemingly confined to patients with stage II or III disease (Table 107-10). By contrast, survival was actually worsened in stage IA patients with the application of adjuvant therapy. In stage IB, there was a modest improvement in survival of questionable clinical significance. Adjuvant chemotherapy was .03 240 54 407 60 .017 433 58 548 50 .49 540 45 192 60 .90 189 58 173 59 .10 171 57 Abbreviations: ALPI, Adjuvant Lung Cancer Project Italy; ANITA, Adjuvant Navelbine International Trialist Association; BLT, Big Lung Trial; CALGB, Cancer and Lung Cancer Group B; IALT,


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InternalMed_Harrison. Abbreviations: ALPI, Adjuvant Lung Cancer Project Italy; ANITA, Adjuvant Navelbine International Trialist Association; BLT, Big Lung Trial; CALGB, Cancer and Lung Cancer Group B; IALT, International Adjuvant Lung Cancer Trial; MVP, mitomycin, vindesine, and cisplatin. also detrimental in patients with poor performance status (Eastern Cooperative Oncology Group [ECOG] performance status = 2). These data suggest that adjuvant chemotherapy is best applied in patients with resected stage II or III NSCLC. There is no apparent role for adjuvant chemotherapy in patients with resected stage IA or IB NSCLC. A possible exception to the prohibition of adjuvant therapy in this setting is the stage IB patient with a resected lesion ≥4 cm.


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InternalMed_Harrison. As with any treatment recommendation, the risks and benefits of adjuvant chemotherapy should be considered on an individual patient basis. If a decision is made to proceed with adjuvant chemotherapy, in general, treatment should be initiated 6–12 weeks after surgery, assuming the patient has fully recovered, and should be administered for no more than four cycles. Although a cisplatinbased chemotherapy is the preferred treatment regimen, carboplatin can be substituted for cisplatin in patients who are unlikely to tolerate cisplatin for reasons such as reduced renal function, presence of neuropathy, or hearing impairment. No specific chemotherapy regimen is considered optimal in this setting, although platinum plus vinorelbine is most commonly used.


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InternalMed_Harrison. Neoadjuvant chemotherapy, which is the application of chemotherapy administered before an attempted surgical resection, has been advocated by some experts on the assumption that such an approach will more effectively extinguish occult micrometastases compared to postoperative chemotherapy. In addition, it is thought that preoperative chemotherapy might render an inoperable lesion resectable. With the exception of superior sulcus tumors, however, the role of neoadjuvant chemotherapy in stage I to III disease is not well defined. However, a meta-analysis of 15 randomized controlled trials involving more than 2300 patients with stage I to III NSCLC suggested there may be a modest 5-year survival benefit (i.e., ∼5%) that is virtually identical to the survival benefit achieved with postoperative chemotherapy. Accordingly, neoadjuvant therapy may prove useful in selected cases (see below). A decision to use neoadjuvant chemotherapy should always be made in consultation with an experienced


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InternalMed_Harrison. chemotherapy. Accordingly, neoadjuvant therapy may prove useful in selected cases (see below). A decision to use neoadjuvant chemotherapy should always be made in consultation with an experienced surgeon.


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InternalMed_Harrison. In should be noted that all patients with resected NSCLC are at high risk of recurrence, most of which occurs within 18–24 months of surgery, or developing a second primary lung cancer. Thus, it is reasonable to follow these patients with periodic imaging studies. Given the results of the NLST, periodic CT scans appear to be the most appropriate screening modality. Based on the timing of most recurrences, some guidelines recommend a contrasted chest CT scan every 6 months for the first 3 years after surgery, followed by yearly CT scans of the chest without contrast thereafter.


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InternalMed_Harrison. Management of patients with stage III NSCLC usually requires a combined-modality approach. Patients with stage IIIA disease commonly are stratified into those with “nonbulky” or “bulky” mediastinal lymph node (N2) disease. Although the definition of “bulky” N2 disease varies somewhat in the literature, the usual criteria include the size of a dominant lymph node (i.e., >2–3 cm in short-axis diameter as measured by CT), groupings of multiple smaller lymph nodes, evidence of extracapsular nodal involvement, or involvement of more than two lymph node stations. The distinction between nonbulky and bulky stage IIIA disease is mainly used to select potential candidates for upfront surgical resection or for resection after neoadjuvant therapy. Many aspects of therapy of patients with stage III NSCLC remain controversial, and the optimal treatment strategy has not been clearly defined. Moreover, although there are many potential treatment options, none yields a very high probability of cure.


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InternalMed_Harrison. remain controversial, and the optimal treatment strategy has not been clearly defined. Moreover, although there are many potential treatment options, none yields a very high probability of cure. Furthermore, because stage III disease is highly heterogeneous, no single treatment approach can be recommended for all patients. Key factors guiding treatment choices include the particular combination of tumor (T) and nodal (N) disease, the ability to achieve a complete surgical resection if indicated, and the patient’s overall physical condition and preferences. For example, in carefully selected patients with limited stage IIIA disease where involved mediastinal lymph nodes can be completed resected, initial surgery followed by postoperative chemotherapy (with or without radiation therapy) may be indicated. By contrast, for patients with clinically evident bulky mediastinal lymph node involvement, the standard approach to treatment is concurrent chemoradiotherapy. Nevertheless, in some


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InternalMed_Harrison. may be indicated. By contrast, for patients with clinically evident bulky mediastinal lymph node involvement, the standard approach to treatment is concurrent chemoradiotherapy. Nevertheless, in some cases, the latter group of patients may be candidates for surgery following chemoradiotherapy.


