|
Etiology
Most lung cancers are caused by carcinogens and tumor
promoters inhaled via cigarette smoking. The prevalence of smoking in the United
States is 28% for males and 25% for females, age 18 years or older; 38% of high
school seniors smoke. The relative risk of developing lung cancer is increased
about thirteenfold by active smoking and about 1.5-fold by long-term passive
exposure to cigarette smoke. Chronic obstructive pulmonary disease, which is
also smoking-related, further increases the risk of developing lung cancer. The
lung cancer death rate is related to the total amount (often expressed in
"cigarette pack-years") of cigarettes smoked, such that the risk is increased
60- to 70-fold for a man smoking two packs a day for 20 years as compared with a
nonsmoker. Conversely, the chance of developing lung cancer decreases with
cessation of smoking but may never return to the nonsmoker level. The increase
in lung cancer rate in women is also associated with a rise in cigarette
smoking. Women have a higher relative risk per given exposure than men
(~1.5-fold higher). This sex difference may be due to a greater susceptibility
to tobacco carcinogens in women, although the data are controversial.
About 15% of lung cancers occur in individuals who have
never smoked. The majority of these are found in women. The reason for this sex
difference is not known but may be related to hormonal factors.
Efforts to get people to stop smoking are mandatory.
However, smoking cessation is extremely difficult, because the smoking habit
represents a powerful addiction to nicotine (Chap. 390). Smoking addiction is
both biologic and psychosocial. Different methods are available to help
motivated smokers give up the habit, including counseling, behavioral therapy,
nicotine replacement (gum, patch, sublingual spray, inhaler), and
antidepressants (such as bupropion). However, one year after starting such
smoking cessation aids, the methods are successful in only 20–25% of
individuals. Preventing people from starting to smoke is thus very important,
and this primary prevention effort needs to be targeted to children since most
cigarette smoking addiction occurs during the teenage years.
Radiation is another environmental cause of lung cancer.
People exposed to high levels of radon or receiving thoracic radiation therapy
have a higher than normal incidence of lung cancer, particularly if they
smoke.
Biology and Molecular Pathogenesis
Molecular genetic studies have shown the acquisition by
lung cancer cells of a number of genetic lesions, including activation of
dominant oncogenes and inactivation of tumor-suppressor or recessive oncogenes
(Chaps. 79 and 80). In fact, lung cancer cells may have to accumulate a large
number (perhaps
Activation of Dominant Oncogenes
Changes in dominant oncogenes include point mutations in
the coding regions of the RAS family of oncogenes (particularly in the
KRAS gene in adenocarcinoma of the lung); mutations in the tyrosine
kinase domain of the EGFR found in adenocarcinomas from nonsmokers (~10% in the
United States with rates >50% in nonsmoking East Asian patients); occasional
mutations in BRAF and PIK3CA or activation of the PIK3CA/AKT/mTor
pathway; amplification, rearrangement, and/or loss of transcriptional control of
myc family oncogenes (c-, N-, and L-myc; changes in c-myc
are found in non-small cell cancers, while changes in all myc family
members are found in SCLC); overexpression of bcl-2 and other antiapoptotic
proteins; overexpression of other EGFR family members such as Her-2/neu, and
ERBB3; and activated expression of the telomerase gene in >90% of lung
cancers. Genome-wide approaches are identifying other amplified or mutated
dominant oncogenes that could be important new therapeutic targets.
Inactivation of Tumor-Suppressor Genes
A large number of tumor-suppressor genes (recessive
oncogenes) have been identified that are inactivated during the pathogenesis of
lung cancer. This usually occurs by a tumor-acquired inactivating mutation of
one allele [seen, for example, in the p53 and retinoblastoma (RB)
tumor-suppressor gene] or tumor-acquired inactivation of expression by
tumor-acquired promoter DNA methylation (seen, for example, in the case of the
p16 and RASSF1A tumor-suppressor genes), which is then coupled
with physical loss of the other parental allele ("loss of heterozygosity"). This
leaves the tumor cell with only the functionally inactive allele and thus loss
of function of the growth-regulatory tumor-suppressor gene. Genome-wide
approaches have identified many such genes involved in lung cancer pathogenesis,
including p53, RB, RASSF1A, SEMA3B, SEMA3F,
FUS1, p16, LKB1, RAR
Autocrine Growth Factors
The large number of genetic and epigenetic lesions shows
that lung cancer, like other common epithelial malignancies, arises as a
multistep process that is likely to involve both carcinogens causing mutation
("initiation") and tumor promoters. Prevention can be directed at both
processes. Lung cancer cells produce many peptide hormones and express receptors
for these hormones. They can promote tumor cell growth in an "autocrine"
fashion.
Highly carcinogenic derivatives of nicotine are formed in
cigarette smoke. Lung cancer cells of all histologic types (and the cells from
which they are derived) express nicotinic acetylcholine receptors. Nicotine
activates signaling pathways in tumor and normal cells that block apoptosis.
Thus, nicotine itself could be directly involved in lung cancer pathogenesis
both as a mutagen and tumor promoter.
Inherited Predisposition to Lung Cancer
While an inherited predisposition to develop lung cancer is
not common, several features suggest a potential for familial association.
People with inherited mutations in RB (patients with retinoblastomas
living to adulthood) and p53 (Li-Fraumeni syndrome) genes may develop
lung cancer. First-degree relatives of lung cancer probands have a two- to
threefold excess risk of lung cancer or other cancers, many of which are not
smoking-related. An as yet unidentified gene in chromosome region 6q23 was found
to segregate in families at high risk of developing lung cancer of all
histologic types. Finally, certain polymorphisms of the P450 enzyme system
(which metabolizes carcinogens) or chromosome fragility (mutagen
sensitivity) genotypes are associated with the development of lung cancer.
The use of any of these inherited differences to identify persons at very high
risk of developing lung cancer would be useful in early detection and prevention
efforts.
Therapy Targeted at Molecular Abnormalities
A detailed understanding of the molecular pathogenesis
should be applicable to new methods of early diagnosis, prevention, and
treatment of lung cancer. Two examples of this translation involve EGFR and
vascular endothelial growth factor (VEGF). EGFR belongs to the ERBB (HER) family
of protooncogenes, including EGFR (ERBB1), Her2/neu (ERBB2), HER3 (ERBB3), and
HER4 (ERBB4), cell-surface receptors consisting of an extracellular
ligand-binding domain, a transmembrane structure, and an intracellular tyrosine
kinase (TK) domain. The binding of ligand to receptor activates receptor
dimerization and TK autophosphorylation, initiating a cascade of intracellular
events, leading to increased cell proliferation, angiogenesis, metastasis, and a
decrease in apoptosis (Chap. 80). Overexpression of EGFR protein or
amplification of the EGFR gene has been found in as many as 70% of
NSCLCs.
