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`NINTH EDITION, 2005-2006
`
`Cancer
`
`Management:
`A Multidisciplinary
`Approach
`
`Medical, Surgical, e’74 Radiation Oncology
`
`Edited by
`
`Richard Pazdur, MD
`
`Director, Office of Oncology Drug Products
`Center for Drug Evaluation and Research
`US Food and Drug Administration
`
`Lawrence R. Coia, MD
`Chairman, Department of Radiation Oncology
`Community Medical Center, Toms River, Newjersey
`An affiliate of Saint Barnabas Health Care System
`
`William]. Hoskins, MD
`Director, Curtis and Elizabeth Anderson Cancer Institute
`
`at Memorial Health University Medical Center
`Savannah, Georgia
`
`Lawrence D. Wagman, MD
`Chairman, Division of Surgery
`City of Hope National Medical Center
`
`And the publishers of the iournal ONCOLOGY
`
`‘u.
`.3
`
`tou onn onco
`‘incl’
`
`CMP
`Unlled Business Media
`
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`Note to the reader
`
`The information in this volume has been carefully reviewed for accuracy of
`dosage and indications. Before prescribing any drug, however, the clinician
`should consult the manufacturer’s current package labeling for accepted indica-
`tions, absolute dosage recommendations, and other information pertinent to the
`safe and effective use ofthe product described. This is especially importantwhen
`drugs are given in combination or as an adjunct to other forms of therapy.
`Furthermore, some of the medications described herein, as well as some of the
`indications mentioned, had not been approved by the US Food and Drug
`Administration at the time of publication. This possibility should be borne in
`mind before prescribing or recommending any drug or regimen.
`
`
`
`The views expressed are the result of independent work and do not
`necessarily represent the views or findings of the US Food and Drug
`Administration or the United States.
`
`Copyright © 2005 by CMP Healthcare Media. All rights reserved. This book is
`protected by copyright. No part of it may be reproduced in any manner or by any
`means, electronic or mechanical, without the written permission of the publisher.
`
`Library of Congress Catalog Card Number 2005921293
`ISBN Number 1-891483-358
`
`For information on purchasing additional copies of this publication, contact us at this
`address, Cancer Management Handbook, CMP Media LLC, 4601 W. 6th St., Ste. B,
`Lawrence, KS 66049. Phone: 1-800-444-4881 or 1-785-838-7576‘, fax: 1-785-838-7566,
`or e-mail: orders@crnp.com. Single-copy price, $59.95.
`
`'-
`on‘
`oo
`oo
`1: 22
`.,_.,.
`
`CMP
`United Business Media
`
`Publishers of
`ONCOLOGY
`
`Oncology News International
`cancernet'wor1<.com
`
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`CHAPTER 6
`
`Non—small—cell
`lung cancer
`
`Benjamin Movsas, MD, Fadlo R. Khuri, MD and Kemp Kernstine, MD, PhD
`
`Lung cancer has been the leading cause of cancer death among men in the
`United States for years, and since 1988, it has become the number—one cause of
`cancer deatharnong women. An estimated 172,570 new cases of lung cancer
`are expected in 2005, and 163,510 deaths due to this disease are expected to
`" occur. This exceeds the combined number of deaths from the leading causes of
`cancer (breast, prostate, and colon cancer). It accounts for 6% of all deaths in
`the United States.
`
`Lung cancer develops from pulmonary parenchymal or bronchial supportive
`tissues. Although multiple cell types are often found within a single lung tumor,
`one type usually predominates. Based on therapeutic approach, there are two
`major subdivisions of lung cancer: small—cell lung cancer (SCLC), for which
`chemotherapy is the primary treatment, and non—small—cell lung cancer
`(NSCLC), which in its early stages (I and H) is treated primarily with surgery.
`Nearly all cures in NSCLC involve surgery.