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InternalMed_Harrison. Absent and Nonbulky Mediastinal (N2, N3) Lymph Node Disease For the subset of stage IIIA patients initially thought to have clinical stage I or II disease (i.e., pathologic involvement of mediastinal [N2] lymph nodes is not detected preoperatively), surgical resection is often the treatment of choice. This is followed by adjuvant chemotherapy in patients with microscopic lymph node involvement in a resection specimen. Postoperative radiation therapy (PORT) may also have a role for those with close or positive surgical margins. Patients with tumors involving the chest wall or proximal airways within 2 cm of the carina with hilar lymph node involvement (but not N2 disease) are classified as having T3N1 stage IIIA disease. They too are best managed with surgical resection, if technically feasible, followed by adjuvant chemotherapy if completely resected. Patients with tumors exceeding 7 cm in size also are now classified as T3 and are consider stage IIIA if tumor has spread to N1 nodes.


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InternalMed_Harrison. followed by adjuvant chemotherapy if completely resected. Patients with tumors exceeding 7 cm in size also are now classified as T3 and are consider stage IIIA if tumor has spread to N1 nodes. The appropriate initial management of these patients involves surgical resection when feasible, provided the mediastinal staging is negative, followed by adjuvant chemotherapy for those who achieve complete tumor resection. Patients with T3N0 or T3N1 disease due to the presence of satellite nodules within the same lobe as the primary tumor also are candidates for surgery, as are patients with ipsilateral nodules in another lobe and negative mediastinal nodes (IIIA, T4N0 or T4N1). Although data regarding adjuvant chemotherapy in the latter subsets of patients are limited, it is often recommended.


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InternalMed_Harrison. Patients with T4N0-1 were reclassified as having stage IIIA tumors in the seventh edition of the TNM system. These patients may have involvement of the carina, superior vena cava, or a vertebral body and yet still be candidates for surgical resection in selected circumstances. The decision to proceed with an attempted resection must be made in consultation with an experienced thoracic surgeon often in association with a vascular or cardiac surgeon and an orthopedic surgeon depending on tumor location. However, if an incomplete resection is inevitable or if there is evidence of N2 involvement (stage IIIB), surgery for T4 disease is contraindicated. Most T4 lesions are best treated with chemoradiotherapy.


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InternalMed_Harrison. The role of PORT in patients with completely resected stage III NSCLC is controversial. To a large extent, the use of PORT is dictated by the presence or absence of N2 involvement and, to a lesser degree, by the biases of the treating physician. Using the Surveillance, Epidemiology, and End Results (SEER) database, a recent meta-analysis of PORT identified a significant increase in survival in patients with N2 disease but not in patients with N0 or N1 disease. An earlier analysis by the PORT Meta-analysis Trialist Group using an older database produced similar results.


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InternalMed_Harrison. Known Mediastinal (N2, N3) Lymph Node Disease When pathologic involvement of mediastinal lymph nodes is documented preoperatively, a combined-modality approach is recommended assuming the patient is a candidate for treatment with curative intent. These patients are at high risk for both local and distant recurrence if managed with resection alone. For patients with stage III disease who are not candidates for initial surgical resection, concurrent chemoradiotherapy is most commonly used as the initial treatment. Concurrent chemoradiotherapy has been shown to produce superior survival compared to sequential chemoradiotherapy; however, it also is associated with greater host toxicities (including fatigue, esophagitis, and neutropenia). Therefore, for patients with a good performance status, concurrent chemoradiotherapy is the preferred treatment approach, whereas sequential chemoradiotherapy may be more appropriate for patients with a performance status that is not as good. For patients


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InternalMed_Harrison. concurrent chemoradiotherapy is the preferred treatment approach, whereas sequential chemoradiotherapy may be more appropriate for patients with a performance status that is not as good. For patients who are not candidates for a combined-modality treatment approach, typically due to a poor performance status or a comorbidity that makes chemotherapy untenable, radiotherapy alone may provide a modest survival benefit in addition to symptom palliation.


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InternalMed_Harrison. For patients with potentially resectable N2 disease, it remains uncertain whether surgery after neoadjuvant chemoradiotherapy improves survival. In an NCI-sponsored Intergroup randomized trial comparing concurrent chemoradiotherapy alone to concurrent chemoradiotherapy followed by attempted surgical resection, no survival benefit was observed in the trimodality arm compared to the bimodality therapy. In fact, patients subjected to a pneumonectomy had a worse survival outcome. By contrast, those treated with a lobectomy appeared to have a survival advantage based on a retrospective subset analysis. Thus, in carefully selected, otherwise healthy patients with nonbulky mediastinal lymph node involvement, surgery may be a reasonable option if the primary tumor can be fully resected with a lobectomy. This is not the case if a pneumonectomy is required to achieve complete resection.


