Bethesda Handbook of Clinical Oncology, 2nd Edition

Thorax

2

Non–Small Cell Lung Cancer

Anne M. Horgan

Oscar S. Breathnach

Department of Medicine, Cork University Hospital, Cork, Ireland

Primary carcinoma of the lung was an uncommon cancer until the 1930s. Since then, there has been a dramatic increase in the incidence of lung cancer that has not yet abated. Lung cancer is now the most common cause of cancer mortality in both men and women, having surpassed breast cancer as the leading cause of cancer deaths in women in the mid-1980s.

  • In 2003, approximately 171,900 new cases were expected, with 157,200 resultant deaths.
  • Only 13% of all patients with lung cancer are expected to live for 5 years.
  • Survival rates have been stationary over the last two decades despite new therapeutic agents.
  • The long period between the initial exposure to tobacco carcinogens and the development of clinical lung cancer suggests that multiple steps are required to express the malignant phenotype.
  • Prevention of smoking will have the greatest impact on curbing lung cancer and on ensuring prolonged survival.

RISK FACTORS

  • Smoking:As many as 90% of patients with lung cancer have a history of smoking. The epidemic of lung cancer in the 21st century reflects the birth cohort patterns of active cigarette smoking. However, among the general population of individuals as old as 74 years of age, the cumulative probability of developing lung cancer in those who smoke one or more packs of cigarettes per day is 10% to 15%. Ninety percent of regular smokers aged 30 to 39 years would have smoked their first cigarette before the age of 18, and 70% of them would have been regular smokers by 18 years. Almost none of the regular smokers would have started after the age of 20. Recent evidence suggests that children and young adults are more prone to DNA damage from smoke exposure than older adults are.

The risk of lung cancer after smoking cessation appears to be related to the level of consumption. The risk in persons who had smoked 1 to 20 cigarettes per day falls by 1.6-fold after 16 years of smoking cessation. In those persons who had smoked 21 or more cigarettes per day, the risk of developing lung cancer after 16 years of smoking cessation remains four times greater than that of a person who has never smoked. Of concern is the fact that almost 50% of all high school children in the United States use some form of tobacco. National cigarette smoking rates for high school children have recently risen by 32% (from 1991 to 1997), with little change in the prevalence of smoking among adults (47 million people). New adolescent smokers are replacing those smokers who have died from cancer or other smoking-related causes, and those who have quit. These trends, if left unchecked, will increase the future occurrences of lung cancer.

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According to the U.S. Environmental Protection Agency (EPA), approximately 3,000 nonsmoking adults die from lung cancer each year because of breathing the smoke of others' cigarettes. Analysis shows that sidestream smoke emitted from a smoldering cigarette between puffs contains virtually all the carcinogenic compounds that have been identified in the mainstream smoke that is inhaled by smokers. The risk of dying from lung cancer is 30% higher for a nonsmoker living with a smoker compared to a nonsmoker living with a nonsmoker.

  • Occupational:Exposure to agents such as arsenic, asbestos, beryllium, chloromethylethers, chromium, hydrocarbons, mustard gas, nickel, and radiation (including radon) have been linked to the development of lung cancer. Asbestos exposure in smokers is associated with a synergistic risk for developing bronchogenic carcinoma. Radon exposure in underground mines with poor ventilation is associated with an increased risk for developing lung cancer.
  • Residential:There is no conclusive evidence to state that residential radon exposure significantly contributes to lung cancer, although inferences from the studies on occupational exposure would suggest such a link. Case–control studies have yielded conflicting reports. The exact risk of indoor exposure to radon remains uncertain.

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  • Dietary:Two recent studies have suggested an adverse effect of supplemental β-carotene and retinol administration on the incidence of lung cancer and overall mortality in high-risk individuals.
  • Familial/genetic:The contributions of hereditary factors to the development of lung cancer are probably less well understood than those of the common forms of solid tumors in humans. The proof that the familial occurrence of lung cancer has a genetic basis is complicated by the central role of cigarette smoking in causing this form of cancer. A large number of families will be required for nonclassical linkage analysis, such as segregation analyses and sib-pair linkage approaches, to define the acquired loci involved for inherited forms of lung cancer.

Histologically identifiable preneoplastic lesions found in the respiratory epithelium of lung cancer patients and smokers include hyperplasia, dysplasia, and carcinoma in situ. Loss of heterozygosity (LOH) is common in lung cancer. 3p loss has been shown to occur early in non–small cell lung cancer (NSCLC) and is detectable in hyperplastic, precancerous bronchial lesions. K-ras mutations are detectable in the later carcinoma in situ stage. There is conflicting evidence about the timed appearance of microsatellite deletions.Table 2.1 outlines a summary of these genetic changes in NSCLC.

TABLE 2.1. Suggested Therapeutic Chemotherapy Regimens

Regimen

Dose

Cycle duration

AUC, area under the curve; i.v., intravenous.

Carboplatin–Paclitaxel

   Carboplatin

AUC 5 i.v. d 1

q21d

   Paclitaxel

175–225 mg/m2 i.v. d 1

Carboplatin–Docetaxel

Carboplatin

AUC 5 i.v. d 1

q21d

Docetaxel

75 mg/m2 i.v. d 1

Gemcitabine–Carboplatin

   Gemcitabine

1,000 mg/m2 i.v. d 1, 8

q21d

   Carboplatin

AUC 5 i.v. d 1 only

Vinorelbine–Cisplatin

   Vinorelbine

30 mg/m2 i.v. d 1, 8

q21d

   Cisplatin

80 mg/m2 i.v. d 1 only

   Docetaxel

75 mg/m2 i.v. d 1

q21d

   Gemcitabine

1250 mg/m2 i.v. d 1,8

q21d

   Vinorelbine

30 mg/m2 i.v. d 1,8

q21d

Genetic mutations in non–small cell lung cancers

Recessive oncogene (tumor suppressor gene) and allelotype abnormalities

NSCLC

   Rb mutations (13q14)

~20%

   p16/CDKN2 mutations (9p21)

