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