polymorphisms [SNPs]) in the same region of the long arm of

chromosome 15 was associated with the development of lung

cancer. Among the genes located in this region are those that

encode the nicotinic acetylcholine receptors. One of the studies showed an association with higher smoking rates, whereas

the other two did not. Therefore, it is not entirely clear the role

of these variants on smoking versus directly affecting lung cancer susceptibility.14–17 Separately, a GWAS showed an association

between the presence of SNPs located at chromosome 13q31.3

and lung cancer incidence in nonsmokers. Those nonsmokers

who had higher susceptibility to the disease were more likely to

have variants that down-regulated the expression of GPC5 gene.4

These case-control studies show that genetic variations appear to

contribute to the development of lung cancer. Ideally, if prospective studies were to confirm these findings, then presence of the

polymorphic variations could be considered as risk factors.

A more thorough history from J.W. would be helpful, but

recall for exposure to pollution, chemicals, and secondhand

smoke exposure is difficult to quantify. Hence, the view held by

much of society that lung cancer is a self-inflicted disease is not

entirely true. In summary, there is limited history on J.W.’s exposure to environmental hazards such as radon and secondhand

smoke. His age is close to that of peak incidence. Although he

stopped smoking almost a decade ago, there is still some residual risk associated with past smoking history, and this would

be expected to be higher for those with many pack-years history. Routine screening of asymptomatic patients such as J.W.

remains to be established as an effective means for enhancing

survival from the disease through early detection.

CASE 94-1, QUESTION 2: A CT scan was ordered for further evaluation and it showed an isolated speculated nodule in the right upper lobe with no mediastinal or hilar

adenopathy. The nodule showed no calcification. A CTguided needle biopsy was performed which showed a welldifferentiated adenocarcinoma consistent with a primary

NSCLC. Further staging was carried out with PET scanning

that demonstrated no additional areas of hypermetabolic

activity except for the nodule. What would be the best treatment plan for J.W., given the current information? Would

surgery or neoadjuvant therapy be indicated?

First of all, it is not surprising that J.W. had no symptoms. As

discussed earlier, the disease often goes undetected until symptoms manifest at a later stage. The goals of therapy for this patient

are to achieve a cure, especially since the disease appears to be

in the early stage. Surgery is the best treatment modality for

patients with stages I and II disease because these tumors are limited to one hemithorax and can be readily removed by excision.

In most instances, lobectomy with node dissection is sufficient

for local control. (See http://www.youtube.com/watch?v=

OhZmVCtVqYY for a simulated lobectomy.) During surgery,

2214Section 17 Neoplastic Disorders

the nodes would be sampled for presence of the disease and

to confirm staging. J.W. appears to have limited disease, and so

lobectomy would be recommended for him. For patients whose

primary tumor or lymph node involvement extends to the proximal bronchus or proximal pulmonary artery, or crosses the major

fissure, then a more extensive pneumonectomy is performed.

Therefore, surgery is the treatment of choice, and final staging

during surgery will guide further adjunct treatments. The tumors

can often spread to mediastinal lymph nodes, and for those who

have spread of the disease to this location (stage IIIA), then neoadjuvant chemotherapy can be recommended to reduce the tumor

burden prior to surgery. If neoadjuvant therapy is chosen, the

regimen is usually similar to those used in the adjuvant setting

(Table 94-5).18−21 Therefore, surgery is the primary treatment

modality for patients with stages I, II, and early stage III disease.

J.W.’s disease appears to be localized; therefore, surgical removal

of the tumor would be indicated, and neoadjuvant chemotherapy would not be indicated since there does not appear to be

disease in the mediastinum.22

CASE 94-1, QUESTION 3: J.W. was referred to a thoracic surgeon for resection. A right upper lobe lobectomy

was performed with lymph node dissection. The pathology

report revealed a 3.2 × 4 cm adenocarcinoma with three

associated peribronchial lymph nodes containing cancer

cells. Lymph nodes sampled from the mediastinum demonstrated no cancer. The patient’s tumor was staged as a

T2N1M0 (stage 2A) NSCLC. Now that the tumor is removed

and staging of the disease is finalized, what additional therapy, if any, is recommended now?

Although NSCLC tumors are minimally responsive to

chemotherapy, evidence from several studies (Table 94-5) shows

that adjuvant treatment enhances patient survival, and therefore

should be considered as part of the treatment plan for the patient.

TABLE 94-5

Adjuvant Chemotherapy Regimens for Non–Small Cell

Lung Cancer

Regimen Schedule

Cisplatin, days 1 and 8

Vinorelbine, days 1, 8, 15, 22

Every 28 days for four cycles18

Cisplatin, day 1

Vinorelbine, days 1, 8, 15, 22

Every 28 days for four cycles19,20

Cisplatin, day 1

Vinorelbine, days 1, 8

Every 21 days for four cycles18

Cisplatin, day 1

Etoposide, days 1–3

Every 28 days for four cycles20

Cisplatin, days 1, 22, 43, 64

Vinblastine, days 1, 8, 15, 22, then

every 2 weeks after day 43

Every 21 days for four cycles20

Paclitaxel on, day 1

Carboplatin, day 1

Every 21 days21

Other Acceptable Regimens

Cisplatin, day 1

Gemcitabine, days 1, 8

Every 21 days22

Cisplatin, day 1

Docetaxel, day 1

Every 21 days23

Pemetrexed, day 1

Cisplatin, day 1 for nonsquamous

NSCLC

Every 21 days for four cycles22

NSCLC, non–small cell lung cancer.

Though adjuvant treatment is often recommended, results from

two other studies indicate that adjuvant treatment is not always

effective.24 This suggests that there is a need to identify subsets

of patients who would likely benefit from treatment, and one

group that does not seem to gain benefit are those with stage

I disease. In the CALGB 9633 study, patients were randomly

assigned to receive carboplatin and paclitaxel or placebo, and a

survival benefit was observed for those receiving chemotherapy.

However, this survival was not uniform across the entire cohort.

Subgroup analysis showed that adjuvant chemotherapy should

not be considered standard of care for patients with stage IB disease, unless the tumor size is greater than 4 cm. Collectively,

these studies show that patients with stages II and IIIA disease

gain the most benefit from adjuvant chemotherapy.21 As summarized in Table 94-5, this chemotherapy usually includes cisplatin,

or if the patient is unable to tolerate it, then carboplatin. A second

agent, usually selected from one of those listed in Table 94-5, is

added as doublet therapy, and the goal is for patients to receive

four cycles. Toxicity often becomes worse beyond four cycles and

benefits are diminished thereafter. Therefore, chemotherapy is

beneficial, but has its limitations.

Radiation therapy is frequently used in the treatment of malignancies including later stages of NSCLC and also SCLC (described

subsequently); however, it has no proven benefit for the treatment of early stage disease. The PORT Group conducted a

meta-analysis from nine randomized trials to evaluate the possible role of postoperative radiotherapy in patients with completely resected NSCLC. There were 707 deaths among 1,056

patients assigned postoperative radiotherapy and 661 among

1,072 assigned surgery alone (hazard ratio, 1.21 [95% confidence

interval, 1.08–1.34]). This 21% relative increase in the risk of death

with radiotherapy is equivalent to a reduction in overall survival

from 55% to 48%. Subgroup analysis showed that the increased

risk of death was greatest for patients with stage I/II, N0 or N1,

but no clear evidence for those with stage III, N2 disease.25 Separately, another postoperative radiotherapy study was conducted,

using data from 7,465 patients in the Surveillance, Epidemiology,

and End Results database. The investigators for this study also

found no benefit for radiotherapy, especially for patients with N1

and N0 nodal disease. However, an increase in survival was associated with radiotherapy for patients who had N2 nodal disease.26

Hence, based on these two studies, radiation therapy is harmful for patients with early stage disease, but patients with higher

stage NSCLC may benefit from the treatment.