`
`This chapter provides basic information on the epidemiology, etiology, screen-
`ing, prevention, and signs and symptoms oi” lung cancer in general, and then
`focuses specifically on the diagnosis, staging, pathology, and treatment of
`NSCLC and carcinoid tumors of the lungs, as well as the pulmonary cvalua—
`tion of lung cancer patients and follow—up of long—term survivors.
`
`Chapter 7 provides information on the staging, pathology and pathophysiol—
`ogy, and treatment of the far less common SCLC and concludes with brief
`discussions of mesothelioma and thymoma.
`
`Epidemiology
`
`Gender From 1995 to l999, there were 86 cases of lung cancer per 100,000
`men and 57 cases of lung cancer per l00,000 women. Although the incidence.
`oflung cancer had been rising in women, the rate ofincreasc has begun to slow
`recently.
`
`Age The age at which lung cancer patients are diagnos<>d varies widely, but the
`median age at diagnosis is approximately 70 yezirs.
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`m
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`Race In the United States, -the highest incidence of lung cancer is found in
`Hawaiians and African—Americans.
`
`Geography There are geographic variations in the incidence of lung cancer,
`with the highest rates worldwide observed in Scotland and Wales and the high-
`. est rates in the United States found in northern urban areas and along the south-
`ern coast from Texas to Florida.
`
`Survival The overall 5-year survival rate for lung cancer is 12%.
`
`Etiology and risk factors
`
`Cigarette smoking Approxima.tely 87°/o of all cases of lung cancer are related
`to cigarette smoking. There is a relatively strong dose—response relationship
`between cigarette smoking and the development of this cancer. The greater the
`number of cigarettes smoked on a daily basis and the greater the number of
`years of smoking, the greater is the risk of lung cancer. An individual who
`smokes one pack of cigarettes daily has a 20-fold increased risk of lung cancer
`compared to a nonsmoker.
`
`The overall incidence of cigarette smoking decreased from 1974 through 1992.
`Smoking cessation decreases the risk oflung cancer, but a significant decrease
`in risk does not occur until approximately 5 years after stopping, and the risk
`remains higher in former smokers than in nonsmokers for at least 25 years.
`The benefit of smoking cessation is greater if it occurs at a younger age.
`
`Smoking cessation is difficult. Recent data have suggested that a variety of he-
`reditary factors increase the risk of addiction to nicotine among some individu-
`als. Nevertheless, millions of former smokers have quit successfully. Smoking
`cessation programs that address both physical withdrawal from nicotine and
`psychological dependence appear to be more effective than either of these ap
`proaches alone. In addition, continued efforts are needed to prevent adoles-
`cents and preadolescents from beginning to smoke or to encourage them to
`quit after a brief period of experimentation.
`
`Several cancer centers have recently reported that more than half of their pa-
`tients with newly diagnosed lung cancer are former smokers, having quit more
`than 1 year before diagnosis. Healthy ex—smokers represent a large group of
`individuals who may benefit from effective tools for early detection and/or
`chemoprevention of lung cancer.
`'
`
`Second/‘Land smoke Not only is smoking risky for those who smoke, but it also
`poses a hazard to nonsmokers who either live or work with smokers. It is esti—
`mated that approximately 3,000 lung cancer deaths per year in the United
`States are due to secondhand smoke. Individuals who live in a household with
`
`a smoker have a‘30% increase in the incidence of lung cancer compared to
`nonsmokers who do not live in such an environment.
`
`Asbestos exposure is another risk factor for lung caiiccr. Cigarette smokers '
`who are exposed to asbestos develop lung cancer at an extremely high rate.
`Exposure to asbestos is also a major‘ risk factor for the development of me-
`sothclioina (see discussion of this cancer in the following chapter).
`
`CANCER MANAGEMENT:
`
`/\ MULTlDlSClPl.lNARYAPPROACH
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`Radioactive dust and radon exposure Uranium miners who have been ex-
`posed to radioactive dust and radon gas also have an increased incidence of
`lung cancer. Although there has been some controversy about the risk posed
`by exposure to residential radon gas, a recent study conducted in Sweden showed
`an increased incidence of lung cancer in individuals who were exposed to a
`high level of radon in their homes.