Activating/oncogenic mutations (usually a missense or a
small deletion mutation) in the TK domain of EGFR have been identified. These
are found most commonly in women, East Asians, patients who have never smoked,
and those with adenocarcinoma and BAC histology. This is also the group of
patients who are most likely to have dramatic responses to drugs that inhibit TK
activation [tyrosine kinase inhibitors (TKIs)]. EGFR mutations are almost never
found in cancers other than lung cancer, nor in lung cancers that have
KRAS mutations. These EGFR mutations, often associated with amplification
of the EGFR gene, usually confer sensitivity of these lung cancers to
EGFR TKIs (such as gefitinib or erlotinib), resulting in clinically beneficial
tumor responses that unfortunately are still not permanent. In many cases the
development of EGFR TKI resistance is associated with the development of another
mutation in the EGFR gene (T790M mutation), or amplification of
the c-met oncogene. However, other drugs with EGFR TKI activity are in
development to which the lung cancers with these resistance mutations will
respond as are drugs targeting c-met or its pathways.
The discovery of EGFR mutation/amplification driving lung
cancer growth and the dramatic response of these tumors to oral EGFR TKI therapy
has prompted a widespread search for other drugs "targeted" against oncogenic
changes in lung cancer. An important example of another such target is VEGF,
which, while not mutated, is inappropriately produced by lung cancers and
stimulates tumor angiogenesis (Chap. 80). VEGF is often overexpressed in lung
cancer, and the resulting increase in tumor microvessel density correlates with
poor prognosis. A monoclonal antibody to the VEGF ligand, bevacizumab, has
significant antitumor effects when used with chemotherapy in lung cancer (see
below).
Molecular Profiles Predict Survival and Response
Just as the presence of EGFR TK domain mutations and
amplification is an excellent predictor of response to EGFR TKIs, molecular
predictors of response to standard chemotherapy and other new targeted agents
are being sought. Lung cancers can be molecularly typed at the time of diagnosis
to yield information that predicts survival and defines agents to which the
tumor is most likely to respond. One example is the identification of
alterations in lung cancer DNA repair pathways that may predict resistance to
chemotherapy. Patients whose tumors exhibit low activity of the
excision-repair-cross complementation group 1 (ERCC1) proteins typically have a
worse prognosis as they are unable to repair DNA adducts in the tumor. However,
retrospective analysis shows that when treated with cisplatin, patients with
tumors expressing low levels of ERCC1 activity appear to do better, as they are
unable to repair DNA adducts caused by cisplatin, while patients with high ERCC1
activity actually do worse with cisplatin-based chemotherapy. Although these
protein or gene expression "signatures" have yet to be validated in large
prospective studies, it is possible that such information will allow future
therapy to be tailored to the characteristics of each patient's tumor. Mass
spectroscopy-based proteomic studies have identified unique protein patterns in
the serum of patients, one of which allows for early diagnosis, while another
can predict sensitivity or resistance to drugs. However, such methods have not
been validated and may be difficult to implement in a patient care
setting.
|
|
Clinical Manifestations
Lung cancer gives rise to signs and symptoms caused by
local tumor growth, invasion or obstruction of adjacent structures, growth in
regional nodes through lymphatic spread, growth in distant metastatic sites
after hematogenous dissemination, and remote effects of tumor products
(paraneoplastic syndromes)
Although 5–15% of patients with lung cancer are identified
while they are asymptomatic, usually as a result of a routine chest radiograph
or through the use of screening CT scans, most patients present with some sign
or symptom. Central or endobronchial growth of the primary tumor may cause
cough, hemoptysis, wheeze and stridor, dyspnea, and postobstructive pneumonitis
(fever and productive cough). Peripheral growth of the primary tumor may cause
pain from pleural or chest wall involvement, dyspnea on a restrictive basis, and
symptoms of 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 nerve paralysis with hoarseness, phrenic nerve paralysis
with elevation of the hemidiaphragm and dyspnea, and sympathetic nerve paralysis
with Horner's syndrome (enophthalmos, ptosis, miosis, and ipsilateral loss of
sweating). Malignant pleural effusion often leads to dyspnea. Pancoast's
(or superior sulcus tumor) syndrome results 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, with shoulder pain that
characteristically radiates in the ulnar distribution of the arm, often with
radiologic destruction of the first and second ribs. Often Horner's syndrome and
Pancoast's 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, BAC can spread
transbronchially, producing tumor growing along multiple alveolar surfaces with
impairment of gas exchange, respiratory insufficiency, dyspnea, hypoxemia, and
sputum production.
Extrathoracic metastatic disease is found at autopsy
in >50% of patients with squamous carcinoma, 80% of patients with
adenocarcinoma and large cell carcinoma, and >95% of patients with small cell
cancer. Lung cancer metastases may occur in virtually every organ system. Common
clinical problems related to metastatic lung cancer include brain metastases
with headache, nausea, and neurologic deficits; bone metastases with pain and
pathologic fractures; bone marrow invasion with cytopenias or
leukoerythroblastosis; liver metastases causing liver dysfunction, biliary
obstruction, anorexia, and pain; lymph node metastases in the supraclavicular
region and occasionally in the axilla and groin; and spinal cord compression
syndromes from epidural or bone metastases. Adrenal metastases are common but
rarely cause adrenal insufficiency.
Paraneoplastic syndromes are common in patients with
lung cancer and may be the presenting finding or 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 biologic activity is secreted by a tumor
(Chap. 96). 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.
Endocrine syndromes are seen in 12% of patients: hypercalcemia and
hypophosphatemia resulting from the ectopic production by squamous tumors of
parathyroid hormone (PTH) or, more commonly, PTH-related peptide; hyponatremia
with the syndrome of inappropriate secretion of antidiuretic hormone or possibly
atrial natriuretic factor by small cell cancer; and ectopic secretion of ACTH by
small cell cancer. ACTH secretion 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.
Skeletal–connective tissue syndromes include
clubbing in 30% of cases (usually non-small cell carcinomas) and hypertrophic
pulmonary osteoarthropathy in 1–10% of cases (usually adenocarcinomas), with
periostitis and clubbing 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 small cell cancer,
while 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 the Eaton-Lambert syndrome
(Chap. 97). Coagulation, 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, 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 or glomerulonephritis (
|
|
Diagnosis and Staging
Screening
Most patients with lung cancer present with advanced
disease, raising the question of whether screening would detect these tumors at
an earlier stage when they are theoretically more curable. The role of screening
high-risk patients (for example current or former smokers >50 years of age)
for early stage lung cancers is debated. Results from five randomized screening
studies in the 1980s of chest x-rays with or without cytologic analysis of
sputum did not show any impact on lung cancer–specific mortality from screening
high-risk patients, although earlier-stage cancers were detected in the screened
groups. These studies have been criticized for their design and statistical
analyses, but they led to current recommendations not to use these tools to
screen for lung cancer. However, low-dose, noncontrast, thin-slice, helical, or
spiral CT has emerged as a possible new tool for lung cancer screening. Spiral
CT is a scan in which only the pulmonary parenchyma is examined, thus negating
the use of intravenous contrast and the necessity of a physician being present
at the exam. The scan can usually be done quickly (within one breath) and
involves low doses of radiation. In a nonrandomized study of current and former
smokers from the Early Lung Cancer Action Project (ELCAP), low-dose CT was shown
to be more sensitive than chest x-ray for detecting lung nodules and lung cancer
in early stages. Survival from date of diagnosis is also long (10-year survival
predicted to be 92% in screening-detected stage I NSCLC patients). Other
nonrandomized CT screening studies of asymptomatic current or former smokers
also found that early lung cancer cases were diagnosed more often with CT
screening than predicted by standard incidence data. However, no decline in the
number of advanced lung cancer cases or deaths from lung cancer was noted in the
screened group. Thus, spiral CT appears to diagnose more lung cancer without
improving lung cancer mortality. Concerns include the influence of lead-time
bias, length-time bias, and over-diagnosis (cancers so slow-growing that they
are unlikely to cause the death of the patient). Over-diagnosis is a
well-established problem in prostate cancer screening, but it is surprising that
some lung cancers are not fatal. However, many of the small adenocarcinomas
found as "ground glass" opacities on screening CT appear to have such long
doubling times (>400 days) that they may never harm the patient. While CT
screening will detect lung cancer in 1–4% of the patients screened over a 5-year
period, it also detects a substantial number of false-positive lung lesions
(ranging from 25 to 75% in different series) that need follow-up and evaluation.