In summary, adjuvant chemotherapy is recommended for all

patients found to have stage II or III NSCLC at surgery, as well as

for larger (>4 cm) tumors. Multiple prospective phase 3 studies

have shown that platinum-based chemotherapy after surgery will

increase the survival rate of patients after surgery by about 10%.

Because J.W. has Stage IIA disease, four cycles of a platinum-based

doublet regimen would be indicated after surgery; however, he

should not receive radiotherapy at this time.

CASE 94-1, QUESTION 4: After surgery, J.W. saw both

a medical oncologist and a radiation oncologist to discuss additional therapies. The radiation oncologist advised

the patient that no radiation was needed, and that studies have demonstrated that for patients with stage 1 or

2 NSCLC, radiation leads to a surprising decrease in survival after surgery. Participation in a clinical trial was also

discussed with J.W. The patient agreed to participate in the

study and was randomly assigned to receive a platinumbased chemotherapy regimen along with bevacizumab.

What place in therapy do targeted agents have?

2215Lung Cancer Chapter 94

As will be discussed later in this chapter, targeted therapies

such as anti-angiogenesis and anti-EGFR therapies are useful

for the treatment of advanced stage NSCLC. However, their

role has not been established for patients like J.W. who have

early stage disease. Currently, a large international phase 3 study

(ECOG 1505) is investigating the role of adding anti-angiogenic

therapy with bevacizumab to standard platinum-based adjuvant

chemotherapy.27

Late-Stage Non–Small Cell Lung Cancer

CASE 94-2

QUESTION 1: L.L., an 85-year-old woman, presented with

mild cough productive with non-bloody sputum. There was

associated fever and shortness of breath. She was initially

seen by primary care physicians who treated her with antibiotics for possible pneumonia; however, the radiogram of

the chest obtained showed persisting infiltrate in the left

upper lung. This was later confirmed on a CT scan that

showed the presence of a 6 × 3 × 3.6 cm mass in the left

upper lobe. Tumor extended to left superior hilum. There

were also mediastinal adenopathy and multiple pulmonary

nodules seen in the right upper lobe with associated scarring, the largest of them measuring 14 × 9 mm in the right

upper lobe anteriorly. Transbronchial biopsy led to a diagnosis of adenocarcinoma with pathologic grade 3 out of 4.

The PET scan confirmed the presence of metabolic activity in the left primary tumor mass and right apical lesion as

well. Because of the spread of disease to contralateral lung,

disease was staged as IV. Pertinent patient history included

hypertension and hyperlipidemia. The patient also had a

hemangioma of the brain resected in 1950, and a history

of cervical cancer treated with abdominal hysterectomy in

1952. She has never been a smoker. Upon evaluation, she

was found to have hemoglobin slightly low at 11.3 g/dL

with white blood cell count of 5,200 cells/μL and a platelet

count of 245,000/μL. The electrolytes showed normal

sodium 143 mEq/L, normal potassium of 4.4 mEq/L, and creatinine 1.08 mg/dL, with estimated creatinine clearance of

48 mL/minute. Performance status 0–1. What are the treatment options for patients such as L.L. with advanced (stage

IIIB and IV) disease?

SURGERY

In general, tumors in patients with stage IIIB and IV disease are

inoperable. These tumors often invade the carina, great vessels,

vertebral bodies, more distant lymph nodes, metastases, and are

frequently associated with malignant pleural effusions. Hence,

combined modality treatments such as chemotherapy and radiation are the preferred treatments for patients with advanced stage

disease.28,29 Surgery to remove solitary metastatic sites may also

be considered.

RADIATION

Radiotherapy is the primary local treatment (i.e., definitive radiotherapy) for inoperable NSCLC, and is also used as a palliative modality for patients with incurable disease. For tumors

classified as stage III, radiotherapy is often given concurrently

with chemotherapy, as this has been shown to be superior

to both radiation alone and also sequential radiation followed

by chemotherapy.22 The radiation dose, in combination with

chemotherapy, usually ranges between 60 Gy and 65 Gy, given in

2-Gy fractions. Metastases may also be treated locally with radiotherapy. For example, brain metastases, spinal cord compression,

and impending fractures of weight-bearing bones can be treated

with radiation or surgery before systemic therapy commences.

In contrast to patients with stage III disease, those with stage IV

disease usually receive local treatment with radiotherapy first,

followed by chemotherapy, because therapy given concurrently

is often not well tolerated by patients with this stage of disease.

CHEMOTHERAPY

Patients with advanced disease and good performance status usually benefit from chemotherapy. Similar to early stage disease,

these tumors often respond to treatment with platinum-based

doublet cytotoxic combination therapy, which refers to treatment with either cisplatin or carboplatin plus a second cytotoxic

agent. These doublets may also include targeted treatments such

as bevacizumab or cetuximab (Table 94-6).30−35 Many of these

platinum doublet regimens are associated with similar response

rates and survival to one another. They differ in their toxicity

profiles and cost, and until recently, these considerations were

the only means available to guide treatment decisions.

NSCLC was treated as a single disease despite recognition of its

histologic and molecular heterogeneity, but recent clinical trials

demonstrate that histology is an important factor for individualizing treatment based either on safety or efficacy outcomes.

Hence, once the biopsy is obtained, it is crucial to differentiate the

histiologic subtype (i.e., squamous vs. nonsquamous). The role

of histology in the management of advanced NSCLC is reviewed

more extensively elsewhere.36 In developed countries, an increasing incidence of adenocarcinoma and a decline in squamous cell

carcinomas has been observed in recent years. This appears to be

correlated to declines in smoking rates. Many agents are effective against all histiologic types, such as cisplatin, carboplatin,

gemcitabine, and paclitaxel. However, other agents such as bevacizumab and pemetrexed are only indicated for use in patients

who have the nonsquamous histology. Squamous cell histology is

associated with increased risk for severe pulmonary hemorrhage

TABLE 94-6

Representative Regimens for Advanced or Metastatic

Non–Small Cell Lung Cancer

Regimen Schedule

Cisplatin, day 1

Paclitaxel, day 1

Every 21 days30

Cisplatin, day 1

Gemcitabine, days 1, 8, 15

Every 28 days30,31

Cisplatin, day 1

Docetaxel, day 1

Every 21 days30

Paclitaxel, day 1

Carboplatin, day 1

Every 21 days30

Cisplatin, day 1

Vinorelbine, days 1, 8

Cetuximab weekly

Nonsquamous histology

Every 21 days32

Cisplatin, day 1

Gemcitabine, days 1, 8

Bevacizumab, day 1

Every 21 days33

Paclitaxel, day 1

Carboplatin, day 1

Bevacizumab, day 1

Every 21 days34

Pemetrexed, day 1

Cisplatin, day 1

Every 21 days31

Erlotinib daily for known EGFR

mutation status

Until disease progression or

unacceptable toxicity35

EGFR, epidermal growth factor receptor.

2216Section 17 Neoplastic Disorders

compared with adenocarcinoma.37 For pemetrexed, significant

association between improved efficacy and the nonsquamous

subtype has been reported.38,39

Characterization of advanced NSCLC tumors at the molecular level has also recently become part of clinical practice. It is

recommended that tumor tissues from patients with nonsquamous histology tumors should be analyzed for the presence of

EGFR mutation status.22 Tumors that are positive for EGFR

somatic mutations are often more responsive to erlotinib therapy, and evidence also suggests that this would be a preferred

treatment, rather than cytotoxic chemotherapy, for the first-line

setting. This analysis is limited to patients with stages IIIB or IV

disease, because there is yet no proven benefit for erlotinib in

patients with earlier-stage disease and EGFR mutations.40 For

the advanced disease setting, therefore, treatment decisions are

becoming more individualized on the basis of tumor histology

and somatic mutations. As more targeted therapies, designed to

inhibit other targets, are approved it is likely that their use will

be based upon at least some of these same principles.