`
`Screening and prevention
`
`Screening
`
`Currently, screening for lung cancer among asymptomatic individuals at el-
`evated risk due to smoking history or occupational exposures is not recom-
`mended, and the US strategy for diagnosis and treatment of lung cancer is to
`do nothing until the patient presents with symptoms. Anunfortunate result of
`- this policy is that most patients present in advanced stage, and cure rates have
`improved little over the past 30 years. Only 7% of N SCLC patients are diag-
`nosed in stage IA.
`
`Three randomized screening trials conducted in the United States in the 1970s
`failed to show a reduction in lung cancer mortality among the smokers who
`were screened by sputum cytology and chest x—ray for lung cancer. Despite the
`fact that these American trials were not designed to evaluate chest x—ray as a
`screening tool, the results led most experts to conclude that screening for lung
`cancer was not worthwhile. In addition, most investigators recommended that
`research efforts and resources be allocated to the }2revent2'07z of lung cancer. A
`more recent, randomized, prospective trial from Czechoslovakia showed that
`screening with a chest x—ray increased the diagnosis of earl)/—stage lung cancer
`but failed to reduce the mortality from lung cancer.
`
`The potential to screen for lung cancer has received renewed interest due to
`the superior performance of low—dose helical CT compared with chest radiog-
`raphy in detecting small lesions. Although there is insufficient evidence to es-
`tablish policy related to routine screening for lung cancer with spiral CT, there
`is a growing trend toward promoting screening with this new technology to
`individuals at increased risk for lung cancer.
`
`Numerous studies are Currently under way to evaluate chest CT scan for lung
`cancer screening. Several recent reports fromjapan, Germany, and the United
`States have documented the ability of low~dose spiral CT scans to detect lung
`cancer at an early stage. In some recent trials, more than 80% of lung cancers
`detected by screening were diagnosed in stage I. ‘
`
`Kaneko screened male smokers > 50 years of age. Of the 15 cancers detected
`by CT scan, only 4 were seen on chest x—ray; 14 of the 15 cancers were stage I,
`with an average diameter of 1.6 cm. Ohrnatsu found 35 lung cancers (0.370/0
`detection rate) with 9,452 CT scans. Of these cancers, 27 were stage IA. These
`patients had a 3-year survival rate of 83°/0.
`
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`(I—ELCAP,
`The International Early Lung Cancer Action Project
`http://www.ielcap.org/professionalshtm) is a singleaarm prospective study that
`has accrued more than 26,000 study subjects and documented that a high per—
`centage of lung cancers are detected in stage I, a stage in which long-term
`survival can reasonably be anticipated in more than 60% of patients. These
`studies provide early evidence to ‘suggest that CT lung cancer population screen-
`ing has the potential to reduce lung cancer mortality in the near future.
`
`Henschke et al recently reported encouraging results from ELCAP of screen-
`ing with spiral CT scan. Included in the initial report were 1,000 symptom—free
`volunteers, aged 60 years or older, with at least 10 pack—years of cigarette smok-
`ing and no previous cancer who were medically fit to undergo thoracic surgery.
`Noncalcified pulmonary nodules were detected in 233 participants (2 3% [950/o
`Cl: 2126]) by low—dose CT at baseline, compared with 68 (7% [950/o CI: 5—9])
`by chest radiography. Lung cancer was detected by CT in 27 patients (2.7%
`[950/o CI: 1.8—3.8]) and by chest radiography in 7 patients (0.7% [950/o CI: 0.3-
`13]).