~50%

   p53 mutations (17p13)

>50%

   3p deletions

>80%

   Microsatellite alterations

Present

Dominant oncogene abnormalities

   ras mutations

~30%

   Her-2/neu overexpression

~30%

   myc family amplification

>50%

   bcl-2 overexpression

>50%

   Telomerase expression

~90%

PATHOLOGY

Table 2.2 outlines the World Health Organization WHO classification of NSCLC. Adenocarcinoma is the most frequently diagnosed form of NSCLC in both men and women, having replaced squamous cell carcinoma. The reason for this is unclear, but the following hypothesis has been proposed. Increased strength and frequency of inhalation is required to maintain nicotine levels in chronic smokers who smoke low-tar, filtered cigarettes. Low-tar cigarettes are less irritating to the proximal bronchial tree, thereby allowing deeper inhalation, which permits the carcinogens in the inhaled vapor to penetrate deeply.

TABLE 2.2. WHO Classification of Non–small Cell Lung Cancer

Histologic types of NSCLC: Modified WHO classification

NSCLC, non–small cell lung cancer; WHO, World Health Organization.

1. Squamous cell carcinoma

1. Epidermoid

2. Spindle cell variant

2. Adenocarcinoma

1. Acinar

2. Papillary

3. Bronchioloalveolar

4. Solid carcinoma with mucin

3. Large cell

1. Giant cell

2. Clear cell

4. Adenosquamous

Bronchioloalveolar carcinoma, although currently classified as a subtype of adenocarcinoma, demonstrates clinical features, suggesting that it represents a distinct histologic form of NSCLC. These features are manifested as a greater tendency for occurrence in women and nonsmokers; the development of bilateral, multifocal pulmonary involvement, with a lesser tendency for extrathoracic metastases; and a better survival rate than a similar stage of NSCLC.

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SYMPTOMS AND SIGNS OF LUNG CANCER

  • A minority of patients present with an asymptomatic lesion that is discovered incidentally on a chest radiograph.
  • Most lung cancers are discovered because of the development of a new symptom or worsening of a clinical symptom or sign.
  • No set of signs or symptoms are pathognomonic of lung cancer, and so the diagnosis is usually delayed.
  • Clinical signs and symptoms of lung cancer may be divided into four categories: the symptoms (a) resulting from local tumor growth, (b) resulting from regional spread, (c) caused by distant metastases, and (d) related to paraneoplastic syndromes. Table 2.3 outlines the characteristic symptoms or signs.

TABLE 2.3. Symptoms and Signs of Lung Cancer

·         Primary Disease
   Central or endobronchial tumor growth
      Cough
      Sputum production
      Hemoptysis
      Dyspnea
      Wheeze (classically unilateral)
      Stridor
      Pneumonitis, with fever and productive cough (secondary to obstruction)
   Peripheral tumor growth
      Pain, from pleural or chest wall involvement
      Cough
      Dyspnea
      Pneumonitis

·         Regional Involvement (Either Direct or Metastatic Spread)
      Hoarseness (recurrent laryngeal nerve paralysis)
      Tracheal obstruction
      Dysphagia (esophageal compression)
      Dyspnea (pleural effusion, tracheal or bronchial obstruction, pericardial effusion, phrenic nerve palsy, lymphatic infiltration, and superior vena cava obstruction)
      Horner syndrome (sympathetic nerve palsy)

·         Metastatic Involvement (Common Sites)
   Bone involvement
      Pain, exacerbated by movement or weight bearing; often worse at night
      Fracture
   Liver metastases
      Right hypochondrial pain
      Icterus
      Altered mentation
   Brain metastases
      Altered mental status
      Seizures
      Motor and sensory deficits

·         Paraneoplastic Syndromes
      Clubbing
      Hypertrophic pulmonary osteoarthropathy
      Hypercalcemia
      Dermatomyositis
      Eaton-Lambert syndrome
      Hypercoagulable state
      Gynecomastia

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MAKING THE DIAGNOSIS OR PLANNING THERAPY

  • Once a suspected tumor is identified, it is then necessary to obtain a histologic diagnosis and accurately stage the tumor.
  • The stage of the disease provides an index of the prognosis and allows selection of an appropriate therapeutic approach.
  • In some cases, tissue diagnosis may not be established until the time of definitive surgical resection.
  • Because 30% to 50% of patients have metastatic disease at the time of presentation, clues to the clinical stage will often be evident from the patient's clinical history and from his or her physical examination.
  • Sputum cytology is the noninvasive technique used for the diagnosis of NSCLC. It is most sensitive for centrally located tumors.
  • Other noninvasive methods of tumor evaluation include chest radiographs, computerized tomography scan (CT scan) of chest (including the liver and adrenals), magnetic resonance imaging (MRI) (particularly for superior sulcus tumors), and positron emission tomography (PET) scanning. To evaluate the potentially involved sites as directed by a patient's symptoms, plain radiographs, radionucleotide bone scans, and CT scan of the brain are often useful. Apart from sputum cytology, these tests can only infer the presence of cancer.
  • Invasive techniques are usually required to obtain the tissue sample(s) to make a conclusive histologic diagnosis. These include bronchoscopy (with brushings and washings), transthoracic bronchial biopsy, CT scan–guided transthoracic biopsy, thoracocentesis (for pleural effusions), and mediastinoscopy with mediastinal node biopsy.
  • CT scan and MRI can provide information about hilar and mediastinal nodal involvement of the tumor. Size is the criterion used to distinguish normal from abnormal nodes, with a short axis nodal diameter of 1 cm being typically used as the upper limit of normal. However, nodal enlargement may relate to hyperplastic reactive nodes, particularly in patients with postobstructive pneumonia. The accuracy of CT scan and MRI for detecting metastatic hilar (N1) or mediastinal disease is only 62% to 68% and 68% to 74%, respectively.
  • Patients with clinical stage I to III disease with a central tumor or peripheral tumors greater than 2 cm should have a mediastinoscopy with mediastinal node biopsy, particularly if the nodes are greater than 1 cm in diameter on radiologic evaluation.
  • Recent studies have shown that 2-[F-18] fluoro-D-glucose–positron emission tomography (FDG–PET) imaging is more accurate in detecting lymph node metastases. Combination chest CT scan and PET scan may replace the need for mediastinoscopy and help avoid unnecessary thoracotomies.
  • Plain films, CT scan, and MRI findings are often suggestive of chest wall or mediastinal invasion but may not be definitive in confirming the same unless a chest wall mass, rib destruction, or gross encasement of the mediastinal structures is present. An advantage of MRI in evaluating chest invasion is its superior soft-tissue contrast resolution and multiplanar capability. The sensitivity (63% to 90%) and specificity (84% to 86%) of MRI in diagnosing chest wall invasion is similar to that of CT scan. However, MRI is the technique of choice in evaluating superior sulcus tumors, as CT scan is limited by axial plane and streak artifact from the shoulders.
  • Common sites of metastatic disease from NSCLC are lymph nodes, brain, bone, liver, and adrenal glands. Routine radiologic evaluation of occult metastases in the absence of clinical or laboratory findings remains controversial and is not generally recommended. However, if a person with known NSCLC develops bone pain, it is most important to assess the weight-bearing bones to avoid the development of pathologic fractures.
  • Persons with clinically apparent resectable disease commonly have a metastatic work-up, including CT scan of the brain and bone, to avoid potentially unnecessary surgical intervention (see Table 2.4).