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InternalMed_Harrison. Superior Sulcus Tumors (Pancoast Tumors) Superior sulcus tumors represent a distinctive subset of stage III disease. These tumors arise in the apex of the lung and may invade the second and third ribs, the brachial plexus, the subclavian vessels, the stellate ganglion, and adjacent vertebral bodies. They also may be associated with Pancoast syndrome, characterized by pain that may arise in the shoulder or chest wall or radiate to the neck. Pain characteristically radiates to the ulnar surface of the hand. Horner’s syndrome (enophthalmos, ptosis, miosis, and anhydrosis) due to invasion of the paravertebral sympathetic chain may be present as well. Patients with these tumors should undergo the same staging procedures as all patients with stage II and III NSCLC. Neoadjuvant chemotherapy or 519 combined chemoradiotherapy followed by surgery is reserved for those without N2 involvement. This approach yields excellent survival outcomes (>50% 5-year survival in patients with an R0


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InternalMed_Harrison. or 519 combined chemoradiotherapy followed by surgery is reserved for those without N2 involvement. This approach yields excellent survival outcomes (>50% 5-year survival in patients with an R0 resection). Patients with N2 disease are less likely to benefit from surgery and can be managed with chemoradiotherapy alone. Patients presenting with metastatic disease can be treated with radiation therapy (with or without chemotherapy) for symptom palliation.


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InternalMed_Harrison. Approximately 40% of NSCLC patients present with advanced, stage IV disease at the time of diagnosis. These patients have a poor median survival (4–6 months) and a 1-year survival of 10% when managed with best supportive care alone. In addition, a significant number of patients who first presented with early-stage NSCLC will eventually relapse with distant disease. Patients who have recurrent disease have a better prognosis than those presenting with metastatic disease at the time of diagnosis. Standard medical manage ment, the judicious use of pain medications, and the appropriate use of radiotherapy and chemotherapy form the cornerstone of management. Chemotherapy palliates symptoms, improves the quality of life, and improves survival in patients with stage IV NSCLC, particularly in patients with good performance status. In addition, economic analysis has found chemotherapy to be cost-effective palliation for stage IV NSCLC. However, the use of chemotherapy for NSCLC requires


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InternalMed_Harrison. in patients with good performance status. In addition, economic analysis has found chemotherapy to be cost-effective palliation for stage IV NSCLC. However, the use of chemotherapy for NSCLC requires clinical experience and careful judgment to balance potential benefits and toxicities. Of note, the early application of palliative care in conjunction with chemotherapy is associated with improved survival and a better quality of life.


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InternalMed_Harrison. First-Line Chemotherapy for Metastatic or Recurrent NSCLC A landmark meta-analysis published in 1995 provided the earliest meaningful indication that chemotherapy could provide a survival benefit in metastatic NSCLC as opposed to supportive care alone. However, the survival benefit was seemingly confined to cisplatin-based chemotherapy regimens (hazard ratio 0.73; 27% reduction in the risk of death; 10% improvement in survival at 1 year). These data launched two decades of clinical research aimed at detecting the optimal chemotherapy regimen for advanced NSCLC. For the most part, however, these efforts proved unsuccessful because the overwhelming majority of randomized trials showed no major survival improvement with any one regimen versus another (Table 107-11). On the other hand, differences in progression-free survival, cost, side effects, and schedule were frequently observed. These first-line studies were later extended to elderly patients, where doublet chemotherapy was found to


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InternalMed_Harrison. in progression-free survival, cost, side effects, and schedule were frequently observed. These first-line studies were later extended to elderly patients, where doublet chemotherapy was found to improve overall survival compared to single agents in the “fit” elderly (e.g., elderly patients with no major comorbidities) and in patients with an ECOG performance status of 2. An ongoing debate in the treatment of patients with advanced NSCLC is the appropriate duration of platinum-based chemotherapy. Several large phase III randomized trials have failed to show a meaningful benefit for increasing the duration of platinum-based doublet chemotherapy beyond four to six cycles. In fact, longer duration of chemotherapy has been associated with increased toxicities and impaired quality of life. Therefore, prolonged front-line therapy (beyond four to six cycles) with platinum-based regimens is not recommended. Maintenance therapy following initial platinum-based therapy is discussed below.


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InternalMed_Harrison. Although specific tumor histology was once considered irrelevant to treatment choice in NSCLC, with the recent recognition that selected chemotherapy agents perform quite differently in squamous versus adenocarcinomas, accurate determination of histology has become essential. Specifically, in a landmark randomized phase III trial, patients with nonsquamous NSCLC were found to have an improved survival when treated with cisplatin and pemetrexed compared to cisplatin and gemcitabine. By contrast, patients with squamous carcinoma had an improved survival when treated with cisplatin and gemcitabine. This survival difference is thought to be related to the differential expression of thymidylate synthase (TS), Neoplasms of the Lung Median No. of