`
`Of "the 27 CT—detected cancers, 26 were resectable. Stage I cancers were diag-
`nosed in 23 of 27 patients (85%) by CT and 4 of 7 patients (57%) by chest
`radiography. In addition, low—dose CT detected four more nonparenchymal
`cases of lung cancer: two with endobronchial lesions and two in the mediasti-
`num. These cases show an added benefit of low—dose CT over chest radiogra-
`phy, although the data were not included in the analysis. (The study primarily
`focused on malignant disease in noncalcified pulmonary nodules detected by
`low- dose CT or radiography.) It remains to be seen, however, whether lung
`cancer screening with low—dose spiral CT will reduce the lung cancer mortality
`of the study population‘ or only improve the 5-year survival rate of the patients
`diagnosed with lung cancer.
`
`Based on growing evidence that spiral CT may truly provide for a successful
`early detection strategy, the National Cancer Institute (NCI) launched the Na—
`tional Lung Screening Trial (NLST, http://www.nci.nih.gov/ NLST) in Septem-
`ber 2002. NLST has fully accrued 50,000 current and former smokers (aged
`55-7/1.) into a prospective trial, randomizing participants to receive annual spi-
`ral CT or annual chest xerays. Survival data will not be available for a number
`of years.
`
`The efficacy of lung cancer screening is also being evaluated as part of the
`Prostate, Lung, Colorectal, and Ovarian Cancer Screening Trial (PLCO). Men
`and women were randomized to receive annual chest x—ray vs usual care. Eligi—
`bility was not based on risk of lung cancer because given the large size of the
`study (>' 100,000 participants), it was expected that there would be appreciable
`numbers of current and former smokers among the participants.
`
`The lack of demonstrated benefit for the older screening approaches should
`not be misinterpreted as nihilism about the early detection of patients with lung
`cancer. Individuals at risk (current and former smokers) who present with symp»
`toms consistent with lung cancer deserve appropriate evaluation. The lack of
`resolution of radiographic abnormalities on a chest x—ray obtained after‘ the
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`
`
`completion of empiric antibiotic therapy for pneumonia should prompt further
`evaluation for possible lung cancer.
`
`Chemoprevention
`Second primary lung tumors develop at a rate of 1°/o-3°/0 annually for the first 5
`years following resection of stage I NSCLC. The retinoid l3—cz's—retinoic acid
`(isotretinoin [Accutane]) has reduced the incidence of second primary cancer
`in head and neck cancer patients in one small randomized trial.
`
`The intergroup randomized trial that assessed the ability of l3-cz‘s—retinoic acid
`to prevent the occurrence of a second primary cancer in patients with com-
`pletely resected stage I NSCLC showed no impact of treatment on the inci-
`dence of second primary tumors. Furthermore, patients who continued to smoke
`and who received isotretinoinhad a higher risk of recurrence of their index
`cancer. The early findings have demonstrated a higher—tl1an~expected recur-
`rence rate in patients with early-stage lung cancer who received 13-cz's—retinoic
`acid and continued to smoke. Also, there was no reduction in second primary
`tumors in the 13-czrretinoic acid—treated group.
`
`Educational programs Although the information from the intergroup ran-
`domized chemoprevention study is being collected, it is important to continue
`educational efforts to prevent adolescents from starting to smoke cigarettes and
`to advocate smoking cessation in active‘ smokers. Some experts believe that
`educational programs must begin during childhood, probably between the ages
`of 6 and 10 years.
`
`Signs and symptoms
`
`The clinical manifestations of lung cancer depend on the location and extent of
`the tumor. In patients who have localized disease, the most common symp—
`toms are related to obstruction of major airways, infiltration of lung paren~
`chyma, and invasion of surrounding structures, including the chest wall, major
`blood vessels, and viscera.
`
`Cough is a major manifestation of lung cancer and is present in nearly 80% of
`patients with symptomatic lung cancer. It is important to remember, however,
`that most lung cancer patients are current or former smokers and may have a
`cough related to chronic irritation of the upper and/or lower airways from ciga-
`rette smoke. Therefore, smokers should be asked whether there has been a
`change in their cough, such as an increase in frequency or severity.