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  • The TNM staging system followed earlier was revised in June 1997 (see Table 2.5). The revised staging divides stage I and stage II into A and B categories and modifies stage IIIA to more accurately represent the prognostic implications of the anatomic extent of disease.
  • The T1 N0 M0, T2 N0 M0, and T1 N1 M0 anatomic subsets are designated as separate entities and the T3 N0 M0 category is placed in stage IIB to more accurately reflect differences in clinical outcome.
  • Stage IIIB and IV categories have remained unchanged, with two exceptions: satellite tumor nodule(s) in the primary-tumor lobe are designated T4, and separate metastatic tumor nodule(s) in the ipsilateral nonprimary-tumor lobe(s) of the lung are designated M1. However, it is still difficult to separate a single satellite or metastatic nodule in the non–tumor-bearing lobe from a synchronous primary lung cancer unless they are of different histologic type.
  • Despite different clinical outcomes, no distinction has been made between stage IIIB disease with and without malignant effusion.
  • Tables 2.5, 2.6, and 2.7 provide TNM descriptions and stages, the prognosis per clinical and pathologic stage, and the description of mediastinal nodal status, respectively.

TABLE 2.4. Imaging Options

Local disease evaluation

Metastatic disease evaluation

CT scan, computerized tomography scan; MRI, magnetic resonance imaging; PET, positron emission tomography.

Plain radiographs

Bone: plain films and bone scan

CT scan of chest (including adrenals and liver)

Brain: CT scan or MRI

MRI chest

Liver: CT scan (part of the CT scan of chest)

PET

Spinal cord: MRI

PET: optional

TABLE 2.5. Staging System for Non–small Cell Lung Cancer

Lung cancer staging: TNM classification

From Mountain CF. Revisions in the international system for staging lung cancer. Chest 1997; 111(6): 1710-1717, with permission.

TX

Primary tumor cannot be assessed, or tumor is proven by the presence of malignant cells in sputum or bronchial washings but not visualized by imaging or bronchoscopy

T0

No evidence of primary tumor

Tis

Carcinoma in situ

T1

Primary tumor <3 cm in greatest dimension, surrounded by lung or visceral pleura, without bronchoscopic evidence of invasion more proximal than in the lobar bronchus (i.e., not in the main bronchus)

T2

Tumor with any of the following features:

   >3 cm in greatest dimension

   Involves main bronchus, ≥2 cm from carina

   Invades the visceral pleura

   Associated with atelectasis or obstructive pneumonitis that extends to the hilar region but does not involve the entire lung

T3

Tumor of any size that directly invades any of the following:

   Chest wall (including superior sulcus tumors)

   Diaphragm

   Mediastinal pleura

   Parietal pericardium

   Involves main bronchus <2 cm from the carina

   Associated atelectasis or obstructive pneumonitis of the whole lung

T4

Tumor of any size that directly invades the following:

   Mediastinum, trachea or carina, and esophagus

   Vertebral body, heart, and great vessels

   Malignant pleural or pericardial effusion

   Satellite tumor within the ipsilateral primary-tumor lobe of the lung

N1

Ipsilateral: peribronchial and/or hilar lymph nodes,

intrapulmonary nodes by direct extension of primary tumor

N2

Ipsilateral: mediastinal and/or subcarinal lymph nodes

N3

Contralateral: mediastinal, hilar, scalene, and supraclavicular lymph nodes

Ipsilateral: scalene and supraclavicular lymph nodes

M1

Presence of distant metastases.

Stage I

T1–T2

N0

 

M0

Stage II

T1–T2,

N1(T1–2)

T3 N0

M0

Stage IIIA

T3 N1 M0,

N2 (T1–T3)

 

M0

Stage IIIB

N3 (T1–T4)

T4 (N0–N3)

 

M0

Stage IV

Any T

Any N

 

M1

TABLE 2.6. Prognosis for Clinical and Pathologic Stage of Disease

Stage

 

Clinical stage 5-year survival (%)

Pathologic stage 5-year survival (%)

From Mountain CF. Revisions in the international system for staging lung cancer. Chest 1997; 111(6): 1710-1717, with permission.

T1 N0 M0

(IA)

61

67

T2 N0 M0

(IB)

38

57

T1 N1 M0

(IIA)

34

55

T2 N1 M0

(IIB)

24

39

T3 N0 M0

(IIB)

22

38

T3 N1 M0

(IIIA)

9

25

T1–3 N2 M0

(IIIA)

13

23

T4 N0–2 M0

(IIIB)

7

T1–4 N3 M0

(IIIB)

3

T1–4 N0–3 M1

(IV)

1

TABLE 2.7. Nodal Stations for Intrapulmonary, Hilar, and Mediastinal Adenopathy

From Mountain CF. Revisions in the international system for staging lung cancer. Chest 1997; 111(6): 1710-1717, with permission.