Patients who respond to treatment or achieve stable disease after four to six cycles may be given maintenance therapy.

The intention of such additional treatment would be to prolong the response and survival made possible by first-line treatment, while minimizing the chances for toxicity associated with

platinum-based doublet regimens. Maintenance therapy differs

from second-line therapy in that second-line treatment is only

used when the patient has progressed during or after first-line

treatment or is unable to tolerate it. Maintenance may be given

as continuation maintenance, which refers to the use of one of the

agents given in first line. Often, biologic agents that were given

as part of the first line regimen (e.g., bevacizumab or cetuximab)

are continued due to their better tolerability relative to the cytotoxic agents.34,41 Pemetrexed may also be given as continuation

maintenance treatment, though there is not a uniform consensus

to support its use in this setting, according to the National Comprehensive Cancer Network guidelines.22 Overall, continuation

maintenance is associated with an improvement in progressionfree survival, but not overall survival. Alternatively, the agent

may be different from those used in first-line treatment, and is

referred to as switch maintenance. Pemetrexed, erlotinib, and

docetaxel are three agents for which there is supportive clinical trial data in the switch-maintenance setting.22,38,42 The first

two agents are associated with an improvement in overall survival, and have an indication for use in this setting. Maintenance

therapy is reviewed more extensively elsewhere.43

PALLIATION

Patients with metastatic NSCLC receive benefit from palliative

care early after diagnosis, rather than waiting until end-of-life

care. This palliative care includes helping the patient deal with

the psychosocial aspects of their disease through methods such as

counseling (e.g., expectation of treatment outcomes and affordability of treatment). In a study of patients with metastatic disease, subjects were randomly assigned to receive either early palliative care integrated with standard oncologic care vs. standard

oncologic care alone. Patients assigned to early palliative care

experienced a better quality of life and survival (11.6 months vs.

8.9 months) than patients assigned to standard care alone. They

also experienced fewer depressive symptoms (16% vs. 38%). The

results show that palliative care is appropriate and potentially

beneficial when it is introduced at the time of diagnosis at the

same time as other benefical therapies.44

In conclusion, L.L. would not likely receive benefit from surgical removal of the primary tumor or metastatic site. Instead, radiation and chemotherapy are the definitive treatments of choice

TM

Tyrosine kinase

EGF ligand

binding Autophosphorylation

FIGURE 94-1 Tumor epidermal growth factor receptor. Mutations in the tyrosine kinase domain (Exons 18-21) render tumors more

sensitive to the antitumor effects of small-molecule kinase inhibitors

such as erlotinib. Once treatment with erlotinib has

begun, other mutations can arise that are associated with reduced

sensitivity. TM = transmembrane domain.

because these modalities are more effective for controlling disease that has already spread. If this option is chosen, the radiation

should be given prior to the chemotherapy (Table 94-6) to minimize toxicity for this patient with stage IV disease. Consideration

for palliative care would also be beneficial.

CASE 94-2, QUESTION 2: The tumor tissue was sent out for

analysis of presence of EGFR mutation. What characteristics

for L.L. would prompt a decision to send a tumor specimen

for analysis of EGFR mutation?

The mutations that have been described reside in exons 18–24

(amino acids 718–964) of the tyrosine kinase domain of the EGFR

gene (which behaves as an oncogene). Of those, 90% reside in

exon 19 or 21 (Figure 94-1).45 The role of these mutations are

thought to constitutively activate the receptor. Such an activated

receptor is likely to be important for the pathogenesis of the

disease by tumors. Exon 19 deletions are associated with longer

median time to disease progression than L858R mutations, suggesting that all mutations are not equivalent with respect to tyrosine kinase responsiveness.35,46

The importance of this analysis is underscored by the fact that

patients with EGFR-mutation–positive advanced stage tumors

respond better to treatment with erlotinib than they do with conventional chemotherapy.35 Further, erlotinib is better tolerated

than doublet platinum-based therapies; therefore, patients with

 Non–Small Cell Lung Cancer

EPIDEMIOLOGY

Incidence for NSCLC in the United States is second to prostate

cancer in men and breast cancer for women. Lung cancer is

the leading cause of death relative to all of the other cancers.

As with most solid tumors, survival is better for patients diagnosed with early stage disease than it is for those with more

advanced disease. However, for many patients the disease often

2210

2211Lung Cancer Chapter 94

goes undetected either due to the lack of noticeable symptoms

or because they may be masked by concurrent diseases such as

chronic obstructive pulmonary disease (COPD), which can cause

similar symptoms.

PATHOPHYSIOLOGY

NSCLC tumorigenesis is a multistep process in which neoplastic

tissue arises from bronchial epithelium. These cells, which form

the inner lining of bronchial tissue, develop genetic lesions to

protooncogenes and tumor suppressor genes, resulting in the

dysregulation of key molecular signaling pathways. As a result,

cellular proliferation occurs and responsiveness to apoptotic signaling is often diminished. Eventually, accumulation of additional

genetic abnormalities can influence the cell’s ability to metastasize, resulting in the spread of tumorous tissue locally or to more

distant sites in the lymph nodes and organs.

Non–small cell lung tumors are classified further according

to tumor tissue histology. The three major histiologic types

include squamous cell carcinoma, adenocarcinoma, and large

cell carcinomas. Although these different variants were identified

several decades ago, it was only recognized recently that they

differ in their sensitivities to certain chemotherapeutic agents.

These three may be subcategorized further, and other variants

of NSCLC also exist; however, discussion in this chapter will

be limited to these three. The adenocarcinomas and large cell

carcinomas are commonly grouped together as nonsquamous

carcinomas. These tumors commonly arise in the periphery of

the lung and the smaller airways. After various periods of growth

in the lung parenchyma or bronchial wall, these primary tumors

invade the vascular and lymphatic system, enabling metastases

to regional lymph nodes and more distant sites.1

RISK FACTORS AND CLINICAL PRESENTATION

There are several risk factors for developing lung cancer, but

the biggest factor is cigarette smoking, which is estimated to

increase the risk by up to 30-fold. The prevalence of smoking

peaked in the early 1960s just prior to the Surgeon General’s

first report regarding the harms of smoking. Since that time,

the per capita cigarette consumption in the United States has

steadily decreased up to the year 2000, for which the latest data

are available. Death rates for both men and women followed

this trend. For men, deaths due to lung cancer peaked in the

1980s and has since steadily decreased. For women, deaths due

to lung cancer appear to have reached a plateau around the year

2000. The most recent Surgeon General’s report emphasizes the

relation between exposure to secondhand smoke and increased

risk for lung cancer. The report also addresses the risks associated with newer types of cigarettes developed by the tobacco

industry. Other risk factors include cigar and pipe smoking, occupational and environmental exposures, radon, asbestos, certain

metals such as chromium and cadmium, various organic chemicals, radiation, air pollution, history of tuberculosis, and genetic

factors. The latter appears to be related to those who exhibit the

disease early in life. The probability for exhibiting invasive lung

cancer increases with age and peaks during the seventh decade of

life. Lifetime, the probability is 1 in 13 men and 1 in 16 women.2–5

The disease is detected either because a person presents with

signs and symptoms commonly associated with lung cancer or by

chance, when the patient is under evaluation for other disorders

or procedures. Selected signs and symptoms are listed in Table

94-1, but vary widely between patients according to tumor size,

stage, and location.