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InternalMed_Harrison. Cisplatin + paclitaxel Cisplatin + gemcitabine Cisplatin + docetaxel Carboplatin + paclitaxel Cisplatin + docetaxel Cisplatin + vinorelbine Carboplatin + docetaxel Cisplatin + paclitaxel Cisplatin + gemcitabine Paclitaxel + gemcitabine Cisplatin + gemcitabine Carboplatin + paclitaxel Cisplatin + vinorelbine Cisplatin + vinorelbine Carboplatin + paclitaxel Cisplatin + irinotecan Carboplatin + paclitaxel Cisplatin + gemcitabine Cisplatin + vinorelbine Cisplatin + gemcitabine Cisplatin + pemetrexed Carboplatin + paclitaxel Gefitinib 288 21 7.8 288 22 8.1 289 17 7.4 290 17 8.1 406 32 11.3 394 25 10.1 404 24 9.4 159 32 8.1 160 37 8.9 161 28 6.7 205 30 9.8 204 32 9.9 203 30 9.5 202 28 8.0 206 25 8.0 145 31 13.9 145 32 12.3 146 30 14.0 145 33 11.4 863 28 10.3 862 31 10.3 608 32 17.3 609 43% 18.6 aEnrolled selected patients: 18 years of age or older, had histologic or cytologically confirmed stage IIIB or IV non-small-cell lung cancer with histologic features of adenocarcinoma (including


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InternalMed_Harrison. 18.6 aEnrolled selected patients: 18 years of age or older, had histologic or cytologically confirmed stage IIIB or IV non-small-cell lung cancer with histologic features of adenocarcinoma (including bronchioloalveolar carcinoma), were nonsmokers (defined as patients who had smoked <100 cigarettes in their lifetime) or former light smokers (those who had stopped smoking at least 15 years previously and had a total of ≤10 pack-years of smoking), and had had no previous chemotherapy or biologic or immunologic therapy.


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InternalMed_Harrison. Abbreviations: ECOG, Eastern Cooperative Oncology Group; EORTC, European Organization for Research and Treatment of Cancer; ILCP, Italian Lung Cancer Project; SWOG, Southwest Oncology Group; FACS, Follow-up After Colorectal Surgery; iPASS, Iressa Pan-Asian Study. one of the targets of pemetrexed, between tumor types. Squamous cancers have a much higher expression of TS compared to adenocarcinomas, accounting for their lower responsiveness to pemetrexed. By contrast, the activity of gemcitabine is not impacted by the levels of TS. Bevacizumab, a monoclonal antibody against VEGF, has been shown to improve response rate, progression-free survival, and overall survival in patients with advanced disease when combined with chemotherapy (see below). However, bevacizumab cannot be given to patients with squamous cell histology NSCLC because of their tendency to experience serious hemorrhagic effects.


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InternalMed_Harrison. Agents That Inhibit Angiogenesis Bevacizumab, a monoclonal antibody directed against VEGF, was the first antiangiogenic agent approved for the treatment of patients with advanced NSCLC in the United States. This drug primarily acts by blocking the growth of new blood vessels, which are required for tumor viability. Two randomized phase III trials of chemotherapy with or without bevacizumab had conflicting results. The first trial, conducted in North America, compared carboplatin plus paclitaxel with or without bevacizumab in patients with recurrent or advanced nonsquamous NSCLC and reported a significant improvement in response rate, progression-free survival, and overall survival in patients treated with chemotherapy plus bevacizumab versus chemotherapy alone. Bevacizumab-treated patients had a significantly higher incidence of toxicities. The second trial, conducted in Europe, compared cisplatin/gemcitabine with or without bevacizumab in patients with recurrent or advanced


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InternalMed_Harrison. patients had a significantly higher incidence of toxicities. The second trial, conducted in Europe, compared cisplatin/gemcitabine with or without bevacizumab in patients with recurrent or advanced nonsquamous NSCLC and reported a significant improvement in progression-free survival but no improvement in overall survival for bevacizumab-treated patients. A randomized phase III trial compared carboplatin/pemetrexed and bevacizumab to carboplatin/paclitaxel and bevacizumab as first-line therapy in patients with recurrent or advanced nonsquamous NSCLC and reported no significant difference in progression-free survival or overall survival between treatment groups. Therefore, currently carboplatin/paclitaxel and bevacizumab or carboplatin/pemetrexed and bevacizumab are appropriate regimens for first-line treatment for stage IV nonsquamous NSCLC patients. Of note, there are many small-molecule inhibitors of VEGFR; however, these VEGFR TKIs have not proven to be effective in the treatment of


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InternalMed_Harrison. first-line treatment for stage IV nonsquamous NSCLC patients. Of note, there are many small-molecule inhibitors of VEGFR; however, these VEGFR TKIs have not proven to be effective in the treatment of NSCLC.


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InternalMed_Harrison. Maintenance Therapy for Metastatic NSCLC Maintenance chemotherapy in nonprogressing patients (patients with a complete response, partial response, or stable disease) is a controversial topic in the treatment of NSCLC. Conceptually, there are two types of maintenance strategies: (1) switch maintenance therapy, where patients receive four to six cycles of platinum-based chemotherapy and are switched to an entirely different regimen; and (2) continuation maintenance therapy, where patients receive four to six cycles of platinum-based chemotherapy and then the platinum agent is discontinued but the agent it is paired with is continued (Table 107-12). Two studies investigated switch maintenance single-agent chemotherapy with docetaxel or pemetrexed in nonprogressing patients following treatment with first-line platinum-based chemotherapy. Both trials randomized patients to immediate single-agent therapy versus observation and reported improvements in progression-free and overall survival.