The appropriate management of these small lesions is undefined. Unnecessary
treatment of these patients may include thoracotomy and lung resection, thus
adding to the cost, mortality, and morbidity of treatment. A large, randomized
trial of CT screening for lung cancer (National Lung Cancer Screening Trial)
involving ~55,000 individuals has completed accrual and will provide definitive
data in the next several years on whether screening reduces lung cancer
mortality. Until these results become available, routine CT screening for lung
cancer cannot be recommended for any risk group. For those patients who want to
be screened, physicians need to discuss the possible benefits and risks of such
screening, including the risk of false-positive scans that could result in
multiple follow-up CTs and possible biopsies for a malignancy that may not be
life-threatening.
Establishing a Diagnosis of Lung Cancer
Once signs, symptoms, or screening studies suggest lung
cancer, a tissue diagnosis must be established. Tumor tissue can be obtained by
a bronchial or transbronchial biopsy during fiberoptic bronchoscopy; by node
biopsy during mediastinoscopy; from the operative specimen at the time of
definitive surgical resection; by percutaneous biopsy of an enlarged lymph node,
soft tissue mass, lytic bone lesion, bone marrow, or pleural lesion; by
fine-needle aspiration of thoracic or extrathoracic tumor masses using CT
guidance; or from an adequate cell block obtained from a malignant pleural
effusion. In most cases, the pathologist should be able to make a definite
diagnosis of epithelial malignancy and distinguish small cell from non-small
cell lung cancer.
Staging Patients with Lung Cancer
Lung cancer staging consists of two parts: first, a
determination of the location of tumor (anatomic staging) and, second, an
assessment of a patient's ability to withstand various antitumor treatments
(physiologic staging). In a patient with NSCLC, resectability (whether
the tumor can be entirely removed by a standard surgical procedure such as a
lobectomy or pneumonectomy), which depends on the anatomic stage of the tumor,
and operability (whether the patient can tolerate such a surgical
procedure), which depends on the cardiopulmonary function of the patient, are
determined.
Non-Small Cell Lung Cancer
The TNM International Staging System should be used for
cases of NSCLC, particularly in preparing patients for curative attempts with
surgery or radiotherapy (Table 85-2). The various T (tumor size), N (regional
node involvement), and M (presence or absence of distant metastasis) factors are
combined to form different stage groups. At presentation, approximately
one-third of patients have disease localized enough for a curative attempt with
surgery or radiotherapy (patients with stage I or II disease and some with stage
IIIA disease), one-third have distant metastatic disease (stage IV disease), and
one-third have local or regional disease that may or may not be amenable to a
curative attempt (some patients with stage IIIA disease and others with stage
IIIB disease) (see below). This staging system provides useful prognostic
information.
Small Cell Lung Cancer
A simple two-stage system is used. In this system,
limited-stage disease (seen in about 30% of all patients with SCLC) is
defined as disease confined to one hemithorax and regional lymph nodes
(including mediastinal, contralateral hilar, and usually ipsilateral
supraclavicular nodes), while extensive-stage disease (seen in about 70%
of patients) is defined as disease exceeding those boundaries. Clinical studies
such as physical examination, x-rays, CT and bone scans, and bone marrow
examination are used in staging. In part, the definition of limited-stage
disease relates to whether the known tumor can be encompassed within a tolerable
radiation therapy port. Thus, contralateral supraclavicular nodes, recurrent
laryngeal nerve involvement, and superior vena caval obstruction can all be part
of limited-stage disease. However, cardiac tamponade, malignant pleural
effusion, and bilateral pulmonary parenchymal involvement generally qualify
disease as extensive-stage because the organs within a curative radiation
therapy port cannot safely tolerate curative radiation doses.
Lung Cancer Staging Procedures
(Table 85-3) 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, and a
CT scan of the chest and abdomen with contrast. Positron emission tomography
(PET) scans are sensitive in detecting both intrathoracic and metastatic
disease. PET is useful in assessing the mediastinum and solitary pulmonary
nodules. A standardized uptake value (SUV) of >2.5 is highly suspicious for
malignancy. False negatives can be seen in diabetes, in slow-growing tumors such
as BAC, in concurrent infection such as tuberculosis, and in lesions <8 mm.
False positives can also be seen in infections and granulomatous disease. Thus,
PET should never be used alone to diagnose lung cancer, mediastinal involvement,
or metastases. Instead, its primary function is to help guide a mediastinal
biopsy for staging purposes and to help identify sites of metastatic disease.
Fiberoptic bronchoscopy obtains material for pathologic examination and
information on tumor size, location, degree of bronchial obstruction (i.e.,
assesses resectability), and recurrence.
Chest radiographs and CT scans are needed to evaluate tumor
size and nodal involvement; old radiographs are useful for comparison. CT scans
of the thorax and upper abdomen are of use in the preoperative staging of NSCLC
to detect mediastinal nodes and pleural extension and occult abdominal disease
(e.g., liver, adrenal), and in planning curative radiation therapy. However,
mediastinal nodal involvement should be documented histologically if the
findings will influence therapeutic decisions. Thus, sampling of lymph nodes via
mediastinoscopy or thoracotomy to establish the presence or absence of N2 or N3
nodal involvement is crucial in considering a curative surgical approach for
patients with NSCLC with clinical stage I, II, or III disease, regardless of
whether the PET is positive or negative. A preoperative mediastinoscopy may not
need to be done in patients with normal-size nodes (by CT) that are
PET-negative, as the discovery of micrometastases is unlikely to change the
preoperative management of the disease, although lymph node sampling should be
done intraoperatively. A standard nomenclature for referring to the location of
lymph nodes involved with cancer has evolved (Fig. 85-1). Unless the CT-detected
abnormalities are unequivocal, histology of suspicious extrathoracic lesions
should be confirmed by procedures such as fine-needle aspiration if the patient
would otherwise be considered for curative treatment. In SCLC, CT scans are used
in the planning of chest radiation treatment and in the assessment of the
response to chemotherapy and radiation therapy. Surgery or radiotherapy can make
interpretation of conventional chest x-rays difficult; after treatment, CT scans
can provide good evidence of tumor recurrence.