N2 nodes (lie within the mediastinal pleural envelope)

   Superior mediastinum

1. a. Highest mediastinal nodes

2. b. Upper paratracheal nodes

3. c. Prevascular/Retrotracheal nodes

4. d. Lower paratracheal nodes

   Aortic nodes

1. e. Subaortic nodes (aortopulmonary window)

2. f. Para-aortic nodes (ascending aorta or phrenic)

   Inferior mediastinum

1. g. Subcarinal nodes

2. h. Paraesophageal nodes (below carina)

3. i. Pulmonary ligament nodes

N1 nodes (lie distal to the mediastinal pleural reflection and within the visceral pleura)

1. j. Hilar nodes

2. k. Interlobar nodes

3. l. Lobar nodes

4. m. Segmental nodes

5. n. Subsegmental nodes

Pretreatment Evaluation

It is important that all preexisting medical conditions are evaluated and the required therapeutic interventions instituted to improve the patient's condition. Through selecting appropriate operative candidates, the potential complications in the preoperative period are minimized.

Pulmonary function tests help determine the feasibility of resection and the extent of possible resection. A minimum preresection FEV1(forced expiratory volume in 1 second) of 2 L, 1 L, or 0.6 L is required before considering a pneumonectomy, lobectomy, or segmentectomy, respectively. The FVC (forced vital capacity) should be at least 1.7 to 2 L as a general cutoff for resection candidates. Cigarette smoke acts as an irritant to the bronchial tree, contributing to excess mucus secretion and airway hyperactivity. Patients should be encouraged to stop smoking at least 8 weeks prior to the surgical resection.

Prognostic Features

The patient's performance status (PS) is a key factor in predicting not only the patient's ability to receive therapy but also his or her prognosis. Recognized prognostic factors are

  • Performance status:Patients with PS 3–4 are not considered appropriate candidates for either surgical resection or chemotherapy. Radiation therapy may be appropriate for specific issues, such as relief from bone pain secondary to bone metastases.

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  • Stage of disease:The higher the stage, the worse the prognosis, as outlined in Table 2.6.
  • Weight loss:A documented weight loss of 10% in the 6 months prior to the diagnosis is associated with a poor prognosis.
  • Presence of systemic symptoms:These symptoms usually reflect advanced-stage disease.
  • Histology:Patients with large cell carcinoma, followed by those with adenocarcinoma, are reported as having a poorer prognosis than those with either squamous cell or bronchioloalveolar carcinoma of lung.
  • Sex:Women tend to have a better prognosis than men have.
  • Gene mutations:p53 expression, K-ras mutations at codon 12, and lack of H-ras p21 expression are associated with a poor outcome.

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MANAGEMENT

Early Stage Disease (Stages I and II)

Surgical resection is the treatment of choice in patients with stage I or stage II NSCLC, provided they are medically fit for the procedure. For patients who are medically unfit for surgery, radiation therapy is the treatment of choice. Although no randomized trial has compared these approaches, results from retrospective comparisons favor surgery in terms of long-term survival. However, one must remember that patients who are unfit for surgery, and hence receiving radiation therapy, are also more likely to do less favorably.

A lobectomy is currently the operation of choice in patients with adequate pulmonary reserves, based on results of the Lung Cancer Study Group (LCSG).

The LCSG performed a randomized controlled trial comparing lobectomy to wedge resection in patients with T1 N0 M0 NSCLC.

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  • Local recurrence rate was three times greater for the patients receiving limited resection, although no statistically significant difference was detected in survival.
  • Various authors have reported on the rates of local and distal failure following surgical resection (see Table 2.8).
  • Up to 28% and 47% of patients develop local and distal failure, respectively; therefore, trials of adjuvant chemotherapy and radiation therapy have attempted to address this issue. The major causes of mortality in these patients were distant disease and second primary cancers.
  • Data obtained from the meta-analysis performed by the Non–Small Cell Lung Cancer Collaborative Group included 14 trials comparing surgical resection with or without chemotherapy that involved 4,357 patients with early stage disease. Five of the trials used long-term alkylating agents. Eight more recent trials were cisplatin based, using cyclophosphamide–adriamycin–cisplatin (t= 3), cisplatin–vindesine (t = 3), or cisplatin–adriamycin (t = 2). Alkylating agent–based therapy was associated with a 15% increase in the risk of death (p = 0.005). Cisplatin-based therapy was not associated with a statistically significant survival advantage.
  • The Non–Small Cell Lung Cancer Collaborative Group also assessed data from seven trials comparing surgery with radiation therapy with or without chemotherapy involving 807 patients with early-stage disease. Six of the trials involved cisplatin-based regimens. The overall hazard ratio of 0.98 was not statistically significant.
  • Although neither adjuvant chemotherapy nor radiation therapy can be recommended as the standard of care, patients should be encouraged to participate in clinical trials to evaluate new approaches.
  • Because these patients are at increased risk for second primary tumors or recurrent disease, close follow-up is recommended (see Fig. 2.1).
 

FIG. 2.1. An overview of current approaches in the treatment of patients with non–small cell lung cancer.

TABLE 2.8. Summary of Recurrence Rates Following Surgical Resection in Patients with Early Stage Non–small Cell Lung Cancer

Anatomic failure rates following surgery alone

Author

Stage

No.

Thorax (%)

Distal (%)

Pairolero

T1 N0

170

   6

15

T2 N0

158

   6

23

T1 N1

   18

28

39

Mountain

T3 N0/1

   69

12

25

T1/3 N2

   92

   1

32

Martini

T1 N1

   17

   0

47

T2 N1

   58

14

36

Iascone

T1 N0

   16

19

   6

T2 N0

   20

25

   5

Stage IIIA Disease

The management of patients with stage IIIA disease is difficult. The best treatment is unclear, and the therapeutic approach remains an area of active investigation. Randomized trials and institutional series have sought several different treatment strategies for potentially resectable stage IIIA (N2) disease, including preoperative chemotherapy and radiation therapy, or chemotherapy and radiation therapy without surgery.