`Dyspnea and hemoptysis Increasing dyspnea and hemoptysis may be signs
`of lung cancer. Although in the case of hemoptysis, 70% of patients are bleed-
`ing from nonmalignant causes, mostly infection and more frequently bronchi-
`tis. ln patients who present with hemoptysis, are older than age 40, and have a
`history of smoking and chronic obstructive pulmonary disease without abnor~
`mality on chest radiograph, lung cancer should be considered in the differen-
`tial diagnosis.
`
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`Pneumonia Postobstructive pneumonia secondary to partial or complete bron-
`chial obstruction occurs relatively frequently in association with lung cancer. It
`is important to obtain repeat chest X—rays in adults who have been treated for
`pneumonia to be certain that the radiographic abnormalities have cleared com-
`pletely.
`
`Pleural effusion Lung cancer may spread to the pleural surface or may ob-
`struct segmental or lobar lymphatics, resulting in pleural effusion and increased
`dyspnea.
`
`Chest pain Approximately 5% of lung tumors invade the chest wall. The re-
`sultant pain is a better predictor of chest wall invasion than are chest CT find-
`ings. An individual who complains of persistent chest pain should have a chest
`x—ray to exclude the presence of peripheral lung cancer that has invaded the
`chest wall.
`
`Shoulder and arm pain Apical tumors that infiltrate surrounding structures
`(also called Pancoast’s tumors) produce shoulder and/or arm pain as a result of
`brachial plexus compression. Tumors in the apical lung segments may be diffi~
`cult to detect on a routine chest x—ray; therefore, a person who complains of
`persistent shoulder pain, particularly with signs of neurologic involvement,
`should have a CT scan of the chest to look for an apical tumor. An MRI scan of
`the chest apex may be beneficial. It is also important to examine the lung apex
`in bone films obtained to evaluate shoulder pain.
`Horner’s syndrome. Invasion of the sympathetic ganglion by an apical lung
`tumor causes Horner’s syndrome (ptosis, myosis, and ipsilateral anhidrosis).
`
`Hoarseness secondary to vocal cord paresis or paralysis occurs when tumors
`and lymph node metastases compress, cause dysfunction in, or invade the re-
`current laryngeal nerve. This situation is more common on the left side, where
`the recurrent laryngeal nerve passes under the aortic arch, but it may also oc-
`cur with high lesions on the right side of the mediastinum.
`
`Other symptoms of tumor compression Lung tumors may also cause dys-
`phagia by compression or invasion of the esophagus or superior vena cava
`syndrome by compression or invasion of this vascular structure.
`
`Some tumors may result in wheezing or stridor secondary to compression or
`invasion of the trachea and may also cause signs of cardiac tamponade second-
`ary to involvement of the pericardial surface and subsequent accumulation of
`pericardial fluid.
`
`Signs and symptoms of metastatic disease Lung cancer can metastasize to
`multiple sites, most commonly to bone, liver, brain, lungs (contralateral or ipsi—
`lateral), and adrenal glands.
`
`Lung cancer patients who have brain metastases may complain of headaches
`or specific neurologic symptoms, or family members may notice a decrease in
`the patients’ mental acuity. Also, metastatic lung cancer may cause spinal cord
`compression, resulting in a characteristic sequence of symptoms: pain, followed
`by motor dysfunction, followed by sensory symptoms. The patient may have
`any or all of these symptoms.
`
`I '5
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`Patients who complain of bandlike pain encircling one or both sides of the
`trunk may have spinal cord compression. In addition, coughing and sneezing
`may cause significant exacerbation of pain from spinal cord compression.
`
`Bone x—rays and/or a bone scan are warranted in lung cancer patients who com-
`plain of persistent pain in the trunk or extremities. If performed in the evaluation
`of lung cancer, ‘3F—fluorodeoxyglucose (FD G)—PET supplants the need for bone
`scanning in most patients. PET appears to be more sensitive but less specific for
`bone metastases. If plain films are normal or equivocal for metastases, CT and/or
`MRI may be helpful to evaluate suspicious areas. MRI of the spine is the most
`effective way to evaluate suspected spinal cord compression.