If signs or symptoms suggest involvement by tumor, brain CT
or bone scans are performed, as well as radiography of any suspicious bony
lesions. Any accessible lesions suspicious for cancer should be biopsied if
involvement would influence treatment.
In patients presenting with a mass lesion on chest x-ray or
CT scan and no obvious contraindications to a curative approach after the
initial evaluation, the mediastinum must be investigated. Approaches vary among
centers and include performing chest CT scan and mediastinoscopy (for
right-sided tumors) or mediastinotomy (for left-sided lesions) on all patients
and proceeding directly to thoracotomy for staging of the mediastinum. Patients
who present with disease that is confined to the chest but not resectable, and
who thus are candidates for neoadjuvant chemotherapy plus surgery or for
curative radiotherapy with or without chemotherapy, should have additional tests
done as indicated to evaluate specific symptoms. In patients presenting with
NSCLC that is not curable, all the general staging procedures are done, plus
fiberoptic bronchoscopy as indicated to evaluate hemoptysis, obstruction, or
pneumonitis, as well as thoracentesis with cytologic examination (and chest tube
drainage as indicated) if fluid is present. As a rule, a radiographic finding of
an isolated lesion (such as an enlarged adrenal gland) should be confirmed as
cancer by fine-needle aspiration before a curative attempt is rejected.
Staging of Small Cell Lung Cancer
Pretreatment staging for patients with SCLC includes the
initial general lung cancer evaluation with chest and abdominal CT scans
(because of the high frequency of hepatic and adrenal involvement) as well as
fiberoptic bronchoscopy with washings and biopsies to determine the tumor extent
before therapy; brain CT scan (10% of patients have metastases); and
radionuclide scans (bone) if symptoms or other findings suggest disease
involvement in these areas. Bone marrow biopsies and aspirations are rarely
performed given the low incidence of isolated bone marrow metastases. Chest and
abdominal CT scans are very useful to evaluate and follow tumor response to
therapy, and chest CT scans are helpful in planning chest radiotherapy
ports.
If signs or symptoms of spinal cord compression or
leptomeningitis develop at any time in lung cancer patients with disease of any
histologic type, a spinal CT scan or MRI scan and examination of the
cerebrospinal fluid cytology are performed. If malignant cells are detected,
radiotherapy to the site of compression and intrathecal chemotherapy (usually
with methotrexate) are given. In addition, a brain CT or MRI scan is performed
to search for brain metastases, which often are associated with spinal cord or
leptomeningeal metastases.
Resectability and Operability
In patients with NSCLC, the following are major
contraindications to curative surgery or radiotherapy alone: 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 (not curable by surgery but potentially curable by
radiotherapy); metastasis to the contralateral lung; bilateral endobronchial
tumor (potentially curable by radiotherapy); metastasis to the supraclavicular
lymph nodes; contralateral mediastinal node metastases (potentially curable by
radiotherapy); and involvement of the main pulmonary artery. Pleural effusions
are generally considered malignant regardless of whether they are cytology
positive, particularly if they are exudative, bloody, and have no other probable
etiology. Most patients with SCLC have unresectable disease; however, if
clinical findings suggest the potential for resection (most common with
peripheral lesions), that option should be considered.
Physiologic Staging
Patients with lung cancer often have cardiopulmonary and
other problems related to chronic obstructive pulmonary disease as well as other
medical problems. To improve their preoperative condition, correctable problems
(e.g., anemia, electrolyte and fluid disorders, infections, and arrhythmias)
should be addressed, smoking stopped, and appropriate chest physical therapy
instituted. Since 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 resectional surgery to patients who could potentially
tolerate a pneumonectomy. In addition to nonambulatory performance status, 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 major arrhythmias, an FEV1 (forced expiratory
volume in 1 s) <1 L, CO2 retention (resting PCO2
>45 mmHg), DLCO <40%, and severe pulmonary hypertension.
Recommending surgery when the FEV1 is 1.1–2.0 L or <80% predicted
requires careful judgment, while an FEV1 >2.5 L or >80%
predicted usually permits a pneumonectomy. 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 (
| |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
|
Lung Cancer: Treatment
The overall treatment approach to patients with lung cancer
is shown in Table 85-4. Patients should be encouraged to stop smoking,
particularly if they will be undergoing surgery or radiation therapy. Those who
do fare better than those who continue to smoke.
Management of Occult and Stage 0 Carcinomas
In the uncommon situation where malignant cells are
identified in a sputum or bronchial washing specimen but the chest radiograph
appears normal (TX tumor stage), the lesion must be localized. More than 90% 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. Often, carcinoma in situ or multicentric lesions are
found in these patients. Current recommendations are for the most conservative
surgical resection, allowing removal of the cancer and conservation of lung
parenchyma, even if the bronchial margins are positive for carcinoma in situ.
The 5-year overall survival rate for these occult cancers is ~60%. Close
follow-up of these patients is indicated because of the high incidence of second
primary lung cancers (5% per patient per year). One approach to in situ or
multicentric lesions uses systemically administered hematoporphyrin (which
localizes to tumors and sensitizes them to light) followed by bronchoscopic
phototherapy.
Solitary Pulmonary Nodule and "Ground Glass" Opacity
Occasionally, when an x-ray or CT scan is done for another
purpose, a patient will present with an incidental finding of an asymptomatic,
solitary pulmonary nodule (SPN, 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). A decision to resect or follow the nodule
must be made. Nodules of this size discovered in CT screening for lung cancer
would also be of the size requiring a biopsy for tissue. Approximately 35% of
all such lesions in adults are malignant, most being primary lung cancer, while
<1% are malignant in nonsmokers <35 years of age. A complete history,
including a smoking history, physical examination, routine laboratory tests,
chest CT scan, fiberoptic bronchoscopy, and old chest x-rays or CT scans are
obtained if available.
PET scans are useful in detecting lung cancers >7–8 mm
in diameter. If no diagnosis is immediately apparent, the following risk factors
would all argue strongly in favor of proceeding with resection to establish a
histologic diagnosis: a history of cigarette smoking; age
When old x-rays are not available, the PET scan is
negative, and the characteristic calcification patterns are absent, the
following approach is reasonable. Nonsmoking patients <35 years can be
followed with serial CT every 3 months for 1 year and then yearly; if any
significant growth is found, a histologic diagnosis is needed. For patients
>35 years and all patients with a smoking history, a histologic diagnosis
must be made, regardless of whether the lesion is PET positive or negative,
since slow-growing cancers such as BAC can be PET negative. The sample for
histologic diagnosis can be obtained either at the time of nodule resection or,
if the patient is a poor operative risk, via video-assisted thoracic surgery
(VATS) or transthoracic fine-needle biopsy. Some institutions use preoperative
fine-needle aspiration on all such lesions; however, all positive lesions have
to be resected, and negative cytologic findings in most cases have to be
confirmed by histology on a resected specimen. Much has been made of sparing
patients an operation; however, the high probability of finding a malignancy
(particularly in smokers >35 years) and the excellent chance for surgical
cure when the tumor is small both suggest an aggressive approach to these
lesions.
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 BAC. Some of the GGOs are semiopaque and referred
to as "partial" GGOs, which are often more slowly growing, with atypical
adenomatous hyperplasia histology, a lesion of unclear prognostic significance.