  • Surgical resection is the therapy of choice, but it requires an experienced and skilled thoracic surgeon.
  • Patients with clinical (preoperative) N0 or N1 disease but microscopic pathologic (postresection) N2 disease survive longer than patients with clinical N2 disease, with 5-year survival rates of 34% and 9%, respectively.

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  • Neoadjuvant chemotherapy has the theoretical advantage of diminishing nodal involvement, thereby making surgical intervention less difficult, more likely to have an impact on survival, and provide immediate systemic therapy in patients at high risk for distal relapse. However, local treatment is delayed, and the tumor volume, if it does not respond adequately to the chemotherapy, may become unresectable.
  • The continued presence of N2 nodal involvement following neoadjuvant chemotherapy is associated with a grave prognosis.
  • Two prospective randomized phase III trials assessing the role of neoadjuvant chemotherapy showed a statistically significant survival advantage in favor of the chemotherapy arm (see Table 2.9). However, there were a number of potential flaws in these trials. Both trials were

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terminated prematurely in view of the strong statistical significance at the interval evaluation, and so only a limited number of patients were treated per arm in each trial. In one of the trials (Rosell et al.), both arms received radiation therapy after the surgery. There was also stage heterogeneity within the Rosell study, as patients with stage T3 N0 M0 were included who would be considered as having stage II disease under the new staging classification (1). None of the patients in the control arm of this study was alive at 2 years, which was unexpected and did not reflect the usual survival rates of stage IIIA disease. In addition, there were a disproportionate number of patients with K-ras mutations within the control group, potentially biasing the results. This higher proportion of patients with K-ras mutations in the “surgery-alone” arm may have contributed to the poor outcome in this group.

TABLE 2.9. Summary of Selected Phase III Trials in Patients with Stage IIIA Non–small Cell Lung Cancer Comparing Surgical Resection to Neoadjuvant Chemotherapy and Resection Showing a Statistically Significant Difference in Survival

Author

No.

Chemotherapy

Schedule

Median survival

Actuarial survival (%)

CEP, Cyclophosphamide, etoposide, and cisplatin; Surg., surgery; MIC, Mitomycin, ifosphamide, and cisplatin; Postop XRT, postoperative mediastinal radiation therapy.

Roth et al.

26

CEP

CEP–Surg.

64

56 at 3 yr

32

Surg. alone

11

15 at 3 yr

Rosell et al.

30

MIC

MIC–Surg.

26

25 at 2 yr

Postop XRT (50 Gy)

30

Surg. alone

   8

0 at 2 yr

Postop XRT (50 Gy)

Stage IIIB Disease (In Absence of Malignant Pleural Effusions)

  • T4 lesions, bulky multilevel N2, or N3 involvement are not amenable to curative surgical resection. Traditionally, radiation therapy alone was the standard treatment in this setting. However, this was associated with 5-year failure rates of 90% and 50% to 70%, respectively, within the ipsilateral chest and systemically. Chemotherapy was added in an attempt to overcome the high relapse rates and poor outcomes with radiation therapy alone.
  • The most appropriate scheduling of chemotherapy and radiation therapy is still under evaluation, as is the most efficacious fractionation of the radiation therapy.
  • Various options are concurrent, sequential, or alternating schedules. Sequential scheduling aims to avoid the interactions between the two modalities, thereby limiting toxicity. Concurrent scheduling aims to maximize the therapeutic effect from chemosensitization but also results in potentiation of toxicity. Rapidly alternating schedules allow time for recovery from the acute toxicity of each modality.
  • The various forms of radiation fractionation are standard, hyperfractionated, accelerated, continuous hyperfractionated accelerated radiation therapy (CHART), and hypofractionated split-course therapy.
  • Data obtained from the Non–Small Cell Lung Cancer Collaborative Group's meta-analysis included 22 trials with 3,033 patients, in which radical radiation therapy with or without chemotherapy was assessed. Five trials included long-term alkylating agents. Eleven trials (1,780 patients) included cisplatin-based therapy. Chemotherapy showed a significant overall benefit, with a hazard ratio of 0.90 (p= 0.006) and a 10% reduction in the risk of death, which translates into an absolute benefit of 3% at 2 years and 2% at 5 years. Trials using cisplatin-based therapy yielded the strongest evidence for a positive chemotherapy effect, with a hazard ratio of 0.87 (p = 0.005).

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  • Two phase III trials comparing sequential chemoradiation and one phase III trial evaluating concurrent chemoradiation therapy showed statistically significant increases in patient survival compared to radiation therapy alone (see Table 2.10). The chemotherapy regimens tested to date in these settings have been predominantly cisplatin based.
  • The sequential schedule was associated with similar local control in both groups but with lower rates of distal metastases, which may be responsible for the prolonged survival of patients in the combined modality arm of the trials. The concurrent schedule was associated with improved local control with no influence on systemic metastases.
  • A recent phase III study in patients with unresectable stage III NSCLC comparing concurrent and sequential radiation therapy, in association with mitomycin, vindesine, and cisplatin chemotherapy, reported a significantly increased response rate and enhanced median survival duration in favor of the concurrent approach.
  • The role of triple therapy (chemotherapy, radiation therapy, and surgical resection) over combination chemoradiation is under investigation.

TABLE 2.10. Summary of Selected Phase III Trials Showing a Statistically Significant Difference in Survival in Patients with Locally Advanced Non–small Cell Lung Cancera

Selected phase III trials in patients with locally advanced NSCLC (phase III trials showing a statistically significant survival advantage)

 

Survival %

 

No. of patients

Chemotherapy

XRT (Gy)

MST (mo)

1 yr

3 yr

pvalue

XRT, mediastinal radiation therapy; MST, median survival time; PV, cisplatin vinorelbine; VCPC, vindesine lomustine cisplatin cyclophosphamide; P, paclitaxel; NR, not reported; MVC, methotrexate vinblastine cisplatin.
The trials compared sequential or concurrent chemoradiation therapy to radiation alone, and sequential chemoradiation to concurrent therapy.