`
`Systemic paraneoplastic symptoms Lung cancer is commonly associated
`with" systemic manifestations, including weight loss (with or without anorexia).
`In addition, patients frequently complain of fatigue and generalized weakness.
`SCLC is associated with hormone production, which causes endocrine syn-
`dromes in a subset of patients, such as SIADH (syndrome of inappropriate
`antidiuretic hormone secretion) and via secretion of ACTH (adrenocorticotro—
`pic hormone) hypercortisolism.
`
`Specific neurologic syndromes, such as Larnbert—Eaton syndrome (see chap-
`ter 45), cortical cerebellar degeneration, and peripheral neuropathy, may oc-
`cur in lung cancer patients but are relatively rare.
`
`Clubbing Although clubbing may occur in a variety of conditions, it is impor-
`tant for the clinician to evaluate a patient’s hands. If clubbing is noted, obtain-
`ing a chest x—ray may result in the early diagnosis of lung cancer.
`
`Hypertrophic osteoarthropathy A relatively small percentage of patients
`with lung cancer may present with symptomatic hypertrophic osteoarthropa-
`thy. In this syndrome, periosteal inflammation results in pain in affected areas,
`most commonly the ankles and knees.
`
`Carcinoid syndrome is extremely uncommon in patients who have a bron-
`chial carcinoid tumor. Most of these patients are asymptomatic (tumors are
`found by x-ray), and a few have cough from an endobronchial lesion.
`
`TUMOR BIOLOGY
`
`Non~—small~cell tumors account for approximately 80% of all lung cancers. The
`three ‘major tumor types included under this category are adenocarcinoma,
`squamous cell carcinoma, and large~cell carcinoma.
`
`Staging and prognosis
`
`staging
`
`The staging of lung cancer must be conducted in a methodical and detailed
`manner. The TNM staging system, updated by Mountain (Table 1), applies
`equally well to all histologies of NSCLC, but TNM for SCLC is less helpful.
`Most patients have advanced disease at the time of presentation.
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`Stage is commonlylreported as either clinical or pathologic, designated as c or
`p, respectively. Clinical stage is based on noninvasive (or minimally invasive)
`tests, whereas pathologic stage is based on tissue obtained during surgery (see
`section on “Diagnosis and staging evaluation”).
`
`Prognostic factors
`
`Stage The most important prognostic factor in lung cancer is the stage of disease.
`
`Performance status and weight loss Within a given disease stage, the next
`most important prognostic factors are performance status and recent unexplained
`weight loss. The two scales used to define performance status are the Eastern
`Cooperative Oncology Group (ECOG) performance status system and the
`Karnofsky system (see Appendix 1). Simply, patients who are ambulatory have
`a significantly longer survival than those who are nonambulatory. Similarly,
`patients who have lost > 5% of body weight during the preceding 3-6 months
`have a worse prognosis than patients who have not lost a significant amount of
`weight.
`
`Molecular prognostic factors Several studies published over the past decade
`have indicated that mutations of ms proto—0ncogenes, particularly K—ms, por-
`tend a poor prognosis in individuals with stage IV NSCLC. Accordingly, re-
`search has focused on developing molecularly targeted therap.eutic approaches
`to the msproto-oncogenes, in particular, the farnesyl transferase inhibitors (see
`section on “Promising novel agents”).
`
`Of equal relevance was the completion of large studies by Pastorino et al and
`Kwiatowski et al evaluating the prognostic importance of iinrnunocytochemi—
`cal and molecular pathologic markers in stage I NSCLC. The findings of these
`two studies suggest that pathologic invasion and extent of surgical resection
`may yield the most critical prognostic information, but mutation of the K-ms
`oncogene and absence of expression of the H~ras p21 proto—oncogene may
`augment the pathologic information.