DIAGNOSIS

If a malignancy comes under consideration, a computed tomography (CT) or positron emission tomography (PET)–CT scan of

TABLE 94-1

Common Selected Signs and Symptoms for Lung Cancer

Cough

Hemoptysis

Wheeze

Dyspnea

Pain (e.g., chest wall)

Obstruction of vital structures (e.g., esophagus, superior vena cava)

Symptoms are highly dependent on tumor size, location within the chest cavity,

and presence of metastases.

the abdomen and thoracic region is usually performed to identify any possible primary lesions and to look for possible metastases to lymph nodes and other organs or contralateral lung.

If located, a pathological evaluation is performed to confirm

the diagnosis. Magnetic resonance imaging (MRI) to the head

may be ordered if brain metastases are suspected. Preoperatively,

specimens may be obtained through methods such as bronchial

brushings, bronchial washings, fine needle aspiration biopsy, core

needle biopsy, endobronchial biopsy, and transbronchial biopsy.

Mediastinal lymph nodes are also sampled via mediastinoscopy

to assess staging. If surgery is performed, specimens are evaluated during the procedure to determine the resection margin

status, diagnose incidental nodules discovered during surgery,

and sampling of regional lymph nodes. Post operative evaluation provides pathology characteristics necessary for classifying

tumor type and staging.1

Staging is performed to determine prognosis and to guide

treatment decision-making. In general, the prognosis declines

with increasing disease stage at initial diagnosis. Five-year overall

survival rates are 53% for patients with disease that is locally

limited, 24% for regional, and 4% for metastatic disease. For all

stages, five-year overall survival has only marginally improved

over the last 30 years to 16%. Unfortunately, the disease has

already metastasized in greater than 50% of patients upon initial

presentation. Clearly, earlier detection and better treatments are

needed.5

Staging classification is reliant on anatomic characteristics,

and has recently been updated by the International Association

for the Study of Lung Cancer (IASLC) and adopted by the American Joint Committee on Cancer staging. Even though clinicians

are placing more importance on molecular markers such as epidermal growth factor receptor (EGFR) mutations and tumor

histology, the revised system still relies strictly on the TNM system of staging. Shown in Table 94-2 are the definitions for the T,

N, and M descriptors in the staging of NSCLC. Lymph nodes are

classified according to anatomic location (station).

For a visual of a lymph node map, go to

http://thepoint.lww.com/AT10e.

Once these descriptors are determined for a patient, stage is

determined according to the criteria listed in Table 94-3.6,7

OVERVIEW OF TREATMENT

Surgery, radiation, and systemic therapy (i.e., chemotherapy and

targeted therapy) are all treatment modalities used in the treatment of NSCLC. If caught in the early stages of the disease,

surgery offers the best hope for cure. Non–small cell lung tumors

are generally slow growing; however, chemotherapy is associated with enhanced survival depending on the stage of disease.

The remaining discussion of NSCLC in this chapter will outline

2212Section 17 Neoplastic Disorders

TABLE 94-2

Definitions for T, N, M Descriptors in the IASLC Staging Classificationa

TNM Descriptions Subgroupb

T (Primary Tumor)

T0 No primary tumor

T1 Tumor ≤3 cmc , surrounded by lung or visceral pleura, not more proximal than the lobar bronchus

T1a Tumor ≤2 cmc T1a

T1b Tumor >2 but ≤3 cmc T1b

T2 Tumor >3 but ≤7 cmc or tumor with any of the followingd :

Invades visceral pleura, involves main bronchus ≥2 cm distal to the carina, atelectasis/obstructive

pneumonia extending to hilum but not involving the entire lung

T2a Tumor >3 but ≤5 cmc T2a

T2b Tumor >5 but ≤7 cmc T2b

T3 Tumor >7 cmc T3>7

or directly invading chest wall, diaphragm, phrenic nerve, mediastinal pleura, parictal pericardium, T3tav

or tumor in the main bronchus <2 cm distal to the carinac , T3Centr

or atelectasis/obstructive pneumonitis of entire lung, T3Centr

or separate tumor nodule(s) in the same lobe T3Satell

T4 Tumor of any size with invasion of: heart, great vessels, tracheae , recurrent laryngeal nerve, esophagus,

vertebral body, or carinae ; or separate tumor nodule(s) in a different ipsilateral lobe

T4Inv

N (Regional Lymph Nodes)

N0 No regional node metastasis

N1 Metastasis in ipsilateral peribronchial and/or perihilar lymph nodes and intrapulmonary nodes, including

involvement by direct extension

N2 Metastasis in ipsilateral mediastinal and/or subcarinal lymph node(s)

N3 Metastasis in contralateral mediastinal, contralateral hilar, ipsilateral or contralateral scalene or

supraclavicular lymph node(s)

M (Distant Metastasis)

M0 No distant metastasis

M1a Separate tumor nodule(s) in a contralateral lobe; M1aContr,Nod

or tumor with pleural nodules or malignant pleural dissemination f M1aPl,Dissem

M1b Distant metastasis M1b

Special Situations:

TX, NX, MX T, N, or M status not able to be assessed

Tis Focus of in situ cancer Tis

T1c Superficial spreading tumor of any size but confined to the wall of the trachea or mainstem bronchus T1ss

aReflects the IASLC Staging Committee’s recommendations and not necessarily the UICC 7th Edition Staging System.

bThese subgroup labels are not defined in the IASLC publications, but are added here to facilitate a clear discussion. Goldstraw et al. J Thorac Oncol 2007;2:706–714;

Rami-Porta et al. J Thorac Oncol 2007;2:593; Postmus et al. J Thorac Oncol 2007;2:686; Rusch et al. J Thorac Oncol 2007;2:603. c In greatest dimension.

dT2 tumors with these features are classified as T2a if ≤5 cm. eThe uncommon superficial spreading tumor in central airways is classified as T1.

f Pleural effusions are excluded that are cytologically negative, nonbloody, transdative, and clinically judged not to be due to cancer.

IASLC, International Association for the Study of Lung Cancer; TNM, tumor, node, metastasis.

Reprinted with permission from Detterbeck FC et al. Anatomy, biology and concepts, pertaining to lung cancer stage classification. J Thorac Oncol. 2009;4:437.

the key aspects in the treatment of early and late stages of the

disease.

Early-Stage Non–Small Cell Lung Cancer

CASE 94-1

QUESTION 1: A 69-year-old male patient, J.W., was found

to have a 3-cm nodule on a chest x-ray done prior to an elective cataract surgery. The patient was a lifelong cigarette

smoker, having started smoking in his early 20s, approximately one pack of cigarettes per day. He quit smoking

9 years ago. What screening methods might be available

to detect the disease in asymptomatic patients? What risk

factors does J.W. have for lung cancer?

There are currently no screening methods available to detect

early stage lung cancer in asymptomatic patients. Survival would

likely improve if suitable methods could be identified, because

overall survival is much better when detected early. The National

Lung Screening Trial (NLST) is a randomized study of screening

methods to reduce deaths from lung cancer by detecting cancers

at relatively early stages. Thus far, the NLST has enrolled about

53,000 men and women with at least 30 pack-years of smoking history without signs and symptoms of lung cancer. They

have been randomly assigned to receive three annual screens

with either low-dose helical CT or standard chest x-ray. Initial

results appear promising: Researchers report 20% fewer lung

cancer deaths among trial participants screened with low-dose

helical CT relative to chest x-ray. Final data analyses are not yet

complete and application of these results are not yet clear. For

example, it is not known how many cigarettes and for how long

2213Lung Cancer Chapter 94

TABLE 94-3

Stage Groups in the IASLC Staging Classificationa

Stage Group T N M

I

Ia T1a,b N0 M0

Ib T2a N0 M0

II

IIa T1a,b N1 M0

T2a N1 M0

T2b N0 M0

IIb T2b N1 M0

T3 N0 M0

III

IIIa T1–3 N2 M0

T3 N1 M0

T4 N0,1 M0

IIIb T4 N2 M0

T1–4 N3 M0

IV TAny NAny M1a,b

aReflects the IASLC Staging Commitee’s recommendations and not necessarily

the UICC 7th edition staging system.