By contrast, "solid" GGOs have a faster growth rate and usually are typical
adenocarcinomas histologically.
Non-Small Cell Lung Cancer
NSCLC Stages I and II
Surgery
In patients with NSCLC stages IA, IB, IIA and IIB (Table
85-2) who can tolerate operation, the treatment of choice is pulmonary
resection. If a complete resection is possible, the 5-year survival rate for N0
disease is about 60–80%, depending on the size of the tumor. The 5-year survival
drops to about 50% when N1 (hilar node involvement) disease is present.
The extent of resection is a matter of surgical judgment
based on findings at exploration. Clinical trials have shown that lobectomy is
superior to wedge resection in reducing the rate of local recurrence.
Pneumonectomy is reserved for patients with tumors involving multiple lobes or
very central tumors and should only be performed in patients with excellent
pulmonary reserve. In addition, patients undergoing a right-sided pneumonectomy
after induction chemotherapy and radiation therapy (see below) have a high
mortality rate and should be carefully selected before surgery. Wedge resection
and segmentectomy (potentially by VATS) are reserved for patients with poor
pulmonary reserve and small peripheral lesions.
Radiotherapy with Curative Intent
Patients with stage I or II disease who refuse surgery or
are not candidates for pulmonary resection should be considered for radiation
therapy with curative intent. The decision to administer high-dose radiotherapy
is based on the extent of disease and the volume of the chest that requires
irradiation. Patients with distant metastases, malignant pleural effusion, or
cardiac involvement are not considered candidates for curative radiation
treatment. The long-term survival for patients with all stages of lung cancer
who receive radiation with curative intent is about 20%. In addition to being
potentially curative, radiotherapy may increase the quality and length of life
by controlling the primary tumor and preventing symptoms related to local
recurrence in the lung.
Treatment with curative intent usually involves midplane
doses of 60–64 Gy, while palliative thoracic radiation (see below) involves
delivery of 30–45 Gy. The major dose-limiting concern is the amount of lung
parenchyma and other organs in the thorax that are included in the treatment
plan, including the spinal cord, heart, and esophagus. In patients with a major
degree of underlying pulmonary disease, the treatment plan may have to be
compromised because of the deleterious effects of radiation on pulmonary
function.
The most common side effect of curative thoracic radiation
is esophagitis. Other side effects include fatigue, radiation myelitis (rare),
and radiation pneumonitis, which can sometimes progress to pulmonary fibrosis.
The risk of radiation pneumonitis is proportional to the radiation dose and the
volume of lung in the field. The full clinical syndrome (dyspnea, fever, and
radiographic infiltrate corresponding to the treatment port) occurs in 5% of
cases and is treated with glucocorticoids. Acute radiation esophagitis occurs
during treatment but is usually self-limited, unlike spinal cord injury, which
may be permanent and should be avoided by careful treatment planning.
Brachytherapy (local radiotherapy delivered by placing radioactive "seeds" in a
catheter in the tumor bed) provides a way to give a high local dose while
sparing surrounding normal tissue.
NSCLC Stage IA
Patients with resected stage IA NSCLC receive no other
therapy but are at a high risk of recurrence (~2–3% annually) or developing a
second primary lung cancer. Thus, it is reasonable to follow these patients with
CT scans for the first 5 years and consider entering them onto early detection
and chemoprevention studies.
Adjuvant Chemotherapy for NSCLC Stages IB and II
A meta-analysis of more than 4300 patients showed a trend
toward improved survival of ~5% at 5 years with cisplatin-based adjuvant therapy
(p = .08). Subsequently, three randomized studies demonstrated no
significant survival advantage despite the addition of more "modern"
postoperative adjuvant chemotherapy regimens. However, since then at least three
additional randomized trials and two meta-analyses showed a survival benefit in
response to postoperative adjuvant-based therapy (Table 85-5). Consequently,
adjuvant chemotherapy is now routinely recommended in NSCLC patients with a good
performance status and stage IIA or IIB disease, though the beneficial effects
are modest.
The role of adjuvant chemotherapy for stage IB disease is
undefined. Subset analysis of all the randomized studies showed no benefit in
patients with stage IB. In addition, one clinical trial focusing solely on IB
disease and using carboplatin and paclitaxel (one of the most commonly used
regimens for advanced disease) found a hazard ratio of 0.80 (20% reduction in
death with adjuvant chemotherapy) that was not statistically significant. Thus,
patients with stage IB NSCLC are not routinely given adjuvant therapy.
Adjuvant Radiotherapy for NSCLC Stages I–II
After apparent complete resection, postoperative adjuvant
radiation therapy does not improve survival and may actually be detrimental to
survival in N0 and N1 disease.
Superior Sulcus or Pancoast Tumors
Non-small cell carcinomas of the superior pulmonary sulcus
producing Pancoast's syndrome appear to behave differently than lung
cancers at other sites and are usually treated with combined radiotherapy and
surgery. Patients with these carcinomas should have the usual preoperative
staging procedures, including mediastinoscopy and CT and PET scans, to determine
tumor extent and a neurologic examination (and sometimes nerve conduction
studies) to document involvement or impingement of nerves in the region. If
mediastinoscopy is negative, curative approaches may be used in treating
Pancoast's syndrome despite its apparent locally invasive nature. The best
results reported thus employed concurrent preoperative irradiation [30 Gy in 10
treatments] and cisplatin and etoposide, followed by an en bloc resection of the
tumor and involved chest wall 3–6 weeks later; 65% of thoracotomy specimens
showed either a complete response or minimal residual microscopic disease on
pathologic evaluation. The 2-year survival rate was 55% for all eligible
patients and 70% for patients who had a complete resection.
NSCLC with T3, N0 Disease (Stage IIB)
The subset of T3, N0 disease (which does not present as
Pancoast tumor) was initially considered stage III disease. However, it has a
different natural history and treatment strategy than stage III N2 disease and
is now considered as stage IIB. Patients with peripheral chest wall invasion
should have resection of the involved ribs and underlying lung. Chest wall
defects are then repaired with chest wall musculature or Marlex mesh and
methylmethacrylate. Five-year survival rates as high as 35–50% have been found,
and adjuvant chemotherapy is usually recommended.
NSCLC Stage III
Treatment of locally advanced NSCLC is one of the most
controversial issues in the management of lung cancer. Treatment options include
a local therapy (surgery or radiation therapy) combined with systemic
chemotherapy to control micrometastases. Interpretation of the results of
clinical trials involving patients with locally advanced disease has been
clouded by a number of issues, including changing diagnostic techniques,
different staging systems, and heterogeneous patient populations with tumors
that range from nonbulky stage IIIA (clinical N1 nodes with N2 nodes discovered
only at the time of surgery, despite a negative mediastinoscopy) to bulky N2
nodes (enlarged adenopathy clearly visible on chest x-rays or multiple nodal
level involvement) to clearly inoperable stage IIIB disease. Thus, a team
approach involving pulmonary medicine, thoracic surgery, and medical and
radiation oncology is essential for the management of these patients.