Sequential therapy

   Dillman et al.

   78

PV

60

13.8

55

23

0.007

   77

60

   9.7

40

11

   Le Chevalier et al.

176

VCPC

65

12.0

50

11

0.02

177

65

10.0

41

   5

Concurrent therapy

   Schaake-Koning et al.

107

P daily

55

NR

54

16

0.009

110

P weekly

55

NR

44

13

114

55

NR

46

2

Concurrent versus sequential therapy

   Furuse et al.

   Concurrent

156

MVC

56

16.5

NR

22

0.04

   Sequential

158

MVC

56

13.3

NR

15

 

Pancoast Tumor/Superior Sulcus Tumor

The Pancoast tumor described by Pancoast in 1924 comprises the characteristic and constant clinical phenomenon of pain in the distribution of the 8th cervical and 1st and 2nd thoracic spinal nerves, Horner syndrome, radiologic evidence of a small homogenous density at the apex of the lung, and minor or major destruction of the ribs and vertebral infiltration.

  • Superior sulcus tumors are at least T3 and may be T4.
  • Nodal involvement is a prognostic indicator of poor outcome as are positive resection margins and metastatic disease.

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  • Sixty percent of patients have adenocarcinoma.
  • Untreated patients have an average survival of 10 to 14 months.
  • Several early reports suggest that external beam radiation therapy could produce long-term survival. Combination radiation therapy and surgical resection appear most advantageous, when possible, and represents the standard of care. Five-year survival rates of up to 15% to 50% have been reported with this approach. No direct randomized clinical trial has been performed to compare the sequencing of radiation therapy and surgery in these patients. Indirect evidence from Ginsberg et al. suggests similar results with either pre- or postsurgical radiation therapy.
  • T4 lesions (invasion of vertebral bodies, subclavian vessel) pertain to a poorer prognosis with 5-year survival rates of 9% to 11%. In those patients with suspected subclavian vessel involvement, an anterior approach is critical to facilitate resection. Rib involvement may have no impact on survival rates in resectable cases (5-year survival is 45% to 56%); although one study with 23 such patients revealed a statistically significant disadvantage on progression-free survival (PFS) (2-year PFS 37% versus 25%). Of 75 patients, from six studies, with resected N2 N3 disease, the 4-year survival was 8%.
  • Ipsilateral supraclavicular nodal involvement (N3) seems to have a better prognosis than ipsilateral mediastinal nodes (N2).
  • In a nonrandomized review of 100 patients with resected superior sulcus tumors, the 5-year survival of patients treated with lobectomy was twice that of patients treated with wedge resections (65% versus 30%, respectively; p= 0.06). All patients had chest wall resection in addition to the pulmonary resection. The local recurrence rates were similar (23% versus 38%, respectively).
  • Most common sites of residual disease are the brachial plexus, the neural foramina, the vertebral bodies, and the subclavian veins. The most common sites of metastases are brain and bone.
  • Patients with incomplete resections have overall survival rates similar to those who did not undergo resection.
  • It appears that there is no survival benefit to postoperative irradiation in patients with incompletely resected disease.
  • There are insufficient data on the use of combination chemotherapy and radiation therapy and surgery in patients with superior sulcus tumors.

Advanced Disease (Stage IIIB with Malignant Pleural Effusions and Stage IV)

  • The survival of patients with advanced-stage (stage IIIB with malignant effusions and stage IV) NSCLC is extremely poor.
  • The therapeutic approach includes consideration of systemic chemotherapy, or supportive therapy alone if the patient's general condition is not suitable for systemic chemotherapy.
  • Best supportive care (BSC) produces median survival rates of 16 to 17 weeks and 1-year survival rates of 10% to 15%.
  • Data obtained from the meta-analysis performed by Non–Small Cell Lung Cancer Collaborative Group included 1,190 patients with NSCLC from 11 trials and a comparison of supportive care to supportive care plus chemotherapy was evaluated. Eight of the trials included cisplatin-based regimens. Most of the trials, however, included patients with both unresectable locally advanced and systemically advanced disease. Therapy with alkylating agents had a negative impact on survival (hazard ratio 1.26), but the result was based on only two trials.
  • The cisplatin-based trials showed a benefit of chemotherapy with a hazard ratio of 0.73 (p<0.0001), equivalent to an absolute improvement in survival of 10% (5% to 15%) at 1 year or an increase in median survival of 1.5 months (1 to 2.5 months).
  • Completed prospective randomized trials including quality-of-life analyses show that cisplatin-based therapeutic regimens also improve quality of life in these patients.

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  • On the basis of this collective data, the guidelines of the American Society of Clinical Oncology on advanced NSCLC recognize the survival and quality-of-life advantage that chemotherapy can impart to patients with advanced-stage NSCLC. However, the greatest benefit is associated with patients with good PS [Eastern Cooperative Oncology Group (ECOG) PS 0-1]. Treatment-related toxicity is increased in patients with lower PS (ECOG PS 3,4).
  • Agents in phase III trials in patients with advanced NSCLC include the taxanes (paclitaxel and docetaxel), vinca alkaloid (vinorelbine), antimetabolite (gemcitabine), and camptothecin (irinotecan). These agents have all shown promise in both phase I and II trials, both as single agents or in combination with a platinum agent. One-year survival rates of up to 40% have been commonly reported.
  • Because of the modest results from chemotherapy, predictable toxicity, and high costs of new chemotherapy agents, there has been concern about the clinical benefits and economic value of chemotherapy in these patients. However, data from Canada, which compared patients with advanced-stage NSCLC treated either with BSC or with platinum-based chemotherapy, confirmed that systemic chemotherapy is more cost effective than BSC. More recent economic comparisons have focused on newer agents versus older regimens and have reported favorable findings.
  • The optimal duration of therapy remains an important issue. Three recent randomized trials have addressed this issue in stage IIIB/IV NSCLC. No benefit in response rate, symptom relief, quality of life, or survival was noted for the longer duration of therapy; however, cumulative toxicities occurred more frequently in those patients randomized to longer treatment durations. These trials suggest that the duration of first-line therapy in advanced, metastatic NSCLC should be brief (three to four cycles).
  • Second-line therapy has a survival and quality-of-life impact in advanced NSCLC; therefore, patients with a PS of 0–2 should be offered further treatment following progression.