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InternalMed_Harrison. with first-line platinum-based chemotherapy. Both trials randomized patients to immediate single-agent therapy versus observation and reported improvements in progression-free and overall survival. In both trials, a significant portion of patients in the observation arm did not receive therapy with the agent under investigation upon disease progression; 37% of study patients never received docetaxel in the docetaxel study and 81% of patients never received pemetrexed in the pemetrexed study. In the trial of maintenance docetaxel versus observation, survival was identical to the treatment group in the subset of patients who received docetaxel on progression, indicating this is an active agent in NSCLC. These data are not available for the pemetrexed study. Two additional trials evaluated switch maintenance therapy with erlotinib after platinum-based chemotherapy in patients with advanced


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InternalMed_Harrison. Fidias Immediate docetaxel 153 12.3 5.7 Delayed docetaxel 156 9.7 2.7 Ciuleanu Pemetrexed 444 13.4 4.3 BSC 222 10.6 2.6 Paramount Pemetrexed 472 13.9 4.1 BSC 297 11.0 2.8 ATLAS Bev + erlotinib 384 15.9 4.8 Bev + placebo 384 13.9 3.8 SATURN Erlotinib 437 12.3 2.9 Placebo 447 11.1 2.6 ECOG4599 Bev 15 mg/kg 444 12.3 6.2 BSC 434 10.3 4.5 AVAiL Bev 15 mg/kg 351 13.4 6.5 Bev 7.5 mg/kg 345 13.6 6.7 Placebo 347 13.1 6.1 8.6 Bev 15 mg/kg Bev 15 mg/kg 6.9 Abbreviations: Bev, bevacizumab; BSC, best supportive care; CT, chemotherapy; OS, overall survival; PFS, progression-free survival. NSCLC and reported an improvement in progression-free survival and overall survival in the erlotinib treatment group. Currently, maintenance pemetrexed or erlotinib following platinum-based chemotherapy in patients with advanced NSCLC are approved by the U.S. FDA. However, maintenance therapy is not without toxicity and, at this time, should be considered on an individual patient basis.


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InternalMed_Harrison. Targeted Therapies for Select Molecular Cohorts of NSCLC As the efficacy of traditional cytotoxic chemotherapeutic agents plateaued in NSCLC, there was a critical need to define novel therapeutic treatment strategies. These novel strategies have largely been based on the identification of somatic driver mutations within the tumor. These driver mutations occur in genes encoding signaling proteins that, when aberrant, drive initiation and maintenance of tumor cells. Importantly, driver mutations can serve as Achilles’ heels for tumors, if their gene products can be targeted therapeutically with small-molecule inhibitors. For example, EGFR mutations have been detected in 10–15% of North American patients diagnosed with NSCLC. EGFR mutations are associated with younger age, light (<10 pack-year) and nonsmokers, and adenocarcinoma histology. Approximately 90% of these mutations are exon 19 deletions or exon 21 L858R point mutations within the EGFR TK domain, resulting in hyperactivation of


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InternalMed_Harrison. and nonsmokers, and adenocarcinoma histology. Approximately 90% of these mutations are exon 19 deletions or exon 21 L858R point mutations within the EGFR TK domain, resulting in hyperactivation of both EGFR kinase activity and downstream signaling. Lung tumors that harbor activating mutations within the EGFR kinase domain display high sensitivity to small-molecule EGFR TKIs. Erlotinib and afatinib are FDA-approved oral small-molecule TKIs that inhibit EGFR. Outside the United States, gefitinib also is available. Several large, international, phase III studies have demonstrated improved response rates, progression-free survival, and overall survival in patients with EGFR mutation–positive NSCLC patients treated with an EGFR TKI as compared with standard first-line chemotherapy regimens (Table 107-13).


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InternalMed_Harrison. Although response rates with EGFR TKI therapy are clearly superior in patients with lung tumors harboring activating EGFR kinase domain mutations, the EGFR TKI erlotinib is also FDA approved for secondand third-line therapy in patients with advanced NSCLC irrespective of tumor genotype. The reason for this apparent discrepancy is that erlotinib was initially evaluated in lung cancer before the discovery of EGFR activating mutations. In fact, EGFR mutations were initially identified in lung cancer by studying the tumors of patients who had dramatic responses to this agent. With the rapid pace of scientific discovery, additional driver mutations in lung cancer have been identified and targeted therapeutically with impressive clinical results. For example, chromosomal rearrangements involving the anaplastic lymphoma kinase (ALK) gene on chromosome 2 have been found in ∼3–7% of NSCLC. The result of these ALK rearrangements is hyperactivation of the ALK TK domain. Similar to


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InternalMed_Harrison. No. of Study Therapy Patients ORR (%) PFS (months) Abbreviations: CbP, carboplatin and paclitaxel; CD, cisplatin and docetaxel; CG, cisplatin and gemcitabine; CP, cisplatin and paclitaxel; ORR, overall response rate; PFS, progression-free survival. EGFR, ALK rearrangements are typically (but not exclusively) associ-521 ated with younger age, light (<10 pack-year) and nonsmokers, and adenocarcinoma histology. Remarkably, ALK rearrangements were initially described in lung cancer in 2007, and by 2011, the first ALK inhibitor, crizotinib, received FDA approval for patients with lung tumors harboring ALK rearrangements.