IASLC, International Association for the Study of Lung Cancer; TNM, tumor

node metastasis.

Reprinted with permission from Detterbeck FC et al. Anatomy, biology and

concepts, pertaining to lung cancer stage classification. J Thorac Oncol. 2009;4:437.

one would need to smoke to warrant annual screening, and the

question of how long does one need screening (i.e., 10 years,

20 years, lifetime). This could potentially represent several scans

and, therefore, a large radiation burden. Hence, practice is not

expected to change immediately.8–10

The probability for exhibiting the disease increases with age,

and J.W.’s age is close to the median age of peak incidence. Men

also have a slightly higher risk than women as discussed previously. Smoking is the largest risk factor for lung cancer development; however, what if a person stops smoking? Does the risk

decrease with time? These questions are important for health

care providers to address if they are encouraging smoking cessation for their patients. In J.W.’s case, he stopped 9 years ago, so

what impact would this smoking history have on development

of the disease? In general, people who stop smoking, even well

into middle age, avoid almost 90% of the risk attributable to

tobacco. Shown in Table 94-4 are data demonstrating the relation between the age at which a person stops smoking and the

cumulative percent risk (at age 75) for developing lung cancer.11

J.W. stopped when he was approximately 50 years old; therefore,

based on this table, the cumulative risk would approach 6% if he

were 75 years old. Because he is 60 years old, his risk would be

decreased but not to the extent that it would if a longer period

of time had elapsed. If he were still smoking the risk would be

expected to be closer to 15% to 16%. Hence, smoking cessation

is an effective means for lowering the risk over time. He smoked

TABLE 94-4

Cumulative Risk (%) of Death from Lung Cancer at Age

75 Years

Smoking Status Risk at Age 75

Lifelong nonsmoker <1

Stopped at age 30 <2

Stopped at age 40 3

Stopped at age 50 6

Stopped at age 60 10

Continuing smoker 16

for approximately 25 to 30 pack-years, so the total number of

cigarettes would also increase his risk. According to data from

the same studies, risk of disease for a one pack per day smoker

would be approximately twice that of someone who smoked less

than a half pack per day. Survival from the disease is also better

for non-smokers than for smokers.11,12

Frequently, patients will experience remorsefulness for having

smoked, but it is never possible to attribute one’s disease to a single factor such as smoking. In fact, 90% of smokers never exhibit

the disease. Further, 15% of men and 53% of all women with lung

cancer worldwide are never-smokers.13 This would suggest other

factors such as genetics are associated with the development of

the disease. Three independent genome-wide association studies

(GWAS) showed that polymorphic variation (single nucleotide

 

Aromatase Inhibitors

Type Dose Toxicities

Nonsteroidal

Anastrozole

Letrozole

1 mg daily PO

2.5 mg daily PO

Common toxicities: myalgias/

arthralgias, hot flashes,

osteoporosis

Steroidal

Exemestane 25 mg daily PO

PO, orally.

Source: Jones KL, Buzdar AU. A review of adjuvant hormonal therapy in breast

cancer. Endocr Relat Cancer. 2004;11:391; Buzdar AU, Howell A. Advances in

aromatase inhibitors: clinical efficacy and tolerability in the treatment of breast

cancer. Clin Cancer Res. 2001;7:2620.

inhibitors (AIs). Given this number of choices, menopausal status

of the patient is used to guide selection of therapy.

Traditionally, tamoxifen has been the gold standard for adjuvant hormonal therapy. Tamoxifen is a SERM, which works

by blocking estrogen from binding to the estrogen receptor. It

does not alter estrogen production. Tamoxifen has antiestrogenic activity in the breast, although it has estrogenic effects in

other areas such as bone.52,53 Tamoxifen can be used in both

premenopausal and postmenopausal women and is given 20 mg

orally daily for 5 years based on the data from the National Surgical Adjuvant Breast and Bowel Project B-14 trial.54,55 Tamoxifen

should be initiated after chemotherapy because it can antagonize

the antitumor activity of chemotherapy if given concurrently.56

Common toxicities associated with therapy are hot flashes and

vaginal discharge. More thrombosis, pulmonary embolisms, and

strokes can occur in patients (older than 50 years of age) receiving tamoxifen compared to placebo (risk ratio, 1.60, 3.19, 1.59,

respectively).4

Ovarian suppression is an alternative therapy for premenopausal patients as the ovaries are the largest source of

estrogen. This is typically achieved through the use of LH-RH

agonists. Surgery or radiation can also induce ovarian ablation;

however, surgery is irreversible but offers an immediate effect

where as radiation may offer an incomplete response and slower

onset.57 If a woman would like to maintain fertility throughout

chemotherapy, a thorough discussion with her physician should

occur. Studies with the use of LH-RH agents have been tested as

a means to preserve fertility but have shown mixed results.58

Postmenopausal patients also have the option of AI therapy.

Aromatase inhibitors inhibit the production of estrogen by preventing the conversion of androstenedione and testosterone to

estrone and estradiol. There are two classes of agents: nonsteroidal AIs (anastrozole and letrozole) and the steroidal AI,

exemestane. These agents are highly selective for the aromatase

enzyme and have less toxicity than tamoxifen and other hormonal agents. Aromatase inhibitors should only be used in postmenopausal women. If used in the premenopausal setting, initial

surges of estrogen occur due to the body’s compensation mechanisms (i.e., hypothalamic-pituitary axis) and negative feedback

loop. Table 93-5 provides a list of AIs.59–61 If used as single therapy,

AIs are given for 5 years.

The optimal hormonal therapy regimen for the adjuvant

setting has not been identified. In premenopausal women, the

options are 5 years of tamoxifen therapy plus or minus ovarian

suppression with an LH-RH agonist. If, after 2 to 3 years, the

patient is postmenopausal, then 2 to 3 years of an AI may be

given to complete a total of 5 years of therapy. If the patient is

postmenopausal at the beginning of adjuvant hormonal therapy,

an option would be to take an AI for 5 years. There have been

no prospective comparisons of the AIs with each other; therefore, any can be used as first-line treatment.60,61 Another clinical

option is 5 years of tamoxifen and then if the patient is postmenopausal after the end of 5 years, an additional 5 years of an

AI can be given. This was found beneficial in an extended study of

hormonal therapy (the BIG 1–98 trial). At the 2.4-year follow-up,

additional letrozole therapy was associated with a superior 4-year

diseasefree survival (93% with extended letrozole vs. 87% in the

tamoxifen arm; p <0.001).62 Table 93-6 lists adjuvant hormonal

therapy options.29

C.D. is premenopausal, so she would start with tamoxifen

therapy. If after 2 to 3 years of therapy, C.D. becomes postmenopausal, then she could continue the tamoxifen for a total

of 5 years or convert to an AI to complete a total of 5 years of

therapy. Because of her age, she will likely continue to be premenopausal after chemotherapy and be maintained on 5 years

of tamoxifen. If she completes 5 years of tamoxifen therapy and

is postmenopausal at that time, then extended use of an AI for

an additional 5 years would be recommended. Ovarian suppression with an LH-RH agonist can also be added because she is

premenopausal to chemically suppress her ovarian function.

TABLE 93-6

Overview of Adjuvant Hormonal Therapy

Premenopausal at time of

therapy initiation

(Patients can complete one

of 3 different options)

Option 1

Tamoxifen × 5 years ±

LH-RH agonist or ovarian

ablation

Option 2

If still premenopausal after 2–3 years of

tamoxifen therapy, complete a total of

5 years of tamoxifen.