Best Supportive Care

At all stages of disease, it is important to attend to the symptoms experienced by patients.

  • These symptoms include therapy-related factors such as nausea, vomiting, anemia, and disease-related issues such as pain, dyspnea (from either parenchymal involvement or effusions), ataxia (cerebral involvement or peripheral neuropathy), and confusion (metabolic effects).
  • Adequate antiemetic coverage pre- and postchemotherapy is essential and should be based on the emetogenic potential of the chemotherapeutic agent(s) prescribed.
  • Anxiety is a common problem in patients with cancer and can be debilitating.
  • Patients who stop smoking when their lung cancer is diagnosed are prone to develop depression.
  • When chemotherapy no longer has a role, extra support for the patient and family is available through hospice services.

NOVEL THERAPEUTIC APPROACHES

In view of modest results with current therapeutic approaches, it is important to maintain interest in developing new approaches to therapy. New agents are being designed to more specifically target tumor pathways in an effort to reduce treatment-related side effects while preserving or enhancing efficacy. Listed below are several of the current directions in new treatment approaches:

  • Photodynamic therapy
  • Endobronchial implants
  • Hypoxic cytotoxins (e.g., tirapazamine)
  • Monoclonal antibodies to tumor factor receptors (e.g., trastuzumab)
  • Signal transduction modulators (e.g., bryostatin, UCN-01, and farnesyl transferase inhibitors)

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  • Matrix metalloproteinase inhibitors or antiangiogenesis agents (e.g., marimastat, anti-VEGF, and endostatin)
  • Gene replacement therapy (e.g., Ad-p53)
  • Vaccine-based therapy
  • Immunotherapy

Targeted Therapies

Epidermal Growth Factor Receptor (EGFR) is overexpressed in lung cancer, with the reported frequency of EGFR expression in NSCLC being 40% to 80%. The more promising new agents include gefitinib and erlotinib, both capable of inhibiting EGFR tyrosine kinase in vitro. Recent evidence from clinical trials suggests that these agents may have their greatest value in patients whose cancers possess particular mutations in the EGFK tyrosine kinase.

  • Two phase II trials (IDEAL-1 and IDEAL-2) showed gefitinib monotherapy–induced tumor regression in 10% to 20% of NSCLC patients with recurrent, previously treated disease.
  • Tumor-related symptoms improved in approximately 35% to 40% of patients.
  • The median duration of response was 7 months.
  • Two further large, randomized controlled phase III trials (INTACT I and II) showed no benefit from adding gefitinib to standard, platinum-based chemotherapy in chemotherapy-naïve patients with advanced NSCLC. However, no clinical trials of other triplets of chemotherapy have shown an advantage over doublets in terms of survival.
  • A large phase III randomized trial compared single agent erlotinib with placebo in patients with NSCLC who failed at least one prior chemotherapeutic regimen and found a statistically significant survival advantage for those patients treated with erlotinib.

Screening

Screening for lung cancer remains an issue of great debate, both in terms of the most appropriate approach and the expected impact. Four prospective randomized trials evaluating early detection of NSCLC by chest x-ray failed to demonstrate a significant reduction in lung cancer mortality resulting from screening. They included 37,724 male cigarette smokers. No women were included. Two of the studies, the Memorial Sloan–Kettering Lung Project (MSKLP) and the Johns Hopkins Lung Project (JHLP), were designed to assess the impact of the addition of four monthly sputum cytology to annual chest x-ray evaluations. The studies concluded that sputum cytology added no benefit to chest x-ray alone. The long-term survival rates in the experimental and control groups in the MSKLP and JHLP were superior to the surveillance, epidemiology, and end results (SEER) data during the same period.

The other two studies, the Mayo Lung Project (MLP) and the Czechoslovakia study (CS), compared regular screening with chest x-rays in the experimental group and infrequent or no rescreening in the control group. Both studies found advantages favoring the experimental population in stage distribution, resectability, and survival.

In view of the lack of significant reduction in mortality, screening for the detection of early stage lung cancer is not recommended by any major public-policy advisory organization.

Retrospective data shows an increased risk of a second lung cancer following a diagnosis of prior lung cancer. Each year, 1% to 2% of patients with NSCLC will develop a second primary cancer. New techniques such as low-dose spiral CT scan, autofluorescent bronchoscopy, and molecular markers in sputum cytology need to be evaluated. The National Lung Screening Trial, opened for enrollment in September 2002, will compare spiral CT scan and standard chest x-ray, and aims to show whether either test is better at reducing deaths from lung cancer; it will also examine the risks and benefits of spiral CT scans compared to chest x-rays.

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Chemoprevention

No strategy has been proven effective for preventing NSCLC in at-risk individuals.

Two large trials using development of lung cancer as a primary endpoint have now been completed. Both trials demonstrated an adverse risk of lung cancer with β-carotene. The first study involved 29,133 men aged 50 to 69 from Finland, who were heavy cigarette smokers at entry (average one pack per day for 36 years). The study randomized participants to receive supplemental β-carotene, α-tocopherol, the combination, or placebo for 5 to 8 years. Unexpectedly, participants receiving β-carotene (alone or in combination with α-tocopherol) had a statistically significant 18% increase in lung cancer incidence [relative risk (RR), 1.18; 95% confidence interval (CI), 1.03 to 1.36] and an 8% increase in total mortality (RR, 1.08; 95% CI, 1.01 to 1.16) relative to participants receiving placebo. Supplemental β-carotene did not appear to affect the incidence of other major cancers occurring in this population.