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InternalMed_Harrison. In addition to EGFR and ALK, other driver mutations have been discovered with varying frequencies in NSCLC, including KRAS, BRAF, PIK3CA, NRAS, AKT1, MET, MEK1 (MAP2K1), ROS1, and RET. Mutations within the KRAS GTPase are found in approximately 20% of lung adenocarcinomas. To date, however, no small-molecule inhibitors are available to specifically target mutant KRAS. Each of the other driver mutations occurs in less than 1–3% of lung adenocarcinomas. The great majority of the driver mutations are mutually exclusive, and there are ongoing clinical studies for their specific inhibitors. For example, the BRAF inhibitor vemurafenib and the RET inhibitor cabozantinib have already demonstrated efficacy in patients with lung cancer harboring BRAF mutations or RET gene fusions, respectively.


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InternalMed_Harrison. Most of these mutations are present in adenocarcinoma; however, mutations that may be linked to future targeted therapies in squamous cell carcinomas are emerging. In addition, there are active research efforts aimed at defining novel targetable mutations in lung cancer as well as defining mechanisms of acquired resistance to small-molecule inhibitors used in the treatment of patients with NSCLC. to supportive care alone. As first-line chemotherapy regimens improve, a substantial number of patients will maintain a good performance status and a desire for further therapy when they develop recurrent disease. Currently, several agents are FDA approved for second-line use in NSCLC including docetaxel, pemetrexed, erlotinib (approved for second-line therapy regardless of tumor genotype), and crizotinib (for patients with ALK -mutant lung cancer only). Most of the survival benefit for any of these agents is realized in patients who maintain a good performance status.


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InternalMed_Harrison. Immunotherapy For more than 30 years, the investigation of vaccines and immunotherapies in lung cancer has yielded little in the way of meaningful benefit. Recently, however, this perception has changed based on preliminary results of studies using monoclonal antibodies that activate antitumor immunity through blockade of immune checkpoints. For example, ipilimumab, a monoclonal antibody directed at cytotoxic T lymphocyte antigen-4 (CTLA-4), was studied in combination with paclitaxel plus carboplatin in patients with both SCLC and NSCLC. There appeared to be a small but not statistically significant advantage to the combination when ipilimumab was instituted after several cycles of chemotherapy. A randomized phase III trial in SCLC is under way to validate these data. Antibodies to the T cell programmed cell death receptor 1 (PD-1), nivolumab and pembrolizumab, have been shown to produce responses in lung cancer, renal cell cancer, and melanoma. Many of these responses have had very


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InternalMed_Harrison. cell programmed cell death receptor 1 (PD-1), nivolumab and pembrolizumab, have been shown to produce responses in lung cancer, renal cell cancer, and melanoma. Many of these responses have had very long duration (i.e., >1 year). Monoclonal antibodies to the PD-1 ligand (anti-PDL-1), which may be expressed on the tumor cell, have also been shown to produce responses in patients with melanoma and lung cancer. Preliminary studies in melanoma suggest that the combination of ipilimumab and nivolumab could produce higher response rates compared to either agent alone. A similar strategy is being investigated in SCLC patients. Further evaluation of these agents in both NSCLC and SCLC is ongoing in combination with already approved chemotherapy and targeted agents.


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InternalMed_Harrison. Supportive Care No discussion of the treatment strategies for patients with advanced lung cancer would be complete without a mention of supportive care. Coincident with advances in chemotherapy and targeted therapy was a pivotal study that demonstrated that the early integration of palliative care with standard treatment strategies improved both quality of life and mood for patients with advanced lung cancer. Aggressive pain and symptom control is an important component for optimal treatment of these patients. Neoplasms of the Lung only FDA-approved agent for second-line therapy in patients with SCLC. Topotecan has only modest activity and can be given either


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InternalMed_Harrison. SCLC is a highly aggressive disease characterized by its rapid doubling time, high growth fraction, early development of disseminated disease, and dramatic response to first-line chemotherapy and radiation. In general, surgical resection is not routinely recommended for patients because even patients with LD-SCLC still have occult micrometastases. However, the most recent American College of Chest Physicians Evidence-Based Clinical Practice Guidelines recommend surgical resection over nonsurgical treatment in SCLC patients with clinical stage I disease after a thorough evaluation for distant metastases and invasive mediastinal stage evaluation (grade 2C). After resection, these patients should receive platinum-based adjuvant chemotherapy (grade 1C). If the histologic diagnosis of SCLC is made in patients on review of a resected surgical specimen, such patients should receive standard SCLC chemotherapy as well.


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InternalMed_Harrison. Chemotherapy significantly prolongs survival in patients with SCLC. Four to six cycles of platinum-based chemotherapy with either cisplatin or carboplatin plus either etoposide or irinotecan has been the mainstay of treatment for nearly three decades and is recommended over other chemotherapy regimens irrespective of initial stage. Cyclophosphamide, doxorubicin (Adriamycin), and vincristine (CAV) may be an alternative for patients who are unable to tolerate a platinum-based regimen. Despite response rates to first-line therapy as high as 80%, the median survival ranges from 12 to 20 months for patients with LD and from 7 to 11 months for patients with ED. Regardless of disease extent, the majority of patients relapse and develop chemotherapy-resistant disease. Only 6–12% of patients with LD-SCLC and 2% of patients with ED-SCLC live beyond 5 years. The prognosis is especially poor for patients who relapse within the first 3 months of therapy; these patients are said to have