If postmenopausal after 2–3 years:

A. Complete 5 years of tamoxifen followed

by 5 additional years of an AI

OR

B. Convert to an AI × 2–3 years for a total

of 5 years of hormonal therapy

Option 3

If still premenopausal after 5 years

of tamoxifen: Stop therapy

If postmenopausal after 5 years of

therapy give AI × 5 additional

years

Postmenopausal at time of 1. Any AI × 5 years OR

therapy initiation 2. Tamoxifen × 5 years OR

3. Tamoxifen × 2–3 years then AI to complete a total of 5 years OR

4. Tamoxifen × 4–6 years then an AI for 5 additional years

AI, aromatase inhibitor; LH-RH, luteinizing hormone–releasing hormone.

Source: National Comprehensive Cancer Network. Clinical practice guidelines in oncology. Breast Cancer. v2. http://www.nccn.org. Accessed April 22, 2011.

2207Breast Cancer Chapter 93

METASTATIC BREAST CANCER

Treatment

CASE 93-4

QUESTION 1: T.R. is a 65-year-old, postmenopausal woman

diagnosed with breast cancer at the age of 48 years. At

the time of diagnosis she was premenopausal. She underwent surgery with a modified radical mastectomy and was

found to have a 1.5-cm invasive ductal carcinoma of the

right breast. She had two of ten lymph nodes positive.

Her breast cancer was ER-positive, PR-positive, and HER2-

negative. T.R. went on to complete adjuvant chemotherapy

with AC therapy for four cycles followed by weekly paclitaxel for 12 weeks. After completion of her chemotherapy,

she received 5 years of tamoxifen therapy. Ten years after

completing her therapy, she experiences pain in her right

arm and rib cage. A bone scan revealed metastatic breast

cancer. What would be an appropriate treatment regimen

for T.R. at this time?

Early-stage breast cancer is curable. However, if a patient

develops metastatic disease, the goal of treatment shifts from cure

to palliation and stabilization of disease. Treatment is offered to

improve quality of life and alleviate symptoms from treatment or

disease. The mean survival time after diagnosis of metastatic disease is approximately 2 to 4 years; however, this can range from

months to many years depending on the site of the metastases.63

The choice of therapy is based on the site of disease and other

factors that help guide therapy such as ER/PR status. Endocrine

therapy is more likely to be effective in patients with bone-only

disease whereas chemotherapy may be used when there is visceral disease (i.e., liver or lung). Patients with organ involvement

tend to have more rapidly growing disease that generally requires

therapy with a quicker onset of action such as chemotherapy.18

Common sites of metastases include liver, lung, brain, bone, and

lymph nodes.

In addition to systemic therapy (chemotherapy and/or hormonal therapy), the clinician needs to determine whether or not

local therapy (such as radiation or surgery) would be appropriate for a patient. Radiation therapy can be used to target painful

bone metastases, to prevent further tumor growth, and to relieve

pain. Surgery may be performed on bones with impending fractures, spinal cord compression, or brain metastases for palliation.

These modalities of treatment only affect the local site of disease,

so a combination of local and systemic therapy would need to be

administered to fully treat the patient. Chemotherapy generally

offers a much quicker onset of action compared to hormonal

therapy. If a patient is experiencing worsening symptoms such as

shortness of breath due to lung metastases or increased abdominal pain due to liver metastases, the use of chemotherapy may be

preferred over hormonal therapy.64 Disease recurrence greater

than 5 years after diagnosis illustrates a more indolent-growing

disease and is a favorable prognostic factor. Tumors with ER/PRpositive characteristics would also be considered a good prognostic factor. Once therapy is initiated, response to therapy should

be monitored periodically. Tumor markers such as CA.27.29 and

CA.15.3 are commonly monitored in metastatic breast cancer.

In addition, radiologic evaluation of disease progression (such

as a CT scan of the chest, abdomen, and pelvis or bone scan

depending on the sites of disease) would be conducted. A clinical examination in combination with radiologic tests and tumor

markers are assessed to determine response to therapy. Based on

T.R.’s metastatic bone disease and ER/PR-positive tumor characteristics, the use of hormonal therapy would be the most appropriate agent to initiate. T.R. received tamoxifen therapy in the

adjuvant setting. Because she progressed after taking tamoxifen

therapy, this would not be reinitiated. An AI would be started

because she is postmenopausal and should be continued until

there is evidence of progression of disease via radiologic findings

or increases in tumor markers.

CASE 93-4, QUESTION 2: T.R. is started on anastrozole

1 mg orally daily. What are the other hormonal agents that

can be used in the treatment of metastatic breast cancer?

Hormonal therapy in the metastatic setting can provide long

progressionfree survival in patients. If the patient responds for a

long period of time, the likelihood of response to another hormonal agent is high.64 A patient may take multiple hormonal

therapies before ever having to receive chemotherapy. As before,

the decision regarding which hormonal agent to use is based

on one’s menopausal status. If the patient is premenopausal

the options include tamoxifen and LH-RH agonists; however,

if the patient has received these agents in the adjuvant setting,

they would not be used again in the metastatic setting. Aromatase inhibitors are indicated for use in first-line therapy in

the metastatic setting. If an AI is chosen as the first-line agent

in the metastatic setting, use of another AI after progression

would include one from another category (i.e., nonsteroidal vs.

steroidal AI). For example, if anastrozole was used as first-line

therapy for metastatic disease, then when the patient progresses,

exemestane can be used.

Many other hormonal agents are available for use. The pure

antiestrogen, fulvestrant, is the only drug in a unique category

of agents. It exerts its mechanism via binding and blocking of the

estrogen receptor and downregulates the number of estrogen

receptors. Fulvestrant is administered as an intramuscular injection and is dosed 250 mg once a month. It is approved for use after

failure of tamoxifen therapy in the metastatic setting.65 This is an

alternative for patients with compliance issues due to its oncemonthly dosing. Other hormonal agents used in metastatic disease are megestrol acetate, progestins, and high-dose estrogens

(higher doses have been found to inhibit cancer cell growth).

These agents were used routinely before the approval of AIs.

Now they are reserved for use after multiple hormonal therapy

failures due to the toxicities associated with these therapies such

as weight gain, vaginal bleeding, and thromboembolic events.60

T.R. was started on anastrozole therapy. She could have been

initiated on any of the AIs. If her disease progresses, options

include sequential exemestane, then fulvestrant, and then other

agents such as megestrol acetate, high-dose estrogens, or androgens. The goal is to continue T.R. on multiple lines of hormonal therapy (as long as she is responding) before administering

chemotherapy.

Prevention of Skeletal Events

CASE 93-4, QUESTION 3: In addition to anastrozole therapy, what other supportive care medicines should be added

to T.R.’s regimen?

Patients with bone metastases are commonly treated with

bisphosphonate therapy to decrease the risk of skeletal-related

events (i.e., pathologic fractures, spinal cord compression, need

for surgery, or radiation to the bone). Bisphosphonates act by

inhibiting bone resorption. This ultimately will halt osteoclastic

activity leading to stabilization of bony involvement, prevention

of fractures, and reduction in calcium levels.66,67 Bisphosphonates used are pamidronate 90 mg intravenously (IV) for 2 hours

and zolendronic acid 4 mg IV for 15 minutes. Both of these can be

administered once a month. Bisphosphonates are typically well

tolerated although they may cause nausea, increased bone pain,

2208Section 17 Neoplastic Disorders

and fever. Reduced doses should be used in patients with underlying renal dysfunction. A more well-known but uncommon side

effect is osteonecrosis of the jaw.68 The mechanism by which

this occurs is not fully understood, but prevention is critical. If

dental extractions or surgery is needed, patients should not be

initiated on bisphosphonate therapy until these procedures are

completed. If these procedures are required after initiation of

therapy, an oral maxillofacial surgeon should be consulted.