NSCLC Stage IIIA
Nonbulky IIIASurgery for N2 disease is a controversial area
in the management of lung cancer. Patients with N2 disease can be divided into
"minimal" disease (involvement of only one node with microscopic foci, usually
discovered at thoracotomy or mediastinoscopy) and the more common "advanced"
bulky disease, clinically obvious on CT scans and discovered preoperatively.
Patients who have an incidental finding of N2 disease at the time of resection
should receive adjuvant chemotherapy.
Bulky IIIA
No evidence suggests that patients with "bulky," multilevel
ipsilateral mediastinal nodes (N2) have improved survival with surgery and
either pre- or postoperative chemotherapy compared to treatment with
chemotherapy plus radiation therapy. This important issue was addressed in the
multicenter randomized Intergroup 0139 Trial involving patients with
pathologically staged N2 disease who received 45 Gy of induction radiation
therapy plus two cycles of cisplatin and etoposide to "debulk" tumors. The
patients were then randomly assigned to surgical resection of any residual tumor
or to boost radiation therapy plus an additional two cycles of chemotherapy.
Although a significant improvement in progression-free survival was observed at
5 years for those patients randomized to surgical resection (22% vs. 11%; p =
.017), the difference in 5-year overall survival while favoring surgery (22% vs.
11%; p = .10) was not significant. This is important since treatment-related
mortality was greater in the surgery arm (8% vs. 2%), with the majority of
deaths occurring in patients undergoing pneumonectomy. Patients who had
persistent N2 disease following neoadjuvant chemotherapy did particularly
poorly, leading some oncologists to conclude that surgery for bulky IIIA disease
should only be conducted in patients who have clearing of their mediastinal
nodes following neoadjuvant therapy. The main role of neoadjuvant chemotherapy
is to control micrometastatic disease, and if this macroscopically evident
disease is not sensitive to chemotherapy, it is unlikely that the microscopic
disease will be controlled. Thus, surgical removal of the primary tumor after
such chemotherapy is probably fruitless. Likewise, neoadjuvant chemotherapy
generally should not be used to render inoperable disease operable. One
exception to this approach is T4, N0 or T4, N1 (stage IIIB, see below) disease
for which preoperative chemotherapy may provide enough tumor debulking to allow
otherwise unresectable disease to be resected. Chemotherapy may allow chest wall
resection for direct extension of tumor, tracheal sleeve pneumonectomy, and
sleeve lobectomy for lesions near the carina.
Bulky NSCLC Stage IIIA and Dry IIIB (IIIB Without a
Pleural Effusion)
The presence of pathologically involved N2 nodes should be
confirmed histologically because enlarged nodes detected by CT will be negative
for cancer in ~30% of patients. Chemotherapy plus radiation therapy is the
treatment of choice for patients with bulky stage IIIA or IIIB disease without
pleural effusion (referred to as "dry IIIB"). Randomized studies demonstrate an
improvement in median and long-term survival with chemotherapy followed by
radiation therapy, compared with radiation therapy alone. Subsequent randomized
trials have shown that administering chemotherapy and radiation therapy
concurrently results in improved survival compared to sequential chemotherapy
and radiation therapy, albeit with more side effects, such as fatigue,
esophagitis, and neutropenia. Frequently, an additional two to three cycles of
chemotherapy are also given. However, it is not clear whether these additional
cycles should be administered before or after the chemoradiation, what the
optimal drugs are, or whether doses should be attenuated during the radiation
but given more frequently. (Lower doses of drugs may "sensitize" the tumor to
radiation therapy but may not by themselves remove other microscopic disease.)
Disseminated Non-Small Cell Lung Cancer
Symptomatic Management of Metastatic Disease
Patients who present with or progress to metastatic NSCLC
have a poor prognosis, as do patients with pleural effusions. Untreated, the
median survival of both of these patient groups is roughly 4–6 months. They are
often treated in the same way. Standard medical management, the judicious use of
pain medications, the appropriate use of radiotherapy, and outpatient
chemotherapy form the cornerstone of this management.
Palliative Radiation Therapy
Patients whose primary tumor is causing urgent severe
symptoms such as bronchial obstruction with pneumonitis, hemoptysis, upper
airway or superior vena cava obstruction, brain or spinal cord compression, or
painful bony metastases should have radiotherapy to the primary tumor to relieve
these symptoms. Usually, radiation therapy is given as a course of 30–40 Gy over
2–4 weeks for palliative purposes. Radiation therapy provides relief of
intrathoracic symptoms: hemoptysis, 84%; superior vena cava syndrome, 80%;
dyspnea, 60%; cough, 60%; atelectasis, 23%; and vocal cord paralysis, 6%.
Cardiac tamponade (treated with pericardiocentesis and radiation therapy to the
heart), painful bony metastases (with relief in 66%), brain or spinal cord
compression, and brachial plexus involvement may also be palliated with
radiotherapy.
Brain metastases are often isolated sites of relapse
in patients with adenocarcinoma of the lung otherwise controlled by surgery or
radiotherapy. These are usually treated with radiation therapy and, in highly
selected cases, with surgical resection. Usually, in addition to radiotherapy
for brain metastases and cord compression, dexamethasone (25–100 mg/d in four
divided doses) is also given and then rapidly tapered to the lowest dosage that
relieves symptoms. Because of the high frequency of brain metastases, the use of
prophylactic cranial irradiation (PCI, given to the whole brain before
metastatic disease becomes manifest) has been considered. However, PCI is of no
proven value. Screening asymptomatic patients with head CT scans to find such
lesions before such metastases become clinically evident is also not proven
beneficial.
Pleural effusions are common and are usually treated
with thoracentesis. If they recur and are symptomatic, a pleurex catheter or
chest tube drainage followed by pleurodesis with a sclerosing agent such as
intrapleural talc, bleomycin, or tetracycline can be used. These sclerosing
agents may be administered through the chest tube, or, in the case of talc, via
thorascopic insufflation. In the former case, the chest cavity is completely
drained. Xylocaine 1% is instilled (15 mL), followed by 50 mL normal saline.
Then the sclerosing agent is dissolved in 100 mL normal saline, and this
solution is injected through the chest tube. The chest tube is clamped for 4 h
if tolerated, and the patient is rotated onto different sides to distribute the
sclerosing agent. The chest tube is removed 24–48 h later, after drainage has
become slight (usually <100 mL/24 h). While sclerosing agents have been
widely used, an indwelling pleurex catheter is equivalent to chest tube drainage
and better tolerated by patients. In this situation, the pleurex catheter is
tunneled under the skin and can remain in place for weeks. The patient
periodically drains the catheter into a specially designed bag, as needed.
Symptomatic endobronchial lesions that recur after
surgery or radiotherapy or develop in patients with severely compromised
pulmonary function are difficult to treat with conventional therapy.
Neodymium-YAG (yttrium-aluminum-garnet) laser therapy administered through a
flexible fiberoptic bronchoscope (usually under general anesthesia) can provide
palliation in 80–90% of such patients even when the tumor has relapsed after
radiotherapy. Local radiotherapy delivered by brachytherapy, photodynamic
therapy using a photosensitizing agent, and endobronchial stents are other
measures that can relieve airway obstruction from recurrent tumor.