The finding of an increased incidence of lung cancer in β-carotene–supplemented smokers has been replicated in the CARET (Carotene and Retinol Efficacy Trial). CARET was a multicenter lung cancer prevention trial of supplemental β-carotene and retinol versus placebo in asbestos workers and smokers. This trial was terminated prematurely because interim analyses of the data indicated that the supplemented group was developing more lung cancer, not less, consistent with the results of the Finnish trial. Overall, lung cancer incidence was increased by 28% in the supplemented subjects (RR, 1.28; 95% CI, 1.04 to 1.57) and total mortality was also increased (RR, 1.17; 95% CI, 1.03 to 1.33). The increase in lung cancer following supplementation with β-carotene and retinol was observed for current but not former smokers.

cis-Retinoic acid has been shown to be beneficial in patients with leukoplakia and head and neck cancer. The chemopreventive potential of 13-cis-retinoic acid in patients with stage I NSCLC following resection has been assessed. The trial closed in April 1997, and the mature data is awaited. Continued research and patient participation is required to define the best approach toward chemoprevention.

SUGGESTED READING

Incidence

Jemal A, Murray T, Samuels A, et al. Cancer statistics, 2003. CA Cancer J Clin 2003;53:5–26.

Smoking

Garfinkel L, Silverberg E. Lung cancer and smoking trends in the United States over the past 25 years. CA Cancer J Clin 1991;41:137–145.

Villeneuve PJ, Mao Y. Lifetime probability of developing lung cancer, by smoking status, Canada. Can J Public Health 1994;85:385–388.

Wiencke JK, Thurston SW, Kelsey KT, et al. Early age at smoking initiation and tobacco carcinogen DNA damage in the lung. J Natl Cancer Inst 1999;91:614–619.

Wingo PA, Ries LA, Giovino GA, et al. Annual report to the nation on the status of cancer, 1973-1996, with a special section on lung cancer and tobacco smoking. J Natl Cancer Inst 1999;91:675–690.

Pathology and Molecular Features

Salgia R, Skarin A. Molecular abnormalities in lung cancer. J Clin Oncol 1998;16:1207–1217.

The World Health Organization. Histological typing of lung tumors. Am J Clin Pathol 1982;77:123–1136.

Therapeutic Approaches

Albain KS, Rusch VW, Crowley JJ, et al. Concurrent cisplatin/etoposide plus chest radiotherapy followed by surgery for stages IIIA(N2) and IIIB non-small-cell lung cancer: mature results of Southwest Oncology Group phase II study 8805. J Clin Oncol 1995;13(8):1880–1892.

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Bunn PA, Kelly K. New chemotherapeutic agents prolong survival and improve quality of life in non-small cell lung cancer: a review of the literature and future directions. Clin Cancer Res 1998;5:1087–1100.

Dillman RO, Seagren SL, Propert KJ, et al. A randomized trial of induction chemotherapy plus high-dose radiation versus radiation alone in stage III non-small-cell lung cancer. N Engl J Med 1990;323:940–945.

Furuse K, Fukuoka M, Kawahara M, et al. Phase III study of concurrent versus sequential thoracic radiotherapy in combination with mitomycin, vindesine, and cisplatin in unresectable stage III non-small cell lung cancer. J Clin Oncol 1999;17:2692–2699.

Ginsberg RJ, Rubenstein LV. Randomized trial of lobectomy versus limited resection for T1 N0 non-small cell lung cancer. Ann Thorac Surg 1995;60:615–623.

Le Chevalier T, Arriagada R, Quoix E, et al. Radiotherapy alone versus combined chemotherapy and radiotherapy in nonresectable non-small-cell lung cancer: first analysis of a randomized trial in 353 patients. J Natl Cancer Inst 1991;83(6):417–423.

Non-Small Cell Lung Cancer Collaborative Group. Chemotherapy in non-small cell lung cancer: a meta-analysis using updated data on individual patients from 52 randomized clinical trials. Br Med J 1995;311:899–909.

PORT Meta-analysis Trialists Group. Postoperative radiotherapy in non-small-cell lung cancer: systematic review and meta-analysis of individual patient data from nine randomised controlled trials. Lancet 1998;352(9124): 257–263.

Rosell R, Gomez-Codina J, Camps C, et al. A randomized trial comparing preoperative chemotherapy plus surgery with surgery alone in patients with non-small-cell lung cancer. N Engl J Med 1994;330:153–158.

Roth JA, Fossella F, Komaki R, et al. A randomized trial comparing perioperative chemotherapy and surgery with surgery alone in resectable stage IIIA non-small-cell lung cancer. J Natl Cancer Inst 1994;86:673–680.

Schaake-Koning C, Van dan Bogaert W, Dalesio O, et al. Effects of concomitant cisplatin and radiotherapy on inoperable non-small-cell lung cancer. N Engl J Med 1992;326(8):524–530.

Souquet PJ, Chauvin F, Boissel JP, et al. Polychemotherapy in advanced non small cell lung cancer: a meta-analysis. Lancet1993;342(8862):19–21.

Clinical Guidelines

American Society of Clinical Oncology. Clinical practice guidelines for the treatment of unresectable non-small-cell lung cancer. J Clin Oncol 1997;15:2996–3018.

Ettinger DS, Cox JD, Ginsberg RJ, et al. NCCN Non-Small-Cell Lung Cancer Practice Guidelines. The National Comprehensive Cancer Network. Oncology (Huntingt) 1996;10:81–111.

Second Cancers and Screening

Henschke CI, McCauley DI, Yankelevitz DF, et al. Early lung cancer action project: overall design and findings from baseline screening.Lancet 1999;354:99–105.

Johnson BE. Second lung cancers in patients after treatment for an initial lung cancer. J Natl Cancer Inst 1998;90(18):1335–1345.

Strauss GM, Gleason RE, Sugarbaker DJ. Chest X-ray screening improves outcome in lung cancer. A reappraisal of randomized trials on lung cancer screening. Chest 1995;107:270S–279S.