A recently approved agent for use of prevention of skeletal

related events in solid tumors is the humanized monoclonal

antibody denosumab. This therapy offers a unique mechanism

of action targeted against RANK ligand, which is a mediator

in osteoclast activity. Inhibition of osteoclastic activity by denosumab reduces bone pathology in osseous metastases. Denosumab has been compared prospectively with zolendronic acid

in metastatic breast cancer patients and demonstrated significant

delays in and prevention of skeletal-related events.69 Denosumab

is administered as a subcutaneous injection and is given once a

month. It has similar toxicities to zolendronic acid and the dose

does not require adjustments for declining renal function. Denosumab has been added to the American Society of Clinical Oncology guidelines for the prevention of skeletal events in metastatic

breast cancer and other solid tumors.70 T.R. can start on bisphosphonate therapy with zolendronic acid 4 mg IV once a month

to help prevent skeletal-related events.

Progression of Disease

CASE 93-4, QUESTION 4: T.R. has a long progressionfree

survival on hormonal therapy. Over the course of 4 years,

she progresses on sequential anastrozole, then fulvestrant,

then exemestane, and then finally megestrol acetate. Each

time she has progressed, the progressionfree interval has

shortened. Follow-up staging tests reveal new liver lesions

measuring 1 cm × 1 cm and 2 cm × 1 cm. A CT scan of

the chest was negative. She is not currently experiencing

any symptoms of her disease. What should the treatment

course include now that T.R. is progressing on hormonal

therapy?

Because T.R. has progressed through multiple lines of hormonal therapy and the progressionfree interval has shortened

with each treatment course, chemotherapy would now likely

be the best option. Patients with a good performance status, little previous treatment, prolonged progressionfree intervals, and

limited metastatic disease are more likely to respond to further

treatment with chemotherapy.64 Chemotherapy is continued as

long as the person is receiving benefit and is tolerating toxicities

associated with treatment. If the disease progresses or the toxicities become intolerable, therapy should be changed or stopped.

Patients experiencing toxicities may be placed on chemotherapy

holiday until toxicities are resolved or until therapy is tolerable.

In the metastatic setting, the goal of therapy is stabilization of disease and palliation of symptoms. This is considered

when deciding what chemotherapy regimen to use. Sequential

(single agent) versus combination chemotherapy should be discussed. Combination chemotherapy is generally associated with

more toxicities than sequential; however, it provides improved

response rates.71 Patients with substantial symptoms from their

disease may initially be given combination therapy to rapidly

shrink the tumor. Combination therapies that have demonstrated

improvements in survival are docetaxel and capecitabine, paclitaxel and gemcitabine, and doxorubicin and paclitaxel. Based on

T.R.’s lack of symptoms, sequential therapy would be the best

option for her at this time. This would offer her less toxicity and

reserve other chemotherapeutic agents for the future.

TABLE 93-7

Commonly Used Chemotherapy Agents in the

Metastatic Setting

Sequential or single agent Doxorubicin, epirubicin

Liposomal doxorubicin, paclitaxel

Docetaxel, capecitabine

Vinorelbine, gemcitabine

Albumin-bound paclitaxel, eribulin

Combination chemotherapy FAC/CAF, FEC

AC EC

Doxorubicin/docetaxel CMF

Doxorubicin/paclitaxel, GT

Docetaxel/capecitabine

Ixabepilone/capecitabine

Single-agent chemotherapy +

trastuzumab

Docetaxel/trastuzumab TCH

Vinorelbine/trastuzumab

capecitabine/trastuzumab

If previously received

trastuzumab

Lapatinib/capecitabine

Trastuzumab + other first-line

agents

Trastuzumab/capecitabine

Trastuzumab/lapatinib

Single-agent therapy used

after failing standard

options listed here

Cyclophosphamide mitoxantrone

Cisplatin etoposide (oral)

Vinblastine fluorouracil

(continuous infusion)

Ixabepilone

A, doxorubicin; C, cyclophosphamide; E, epirubicin; F, fluorouracil; G,

gemcitabine; H, trastuzumab; M, methotrexate; T, paclitaxel.

Source: National Comprehensive Cancer Network. Clinical practice guidelines

in oncology. Breast Cancer. v2. http://www.nccn.org. Accessed April 22, 2011.

Chemotherapy selection is also based on the therapy received

in the adjuvant setting. Most individuals today will have received

an anthracycline and taxane chemotherapy. If the patient’s disease

recurs quickly after adjuvant therapy, the disease is considered

resistant to that treatment and different agents should be selected.

If a patient receives adjuvant paclitaxel and progresses on therapy,

there are data to support the use of docetaxel in the treatment of

metastatic disease because of the lack of cross-resistance between

taxanes.72

Previous toxicity is also considered when selecting therapy.

In patients with pre-existing neuropathies either from diabetes

or chemotherapy, taxanes may not be an appropriate choice

because these agents can also cause neuropathy. Additionally,

capecitabine may be chosen over intravenous chemotherapy

because this agent is administered orally. Table 93-7 provides

a list of commonly used agents in the metastatic setting. Clinical

trials are always an option for patients if they have a good performance status. Many clinical trials are available and should be

discussed with the patient if clinical trials are possible and available. Because T.R. has received an anthracycline and taxane agent

in the adjuvant setting, an agent such as capecitabine would be

an appropriate choice. This is an oral agent and also has the indication for first-line treatment of metastatic disease after failure

of anthracycline and taxane chemotherapy.

Biologic and Other Targeted Therapies

CASE 93-4, QUESTION 5: Would T.R. be a candidate for any

biologic therapy for the treatment of her metastatic breast

cancer?

Trastuzumab revolutionized the treatment of metastatic,

HER2-positive breast cancer. Now, other biologic therapies are

2209Breast Cancer Chapter 93

used in the metastatic setting. Trastuzumab is a fully humanized

monoclonal antibody that binds to the extracellular HER2 receptor and works via antigen dependent cellular cytotoxicity. When

chemotherapy alone was compared with chemotherapy plus

trastuzumab in HER2-positive, metastatic breast cancer, the addition of trastuzumab therapy significantly increased survival.39

This was the first study of its kind using biologic therapy

and demonstrating survival benefit in metastatic breast cancer.

Current practice is to continue the trastuzumab in patients who

progress on a chemotherapy regimen but switch to an alternative chemotherapy agent. Because T.R. does not have HER2-

positive breast cancer, therapy with trastuzumab would not be

warranted. Trastuzumab resistance can develop and numerous

studies are underway to identify new agents that may overcome

this resistance pattern.

Lapatinib is an oral tyrosine kinase inhibitor (small molecule)

that inhibits both the activity of HER2 and the epidermal growth

factor receptor. Lapatinib received approval based on a study

in which capecitabine was compared with capecitabine plus

lapatinib.73 This trial included patients whose disease had progressed during or after an anthracycline, taxane, and trastuzumab

therapy. Time to progression was statistically significantly better

with the combination therapy compared to capecitabine alone

(HR, 0.46; 95% confidence interval, 0.34–0.71; p <0.001).

After preclinical testing demonstrated synergistic effects of

lapatinib and trastuzumab together, the combination was studied

in patients with trastuzumab-refractory disease.74 The combination provided better progressionfree survival and clinical benefit

rates versus single-agent lapatinib therapy. Toxicities commonly

associated with lapatinib are diarrhea and rash. Concerns of cardiotoxicity associated with lapatinib have been closely monitored

in these trials. Because one of the mechanisms of lapatinib is

blockade of HER2 (like trastuzumab), there is concern regarding

its cardiotoxicity potential. Currently, data do not demonstrate

an increased risk of cardiac dysfunction with lapatinib; however,

long-term data are needed.75 Lapatinib’s indication includes use

in combination with capecitabine or combined with letrozole

therapy for metastatic breast cancer.