Chemotherapy
Chemotherapy palliates symptoms, improves the quality of
life, and improves survival in newly diagnosed patients with stage IV NSCLC,
particularly in patients with good performance status. Whereas the median
survival for untreated patients is roughly 4–6 months, and 1-year survival is
5–10%, with combination chemotherapy the median survival is 8–10 months, 1-year
survival is 30–35%, and 2-year survival 10–15%. Combination chemotherapy
produces an objective tumor response in 20–30% of patients, although the
response is complete in <5%. 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 for these patients.
Chemotherapy for previously untreated,
good-performance-status patients typically consists of two drugs
("doublets"). Traditionally, one of the two drugs has been either cisplatin or
carboplatin, and the other drug is a taxane (paclitaxel or docetaxel),
gemcitabine, or a vinca alkaloid such as vinorelbine. No major difference in
outcome has been observed between the standard chemotherapy doublets, although
they differ in terms of schedule, side effects, and cost. Cytotoxic chemotherapy
for first-line chemotherapy is typically administered for four to six cycles; no
benefit has been shown for continuing the same chemotherapy beyond that point.
After four to six cycles, chemotherapy is usually stopped and the patient
observed closely for tumor progression, at which point second-line chemotherapy
may be started if the patient's performance status remains good. Nausea with
typical first-line regimens is usually mild, particularly when 5-HT3 serotonin
antagonists are used as antiemetics. Hair loss depends on the choice of regimen
and should be discussed with the patient. All regimens cause myelosuppression,
but the incidence of neutropenic fevers, bleeding episodes, or anemia requiring
transfusions is low. Growth-factor support is rarely needed. Elderly patients
without significant comorbid conditions benefit from and tolerate chemotherapy
much the same as their younger counterparts. However, patients with a poorer
performance status seem to obtain less benefit.
Docetaxel and pemetrexed are second-line agents for
patients who have progressive disease on first-line chemotherapy and still have
a good performance status. Docetaxel improves progression-free survival and
overall survival compared to best supportive care, and pemetrexed has roughly
the same efficacy as docetaxel, but with fewer side effects.
VEGF Targeted Therapy
Bevacizumab, a monoclonal antibody to VEGF, improves
response rate, progression-free survival, and overall survival of patients with
advanced disease when combined with chemotherapy (paclitaxel/carboplatin).
Median, 1-year, and 2-year survival in response to chemotherapy plus bevacizumab
was 12.3 months, 51%, and 23%, compared, respectively, to 10.3 months, 44%, and
15% with chemotherapy alone (hazard ratio 0.79, p = 0.003). A 1-year
survival of >50% and a 2-year survival of >20% represents a significant
improvement in long-term prognosis. The dose of bevacizumab administered on this
trial was 15 mg/kg IV every 3 weeks. Bevacizumab side effects include bleeding,
hypertension, and proteinuria, and the hemorrhagic side effects make this agent
risky to use. Patients with squamous cancer cannot receive bevacizumab because
of their tendency toward serious hemorrhagic side effects. Patients with brain
metastases, hemoptysis, and bleeding disorders or who need anticoagulation are
also not eligible to receive the agent. Despite these restrictions and careful
patient selection, significant bleeding is noted in about 4% of patients.
EGFR Targeted Therapy
Erlotinib is an oral inhibitor of the EGFR kinase that is
used in second- and third-line therapy of NSCLC. Clinical responses have been
seen in a large fraction of the small subset of patients with tumors bearing
mutations in the EGFR. Prolonged survival with EGFR TKI treatment has also been
observed in some patients whose tumors have amplification of the EGFR
gene or overexpression of the receptor. Side effects of erlotinib differ from
chemotherapy side effects of hair loss, nausea, and neutropenia, but they
include acneiform skin rash and diarrhea. For patients whose tumors respond to
EGFR TKI therapy, substantial clinical benefit is seen.
Small Cell Lung Cancer
SCLC is a chemotherapy-sensitive disease. Patients with
limited stage disease have high response rates (60–80%) and a 10–30% complete
response rate. The response rates in patients with extensive disease are
somewhat lower (50%) and almost always partial responses. Tumor regressions
usually occur quickly, within the first two cycles of treatment, and provide
rapid palliation of tumor-related symptoms.
Chemotherapy significantly prolongs survival. Untreated,
patients with limited-stage SCLC have a median survival of 12 weeks; the median
survival with chemotherapy is 18 months, and long-term (>3 year) survival is
30–40%. The median survival of extensive-stage patients is 9 months; <5% of
patients survive 2 years. Thus, although initially responsive, most patients
with SCLC relapse, presumably due to the emergence of chemotherapy
resistance.
Chemotherapy
The chemotherapy combination most widely used for SCLC is
etoposide plus cisplatin or carboplatin, given every 3 weeks on an outpatient
basis for four to six cycles. Increased dose intensity of chemotherapy adds
toxicity without clear survival benefit. Appropriate supportive care
(antiemetics, fluid support with cisplatin, monitoring of blood counts and blood
chemistries, monitoring for signs of bleeding or infection, and, as required,
use of hematopoietins) and adjustment of chemotherapy doses on the basis of
nadir granulocyte counts are essential.
The prognosis of patients who relapse is poor. Patients who
relapse >3 months since the completion of their initial chemotherapy
(so-called chemosensitive disease) have a median survival of 4–5 months;
patients who do not respond to initial chemotherapy or relapse within 3 months
(chemorefractory disease) have a median survival of only 2–3 months. Patients
with chemosensitive disease may be retreated with their initial regimen.
Topotecan has modest activity as second-line therapy, or patients can be entered
onto clinical trials testing new agents.
Considerations for Therapy of SCLC Limited-Stage
Disease
Combined-Modality Chemoradiotherapy
Radiation therapy to the thorax is associated with a small
but significant improvement in long-term survival for patients with
limited-stage SCLC (5% at 3 years). Chemotherapy given concurrently with
thoracic radiation is more effective than sequential chemoradiation but is
associated with significantly more esophagitis and hematologic toxicity. In one
randomized study, twice-daily hyperfractionated radiation was compared with a
once-daily schedule; both were administered concurrently with four cycles of
cisplatin and etoposide. Survival was significantly higher with the twice-daily
regimen (median survival 23 months compared with 19 months; 5-year survival 26%
compared with 16%), but the twice-daily regimen gave more grade 3 esophagitis
and pulmonary toxicity. Patients should be carefully selected for concurrent
chemoradiation therapy based on good performance status and pulmonary
reserve.
PCI significantly decreases the development of brain
metastases (which occur in about two-thirds of patients who do not receive PCI)
and results in a small survival benefit (~5%) in patients who have obtained a
complete response to induction chemotherapy. Deficits in cognitive ability
following PCI are uncommon and often difficult to sort out from effects of
chemotherapy or normal aging.
Radiation Therapy for Palliation
Palliative radiation therapy is an important component of
the management of SCLC patients. Cranial radiation often decreases the signs and
symptoms of brain metastases. In the case of symptomatic, progressive lesions in
the chest or at other critical sites, if radiotherapy has not yet been given to
these areas, it may be administered in full doses (e.g., 40 Gy to the chest
tumor mass).