`
`Diagnosis and staging evaluation
`
`History and physical examination
`
`The diagnosis and preoperative staging of lung cancer begin with a good his-
`tory and physical examination. When obtaining the history, the clinician should
`keep in mind the tendency for lung cancer to involve major airways and other
`central structures. Similarly, the patterns of metastatic dissemination and sys
`temic manifestations must be considered when conducting the physical exami-
`nation.
`
`Patients should be questioned specifically about the presence of palpable masses,
`d s ha ia, bone ain, headache, or chan es in vision. Careful auscultation and
`Y P
`8
`P
`8
`percussion may suggest the presence of atelectasis or pleural effusion. Auscul—
`tation of the chest also may provide evidence of large airway obstruction and
`pulmonary consolidation. Ronchi. and wheezing may provide some helpful treat
`merit
`lannin0' information. An enlar ed liver ma indicate he atic metastases.
`P
`D
`5%
`Y
`P
`
`I I8
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`
`TABLE I:TNM staging of lung cancer
`
`Primary tumor (T)
`
`Tx
`
`Tumor proven by the presence of malignant cells in bronchopulmonary
`secretions but not visualized roentgenographically or bronchoscopically
`or any tumor that cannot be assessed, as in pretreatment staging
`
`No evidence of primary tumor
`Carcinoma in situ
`
`Tumor S 3.0 cm in greatest dimension, surrounded by lung or visceral pleura,
`and without evidence of invasion proximal to a lobar bronchus at bronchoscopy
`
`Tumor > 3.0 cm in greatest dimension. or tumor of_any size that either
`invades the visceral pleura or has associated atelectasis or obstructive
`pneumonitis extending to the hilar region (but involving less than the entire
`lung). At bronchoscopy, the proximal extent of demonstrable tumor must be
`within a lobar bronchus or at least 2.0 cm distal to the carina
`
`Tumor of any size with direct extension into the chest wall (including superior
`sulcus tumors), diaphragm, or mediastinal pleura or pericardium without
`involving the heart, great vessels, trachea, esophagus, or vertebral body;
`or tumor in the main bronchus within 2 cm of, but not involving, the carina
`
`Tumor of any size with invasion of the mediastinum or involving the heart,
`great vessels, trachea, esophagus, vertebral body, or carina; or presence of
`malignant pleural effusion (whether cytology positive or negative)
`
`Regional lymph nodes (N)
`
`Nx
`N0
`
`Nl
`
`N2
`N3
`
`Regional lymph nodes cannot be assessed
`N0 demonstrable metastasis to regional lymph nodes
`
`Metastasis to lymph nodes in the peribronchial and/or ipsilateral hilar region,
`including direct extension
`
`Metastasis to ipsilateral mediastinal and subcarinal lymph nodes
`Metastasis to contralateral mediastinal, contralateral hilar, ipsilateral or
`contralateral scalene, or supraclavicular lymph nodes
`
`Distant metastasis (M) '
`Mx
`Distant metastasis cannot be assessed
`M0
`N0 distant metastasis
`Ml
`Distant metastasis
`
`Tx
`
`Tis
`
`Tl
`T2
`
`Stage grouping
`Occult carcinoma
`
`Stage 0
`
`Stage IA
`Stage IB
`Stage llA
`Stage llB
`
`Stage |l|A
`
`Stage |llB
`
`Stage IV
`
`From Moun
`I997.
`
`NON—SMALL-CELL LUNG CANCER
`
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`Palpation of the neck and supraclavicular fossa Discovery of neck and su-
`praclavicular fossa aclenopathy may allow both diagnosis and staging, by needle
`or open biopsy.
`
`Imaging studies
`
`Chest x-rays provide initial helpful information in patients with new respira-
`tory symptoms. Posteroanterior (PA) and lateral chest x—rays are fundamental
`in assessing the local extent of the primary tumor and also may provide valu-
`able information regarding metastatic disease.