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InternalMed_Harrison. with LD-SCLC and 2% of patients with ED-SCLC live beyond 5 years. The prognosis is especially poor for patients who relapse within the first 3 months of therapy; these patients are said to have chemotherapy-resistant disease. Patients are said to have sensitive disease if they relapse more than 3 months after their initial therapy and are thought to have a somewhat better overall survival. These patients also are thought to have the greatest potential benefit from second-line chemotherapy (Fig. 107-7). Topotecan is the


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InternalMed_Harrison. FIGURE 107-7 Management of recurrent small-cell lung cancer (SCLC). CAV, cyclophosphamide, doxorubicin, and vincristine. (Adapted with permission from JP van Meerbeeck et al: Lancet 378:1741, 2011.) intravenously or orally. In one randomized trial, 141 patients who were not considered candidates for further IV chemotherapy were randomized to receive either oral topotecan or best supportive care. Although the response rate to oral topotecan was only 7%, overall survival was significantly better in patients receiving chemotherapy (median survival time, 26 weeks vs 14 weeks; p = .01). Moreover, patients given topotecan had a slower decline in quality of life than did those not receiving chemotherapy. Other agents with similar low levels of activity in the second-line setting include irinotecan, paclitaxel, docetaxel, vinorelbine, oral etoposide, and gemcitabine. Clearly novel treatments for this all too common disease are desperately needed.


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InternalMed_Harrison. Thoracic radiation therapy (TRT) is a standard component of induction therapy for good performance status and limited-stage SCLC patients. Meta-analyses indicate that chemotherapy combined with chest irradiation improves 3-year survival by approximately 5% as compared with chemotherapy alone. The 5-year survival rate, however, remains disappointingly low at ∼10–15%. Most commonly, TRT is combined with cisplatin and etoposide chemotherapy due to a superior toxicity profile as compared to anthracycline-containing chemotherapy regimens. As observed in locally advanced NSCLC, concurrent chemoradiotherapy is more effective than sequential chemoradiation but is associated with significantly more esophagitis and hematologic toxicity. Ideally TRT should be administered with the first two cycles of chemotherapy because later application appears slightly less effective. If for reasons of fitness or availability, this regimen cannot be offered, TRT should follow induction chemotherapy. With


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InternalMed_Harrison. of chemotherapy because later application appears slightly less effective. If for reasons of fitness or availability, this regimen cannot be offered, TRT should follow induction chemotherapy. With respect to fractionation of TRT, twice-daily 1.5-Gy fractioned radiation therapy has been shown to improve survival in LD-SCLC patients but is associated with higher rates of grade 3 esophagitis and pulmonary toxicity. Although it is feasible to deliver once-daily radiation therapy doses up to 70 Gy concurrently with cisplatin-based chemotherapy, there are no data to support equivalency of this approach compared with the 45-Gy twice-daily radiotherapy dose. Therefore, the current standard regimen of a 45-Gy dose administered in 1.5-Gy fractions twice daily for 30 days is being compared with higher-dose regimens in two phase III trials, one in the United States and one in Europe. Patients should be carefully selected for concurrent chemoradiation therapy based on good performance status and


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InternalMed_Harrison. regimens in two phase III trials, one in the United States and one in Europe. Patients should be carefully selected for concurrent chemoradiation therapy based on good performance status and adequate pulmonary reserve. The role of radiotherapy in ED-SCLC is largely restricted to palliation of tumor-related symptoms such as bone pain and bronchial obstruction.


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InternalMed_Harrison. Prophylactic cranial irradiation (PCI) should be considered in all patients with either LD-SCLC or ED-SCLC who have responded well to initial therapy. A meta-analysis including seven trials and 987 patients with LD-SCLC who had achieved a complete remission after upfront chemotherapy yielded a 5.4% improvement in overall survival for patients treated with PCI. In patients with ED-SCLC who have responded to first-line chemotherapy, a prospective randomized phase III trial showed that PCI reduced the occurrence of symptomatic brain metastases and prolonged disease-free and overall survival compared to no radiation therapy. Long-term toxicities, including deficits in cognition, have been reported after PCI but are difficult to sort out from the effects of chemotherapy or normal aging.


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InternalMed_Harrison. The management of NSCLC has undergone major change in the past decade. To a lesser extent, the same is true for SCLC. For patients with early-stage disease, advances in radiotherapy and surgical procedures as well as new systemic therapies have greatly improved prognosis in both diseases. For patients with advanced disease, major progress in understanding tumor genetics has led to the development of


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InternalMed_Harrison. Core biopsy of most distant site of disease Squamous carcinoma Adenocartcinoma Obtain tissue Determine histology Determine molecular status Treatment options EGFRmut Erlotinib or afatinib Crizotinib No mutation or mutation for which there is no FDA approved therapy Platinum-based chemothearpy ± bevacizumab Cisplatin or carboplatin + gemcitabine, doc-etaxel, paclitaxel, or nab-paclitaxel Platinum-based chemotherapy ALK (+) Large-cell neuroendocrine carcinoma FIGURE 107-8 Approach to first-line therapy in a patient with stage IV non-small-cell lung cancer (NSCLC). EGFRmut, EGFR mutation; FDA, Food and Drug Administration.