Surgery
Although surgical resection is not routinely recommended
for SCLC, occasional patients meet the usual requirements for resectability
(stage I or II disease with negative mediastinal nodes). Often this histologic
diagnosis is made in some patients only on review of the resected surgical
specimen. However, when such SCLC patients are discovered, they should receive
standard SCLC chemotherapy. Retrospective series have reported high cure rates
if postoperative chemotherapy is used, although it is unclear what the outcome
would be with chemoradiation therapy alone, given the relatively low bulk
disease of these patients.
|
|
Lung Cancer Prevention
Deterring children from taking up smoking and helping young
adults stop is likely to be the most effective lung cancer prevention. Smoking
cessation programs are successful in 5–20% of volunteers; the poor efficacy is
due to the addictive nature of nicotine use, which is as strong as addiction to
heroin.
Chemoprevention is an experimental approach to reduce lung
cancer risk; no benefit has yet been shown for chemoprevention. Two putative
chemoprevention agents, vitamin E and
|
|
Benign Lung Neoplasms
The benign neoplasms of the lung, representing <5% of
all primary tumors, include bronchial adenomas and hamartomas (90% of such
lesions) and a group of very uncommon benign neoplasms (epithelial tumors such
as bronchial papillomas, fibroepithelial polyps; mesenchymal tumors such as
chondromas, fibromas, lipomas, hemangiomas, leiomyomas, pseudolymphomas; tumors
of mixed origin such as teratomas; and other diseases such as endometriosis).
The diagnostic and primary-treatment approach (surgery) is basically the same
for all these neoplasms. They can present as central masses causing airway
obstruction, cough, hemoptysis, and pneumonitis. The masses may or may not be
visible on radiographs but are usually accessible to fiberoptic bronchoscopy.
Alternatively, they can present without symptoms as SPNs and are evaluated
accordingly. In all cases, the extent of surgery must be determined at
operation, and a conservative procedure with appropriate reconstructions is
usually performed.
Bronchial Adenomas
Bronchial adenomas (80% are central) are slow-growing
endobronchial lesions; they represent 50% of all benign pulmonary neoplasms.
About 80–90% are carcinoids, 10–15% are adenocystic tumors (or cylindromas), and
2–3% are mucoepidermoid tumors. Adenomas present in patients 15–60 years old
(average age 45) as endobronchial lesions and are often symptomatic for several
years. Patients may have a chronic cough, recurrent hemoptysis, or obstruction
with atelectasis, lobar collapse, or pneumonitis and abscess formation.
Bronchial adenomas of all types, because of their
endobronchial and often central location, are usually visible by fiberoptic
bronchoscopy. Because they are hypervascular, they can bleed profusely after
bronchoscopic biopsy, and this problem should be anticipated. Bronchial adenomas
must be considered as potentially malignant, thus requiring removal for symptom
relief and because they can be locally invasive or recurrent, potentially can
metastasize, and may produce paraneoplastic syndromes. Surgical excision is the
primary treatment for all types of bronchial adenomas. The extent of surgery is
determined at operation and should be as conservative as possible. Often
bronchotomy with local excision, sleeve resection, segmental resection, or
lobectomy is sufficient. Five-year survival rate after surgical resection is
95%, decreasing to 70% if regional nodes are involved. The treatment of
metastatic pulmonary carcinoids is unclear because they can either be indolent
or behave more like SCLC (Chap. 344). Assessment of the tempo and histology of
the disease in the individual patient is necessary to determine if and when
chemotherapy or radiotherapy is indicated.
Carcinoid and Other Neuroendocrine Lung Tumors
Neuroendocrine lung tumors represent a spectrum of
pathologic entities, including typical carcinoid, atypical carcinoid, and large
cell neuroendocrine cancer, as well as SCLC. SCLC and large cell neuroendocrine
cancer are high-grade neuroendocrine tumors and in general should be treated as
described for SCLC. By contrast, typical carcinoid and atypical carcinoids are
low- and intermediate-grade tumors with different treatment approaches and in
general are resistant to chemotherapy (Chap. 44). Carcinoids, like SCLCs, may
secrete other hormones, such as ACTH or AVP, and can cause paraneoplastic
syndromes that resolve on resection. Uncommonly, bronchial carcinoid metastases
(usually to the liver) may produce the carcinoid syndrome, with cutaneous flush,
bronchoconstriction, diarrhea, and cardiac valvular lesions, which SCLC does not
do. Carcinoid tumors that have an unusually aggressive histologic appearance
(referred to as atypical carcinoids) metastasize in 70% of cases to
regional nodes, liver, or bone, compared with only a 5% rate of metastasis for
carcinoids with typical histology. Large cell neuroendocrine cancer is a
high-grade NSCLC with neuroendocrine features. These tumors are characterized by
histologic features similar to small cell cancer, but they are formed by larger
cells. The prognosis for patients with large cell neuroendocrine cancer is
significantly worse than that for patients with atypical carcinoid and classic
large cell cancer. Five-year survival is 21% for patients with large cell
neuroendocrine cancer, 65% for atypical carcinoid, and 90% for typical
carcinoid.
Thymomas
Hamartomas
Pulmonary hamartomas have a peak incidence at age 60 and
are more frequent in men than in women. Histologically, they contain normal
pulmonary tissue components (smooth muscle and collagen) in a disorganized
fashion. They are usually peripheral, clinically silent, and benign in their
behavior. Unless the radiographic findings are pathognomonic for hamartoma, with
"popcorn" calcification, the lesions usually have to be resected for diagnosis,
particularly if the patient is a smoker. VATS may minimize the surgical
complications.
|
|
Metastatic Pulmonary Tumors
The lung is a frequent site of metastases from primary
cancers outside the lung. Usually such metastatic disease is incurable. However,
two special situations should be borne in mind. The first is the development of
an SPN or a mass on chest x-ray in a patient known to have an extrathoracic
neoplasm. This nodule may represent a metastasis or a new primary lung cancer.
Because the natural history of lung cancer is often worse than that of other
primary tumors, a single pulmonary nodule in a patient with a known
extrathoracic tumor is approached as though the nodule is a primary lung cancer,
particularly if the patient is >35 years and a smoker. If a vigorous search
for other sites of active cancer proves negative, the nodule is surgically
resected. Second, in some cases multiple metastatic pulmonary nodules can be
resected with curative intent. This tactic is usually recommended if, after
careful staging, it is found that (1) the patient can tolerate the contemplated
pulmonary resection, (2) the primary tumor has been definitively and
successfully treated (disease-free for >1 year), and (3) all known metastatic
disease can be encompassed by the projected pulmonary resection. Patients with
uncontrolled primary tumors and other extrapulmonary metastases are not
considered. Primary tumors whose pulmonary metastases have been successfully
resected for cure include osteogenic and soft tissue sarcomas; colon, rectal,
uterine, cervix, and corpus tumors; head and neck, breast, testis, and salivary
gland cancer; melanoma; and bladder and kidney tumors. Five-year survival rates
of 20–30% have been found in selected series, and dramatic results have been
achieved in patients with osteogenic sarcomas, where resection of pulmonary
metastases (sometimes requiring several thoracotomies) is a standard curative
treatment approach.
|
No comments:
Post a Comment