One concern with lapatinib is its inhibition of the cytochrome

P-450 (CYP) 3A4 and 2C8 isoenzymes. Because of this, when a

patient is initiated on therapy, a full review of medications should

occur to ensure no drug–drug interactions. Recommendations

are included in the package insert for use and dosing of lapatinib

with CYP3A4 inhibitors and inducers. With strong inhibitors,

the dose can be decreased to as low as 500 mg orally daily

and with strong inducers the dose can be increased gradually

from 1,250 mg orally daily to up to 4,500 mg orally daily.76 T.R.

would not receive lapatinib in combination with trastuzumab

or capecitabine because she does not have HER2-positive breast

cancer.

Bevacizumab, a recombinant humanized monoclonal antibody, inhibits vascular endothelial growth factor and, ultimately,

angiogenesis. In first-line treatment of metastatic breast cancer,

bevacizumab plus paclitaxel demonstrated significantly better

response rates and time to progression compared with paclitaxel

alone.77 Subsequent trials evaluating the benefit of bevacizumab

in this setting demonstrated similar results with improvements

in progressionfree survival, but showed no difference in overall

survival. Based on these results, the US Food and Drug Administration removed the indication for first-line use of bevacizumab

in combination with paclitaxel.78 Currently, bevacizumab is generally continued in patients who are receiving benefit or who are

on a clinical trial. This would not be an option for T.R. given the

lack of overall survival benefit.

Other unique targeted therapies are being evaluated in

metastatic breast cancer. Poly-ADP-ribose polymerase (PARP)

inhibitors potentially offer unique activity for patients with triple

negative breast cancers (ER/PR/HER2-negative disease). These

tumors are typically refractory to chemotherapy and difficult

to treat. PARP is an enzyme that repairs DNA breaks and is

overexpressed in triple-negative breast cancers. Hence, this class

of investigational inhibitors is expected to enhance the activity for cytotoxic therapies such as DNA-damaging agents. Initial studies have been promising and currently phase III trials are underway to evaluate the antitumor activity of PARP

inhibitors in the metastatic setting.79 Other agents in the pipeline

are mTOR (mammalian target of rapamycin) inhibitors, HSP90

(heat shock protein 90) inhibitors, multitargeted inhibitors of

vascular endothelial growth factor receptor, and platelet-derived

growth factor, and other monoclonal antibodies.80 At this time,

T.R. would be a candidate for a clinical trial with another targeted

therapy or to receive other cytotoxic chemotherapy agents used

in the metastatic setting.

KEY REFERENCES AND WEBSITES

A full list of references for this chapter can be found at

http://thepoint.lww.com/AT10e. Below are the key references

and website for this chapter, with the corresponding reference

number in this chapter found in parentheses after the reference.

Key References

Briest S, Stearns V. Chemotherapeutic strategies for advanced

breast cancer. Oncology (Williston Park). 2007;21:1325. (64)

Burnstein HJ et al. American Society of Clinical Oncology Clinical practice guideline: update on adjuvant endocrine therapy

for women with hormone receptor-positive breast cancer. J Clin

Oncol. 2010;28:3784. (61)

Carlson RW et al. Invasive breast cancer. J Natl Compr Canc Netw.

2011;9:136. (10)

Early Breast Cancer Trialists’ Collaborative Group (EBCTCG).

Effects of chemotherapy and hormonal therapy for early breast

cancer on recurrence and 15-year survival: an overview of the

randomised trials. Lancet. 2005;365:1687. (35)

Fisher B et al. Tamoxifen for prevention of breast cancer: report

of the National Surgical Adjuvant Breast and Bowel Project P-1

study. J Natl Cancer Inst. 1998;90:1371. (4)

Jatoi I, Proschan MA. Randomized trials of breast conserving

therapy versus mastectomy for primary breast cancer: a pooled

analysis of updated results. Am J Clin Oncol. 2005;28:289. (28)

Lyman GH et al. American Society of Clinical Oncology guideline recommendations for sentinel lymph node biopsy in earlystage breast cancer. J Clin Oncol. 2005;23:7703. (34)

Mayer EL, Burstein HJ. Chemotherapy for metastatic breast cancer. Hematol Oncol Clin North Am. 2007;21:257. (71)

Romond EH et al. Trastuzumab plus adjuvant chemotherapy for operable HER2-positive breast cancer. N Engl J Med.

2005;353:1673. (40)

Slamon DJ et al. Use of chemotherapy plus a monoclonal antibody against HER2 for metastatic breast cancer that overexpresses HER2. N Engl J Med. 2001;344:783. (39)

Tan SH, Wolff AC. Treatment of metastatic breast cancer:

chemotherapy. In: Harris JR et al, eds.Diseases of the Breast. 4th ed.

Philadelphia, PA: Lippincott Williams & Wilkins; 2009:877. (63)

Key Websites

National Comprehensive Cancer Network. Clinical practice

guidelines in oncology. Breast Cancer. v2. http://www.nccn.

org. Accessed April 22, 2011. (29)

94 Lung Cancer

Mark N. Kirstein, Robert A. Kratzke, and Arkadiusz Z. Dudek

CORE PRINCIPLES

CHAPTER CASES

1 Non–small cell lung cancer (NSCLC) and small cell lung cancer (SCLC) together

account for more cancer-related deaths than any other malignancy for both men

and women. Smoking is the biggest risk factor, and is proportional to the number

of pack years. For former smokers, the risk for developing the disease decreases

over time, after smoking cessation.

Case 94-1 (Question 1)

2 Chances for survival are increased for those whose disease is detected early.

However, there are no effective screening methods for detecting early stage

disease in asymptomatic patients, although results from the National Lung

Screening Trial appear promising for improved survival.

Case 94-1 (Question 1)

3 The initial signs and symptoms vary according to location and stage of the disease.

Many patients are asymptomatic upon initial diagnosis, or signs and symptoms

may be masked by other concurrent conditions such as chronic obstructive

pulmonary disease.

Case 94-1 (Question 2),

Case 94-2 (Question 1)

4 Surgery, radiotherapy, and chemotherapy are all modalities used in the treatment

of NSCLC. Treatment decisions are individualized according to disease stage,

tumor histology (e.g., adenocarcinoma, squamous), presence or absence of

molecular marker mutations (e.g., epidermal growth factor receptor), performance

status, co-morbidities, and patient preference.

Case 94-1 (Questions 2, 3),

Case 94-2 (Questions 1–6)

5 SCLC tumors generally have a higher proliferation rate than NSCLC tumors. Hence,

chemotherapy and radiotherapy are the primary treatments. SCLC tumors tend to

grow more centrally than NSCLC tumors; therefore, surgical resection is usually not

performed.

Case 94-3 (Questions 3, 4)

6 Most NSCLC cytotoxic chemotherapy regimens are cisplatin-based or carboplatinbased doublets, which are given for 4 to 6 cycles. Targeted therapies are currently

limited to the treatment of some late-stage inoperable NSCLCs, but their use is

under investigation for patients diagnosed with earlier stages of the disease.

Case 94-1 (Question 4),

Case 94-2 (Questions 1–3)

7 Most SCLC cytotoxic chemotherapy regimens are cisplatin-based or

carboplatin-based doublets in combination with etoposide or sometimes

irinotecan if extensive stage disease. Investigations have not shown the utility for

targeted agents in treating this disease.

Case 94-3 (Questions 3, 4)

LUNG CANCER

Lung cancers may be referred to as non–small cell lung cancer

(NSCLC) or small cell lung cancer (SCLC), and although there

are many similarities between these two, treatments often differ.

Approximately 85% of lung cancers are classified as NSCLC and

the remaining are classified as SCLC. This chapter will initially

focus on the presentation, diagnosis, and treatment of NSCLC,

followed by a shorter section that describes SCLC.