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InternalMed_Harrison. targeted inhibitors based specifically on the tumor’s molecular profile. Furthermore, increased understanding of how to activate the immune system to drive antitumor immunity is proving to be a promising therapeutic strategy for some patients with advanced lung cancer. In Fig. 107-8, we propose an algorithm of the treatment approach for patient with stage IV NSCLC. However, the reality is that the majority of patients treated with targeted therapies or chemotherapy eventually develop resistance, which provides strong motivation for further research and enrollment of patients onto clinical trials in this rapidly evolving area. Marc E. Lippman


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InternalMed_Harrison. Marc E. Lippman Breast cancer is a malignant proliferation of epithelial cells lining the ducts or lobules of the breast. In the year 2014, about 180,000 cases of invasive breast cancer and 40,000 deaths will occur in the United States. In addition, about 2000 men will be diagnosed with breast cancer. Epithelial malignancies of the breast are the most common cause of cancer in women (excluding skin cancer), accounting for about one-third of all cancer in women. As a result of improved treatment and earlier detection, the mortality rate from breast cancer has begun to decrease very substantially in the United States. This Chapter will not consider rare malignancies presenting in the breast, such as sarcomas and lymphomas, but will focus on the epithelial cancers. Human breast cancer is a clonal disease; a single transformed cell—the product of a series of somatic (acquired) or germline mutations—is eventually able to express full malignant potential.


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InternalMed_Harrison. Human breast cancer is a clonal disease; a single transformed cell—the product of a series of somatic (acquired) or germline mutations—is eventually able to express full malignant potential. Thus, breast cancer may exist for a long period as either a noninvasive disease or an invasive but nonmetastatic disease. These facts have significant clinical ramifications. Not more than 10% of human breast cancers can be linked directly to germline mutations. Several genes have been implicated in familial cases. The Li-Fraumeni syndrome is characterized by inherited mutations in the p53 tumor-suppressor gene, which lead to an increased incidence of breast cancer, osteogenic sarcomas, and other malignancies. Inherited mutations in PTEN have also been reported in breast cancer.


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InternalMed_Harrison. Another tumor-suppressor gene, BRCA1, has been identified at the chromosomal locus 17q21; this gene encodes a zinc finger protein, and the protein product functions as a transcription factor and is involved in gene repair. Women who inherit a mutated allele of this gene from either parent have at least a 60–80% lifetime chance of developing breast cancer and about a 33% chance of developing ovarian cancer. The risk is higher among women born after 1940, presumably due to promotional effects of hormonal factors. Men who carry a mutant allele of the gene have an increased incidence of prostate cancer and breast cancer. A fourth gene, termed BRCA2, which has been localized to chromosome 13q12, is also associated with an increased incidence of breast cancer in men and women.


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InternalMed_Harrison. Germline mutations in BRCA1 and BRCA2 can be readily detected; patients with these mutations should be counseled appropriately. All women with strong family histories for breast cancer should be referred to genetic screening programs, particularly women of Ashkenazi Jewish descent who have a high likelihood of a specific founder BRCA1 mutation (substitution of adenine for guanine at position 185).


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InternalMed_Harrison. Even more important than the role these genes play in inherited forms of breast cancer may be their role in sporadic breast cancer. A p53 mutation is present in nearly 40% of human breast cancers as an acquired defect. Acquired mutations in PTEN occur in about 10% of the cases. BRCA1 mutation in sporadic primary breast cancer has not been reported. However, decreased expression of BRCA1 mRNA (possibly via gene methylation) and abnormal cellular location of the BRCA1 protein have been found in some breast cancers. Loss of heterozygosity of BRCA1 and BRCA2 suggests that tumor-suppressor 524 activity may be inactivated in sporadic cases of human breast cancer. Finally, increased expression of a dominant oncogene plays a role in about a quarter of human breast cancer cases. The product of this gene, a member of the epidermal growth factor receptor superfamily, is called erbB2 (HER/2 neu) and is overexpressed in these breast cancers due to gene amplification; this overexpression can


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InternalMed_Harrison. of this gene, a member of the epidermal growth factor receptor superfamily, is called erbB2 (HER/2 neu) and is overexpressed in these breast cancers due to gene amplification; this overexpression can contribute to transformation of human breast epithelium and is the target of effective systemic therapy in adjuvant and metastatic disease settings. A series of acquired “driver” mutations have been identified in sporadic breast cancer by major sequencing consortia. Unfortunately, most occur in no more than 5% of cases and generally do not have effective agents to target them, so “personalized medicine” is for now more of a dream than a reality.


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InternalMed_Harrison. Breast cancer is a hormone-dependent disease. Women without functioning ovaries who never receive estrogen replacement therapy do not develop breast cancer. The female-to-male ratio is about 150:1. For most epithelial malignancies, a log-log plot of incidence versus age shows a single-component straight-line increase with every year of life. A similar plot for breast cancer shows two components: a straight-line increase with age but with a decrease in slope beginning at the age of menopause. The three dates in a woman’s life that have a major impact on breast cancer incidence are age at menarche, age at first full-term pregnancy, and age at menopause. Women who experience menarche at age 16 years have only 50–60% of the breast cancer risk of a woman having menarche at age 12 years; the lower risk persists throughout life. Similarly, menopause occurring 10 years before the median age of menopause (52 years), whether natural or surgically induced, reduces lifetime breast cancer risk by