`
`The chest x-ray should be inspected for the presence of a pleural effusion or
`synchronous’ pulmonary nodules, and the bones should be examined for evi-
`dence of osseous metastases. A widened mediastinum usually indicates meta-
`static disease within the mediastinal lymph nodes. Comparison with previous x-
`rays is helpful and well worth the effort expended in their retrieval.
`
`Chest CT, including the entire liver and adrenal glands with 5-10 mm slices, is
`performed routinely to further define the primary tumor and to identify lym-
`phatic or parenchymal metastases. In a review of 20 studies that assessed the
`value of CT scan to determine mediastinal lymph node involvement, with an
`average prevalence of 28%, CT had a pooled sensitivity of 57%, a specificity of
`82%, and a negative predictive value (NPV) of 83%. Benign enlargement of
`mediastinal nodes is more common in patients with postobstructive infection.
`Histologic confirmation of the presence or absence of tumor within the medi-
`astinal lymph nodes is necessary whenever this information will change treat-
`ment recommendations. In patients who are considered surgical candidates,
`metastatic tumor is found in approximately 15%-20°/0 of mediastinal lymph
`nodes < l cm in greatest diameter.
`
`lt is important to remember that patients with persistent symptoms, such as
`cough and dyspnea, who have a normal chest x-ray may be harboring a central
`lesion that is not obvious on chest x—ray but can be -easily detected by chest CT.
`Also, as previously mentioned, apical tumors (Pancoast tumors) may be diffi-
`cult to detect on a chest radiograph but are usually readily apparent on a CT
`scan.
`
`PET For lung masses, FDG accumulation on PET implies a significant likeli-
`hood of malignancy.
`
`Standardized uptake value (SUV) of 2.5 optimizes the sensitivity and specific-
`ity of PET in assessing suspicious lung lesions la.rger than l cm. FD G—PlL"l‘
`accumulation is not diagnostic for cancer, nor does it exclude a cancer diagno-
`sis. Bronchioalveolar and carcinoid are two cell types that do not readily accu-
`mulate FDG. Furthermore, higher SUV lesions do not imply a greater likeli-
`hood of caricer; the highest SUVS have been found in inflammatory lesions,
`such as granulomas and infections.
`
`A review of l8 studies of the utility of PET to assess the mediastinal lymph
`nodes demonstrated a pooled sensitivity of 84°/0 and a specificity of 89%, with
`a. positive predictive value (PPV) of 79% and an NPV of 93%. Combining the
`results of CT and P ET, the PPV and NPV were 83°/0-93°/0 and 88"/0-950/0, re-
`
`l2°
`
`CANCER MANAGEMENT: A MULTIDISCIFLINARYAPPROACH
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`NOVARTIS EXHIBIT 2010
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`Page 13 of 201
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`spectively. Thus, FD G—PET is superior to CT scanning in staging the mediasti—
`nal lymph nodes. Fifteen to 200/0 of patients with a known or suspected diagno-
`sis benefit from a preoperative FDG—PET, because previously unrecognized
`metastatic disease will be discovered.
`
`Several trials have evaluated the prognostic significance of FDG uptake on
`PET scan in NSCLC. Utilizing multivariate Cox analysis, these studies noted
`that SUV, particularly when > 7-10, was an independent prognostic factor.
`PET scanning may also prove a valuable tool for evaluation of patients with
`NSCLC treated with chemoradiotherapy or irradiation. In a study by MacManus
`et al, the PET response was found to be a powerful predictor of survival.
`
`Adrenal gland The adrenal gland may be the sole site of metastatic disease in
`as many as 10% of patients with NSCLC. Patients should not be assumed to
`have metastatic disease and denied a potentially curative operation on the ba-
`sis of a scan alone. Adrenal masses at least 1 cm that are negative on CT and
`FDG—PET were fo