State of the Art Oncology in EuropeFont: aaa

Non small-cell lung cancer

1. GENERAL INFORMATION

1.1 Incidence and mortality

Lung cancer is the most common cancer in the world. In Europe, it is the most common cancer amon g men, accounting for about one in five cancers (305,000 cases a year). In women it is the fourth most common (72,000 cases a year) after breast cancer, colorectal cancer and stomach cancer (Ferlay 2001). The estimated incidence and mortality rates among European and North American populations are shown in Figure 1 by sex. Incidence rates vary from 70 (Eastern EU) to 44 (Northen EU) in men,and from 34 (North America) to 8 (Southern EU) in women (Ferlay 2001). Non small cell lung carcinoma accounts for about 90-85% of all lung cancers. In men (Figure 2), the incidence by age rises rapidly from 2 per 100,000/year in patients less than 35 years old to 155 per 100,000/year in the age group 50-54, thereafter increasing to 437 per 100,000/year for ages 70-74 and 456 per 100,000/year for those older than 75 years of age. In women the corresponding rates are 1, 21, 84 and 85 per 100,000/year (Ferlay 1999). Incidence rates in men in the UK have fallen by 7-10% every five years since the mid-1970s. In sharp contrast, incidence among UK women has increased by 10% every five years until the 1990s and in 1990 lung cancer overtook breast cancer in Glasgow as the most common cancer in women (Gillis 1992; Coleman 1999). In Italy a progressive decrease of incidence in males is evident with an estimated annual percent change of -1.4% and of ?mortality from lung cancer. Such decrease occurs in the younger age groups, whose smoke quitting was greater. On the contrary, an increasing trend seems to persist for older age groups. Among females, numbers r are rather different from that of males, according to diverging trends in tobacco smoking exposure; in fact both incidence (+1.2%/year) and mortality (+0.9%/year) are increasing (Crosignani 2003). In most countries, lung cancer incidence is greater in lower socio-economic classes; to a large extent, this pattern is explained by differences in the prevalence of smoking (Stewart 2003). Having rising dramatically since the turn of the century, lung cancer mortality amongst males is now abating in several countries, including the USA, the UK, Denmark and Finland (Parkin 2001).

1.2 Survival

Survival for lung cancer patients remain poor, with five-year relative survival of about 10% in the Europe, with no differences between gender (Berrino 2003). Relative survival for lung cancer was strongly dependent on age at diagnosis, being much greater in young than in old patients. In the youngest age group (15-44 years) five-year relative survival was 18% compared to only 6% in those 75 years and above. The age-standardised five-year relative survival for lung cancer varied more than two-fold across Europe for men diagnosed in 1990-1994. Survival was particularly high in Austria, France, Germany, the Netherlands and Spain; and low in the Czech Republic, Denmark, England, Estonia, Malta, Poland, Scotland and Slovakia. These differences were similar for men and women. The considerable variation in lung cancer survival across Europe suggests that care may be important even though it is the most deadly of the common cancers (Janseen 1998). An analysis of survival in Denmark, Finland, and Norway suggested that lower survival in Denmark was due to unfavourable stage distribution (Storm 1999). Patients with advanced cancer rarely survive 5 years or longer (1-2%), but patients with localized stage at diagnosed had 5-year survival of about 30 % (Dickman 1999). Overall there was a modest tendency for lung cancer survival to improve with time. Five-year age-adjusted relative survival increased from 7.5% in men diagnosed in 1983-1985 to 9.2% in 1992-1994. Five-year survival in women increased from 8.1% to 9.8% over the same period (Roazzi 2003). Among both women and men, the group of non small cell carcinoma, mainly adenocarcinoma and squamous cell carcinoma, has the highest survival (16%) compared to small cell carcinoma (3%)(Dickman 1999).

1.3 Prevalence

Prevalence of cancer is the number of people living with a diagnosis of cancer. In Europe for both sexes lung cancer account for 4% of the total cancer prevalence (Micheli 2002).The estimated proportion of European people living with lung cancer was 95 per 100,000. The 5-year prevalence, that is the number of living people with a diagnosis of lung cancer made 2 or 5 or less years before the index date, was 39 and 55 per 100,000 respectively. The last figure demonstrates the need for clinical follow-up and treatment of recurrences. However, slightly less than 60% of all prevalent patients with lung cancer were long survivors that is people living with a diagnosis made 5 or more years before the index date.

1.4 Etiology and risk factors

Cigarette smoking is universally recognized as the most important cause of lung cancer. Cigarette smoking is responsible for 85-90% of new cases of lung cancer (IARC 1986). The risk depends on the number of cigarettes per day, duration, age at onset, time since quitting, type of inhalation, tar and nicotine content and presence of a filter. There is sufficient evidence demonstrating that passive smoking is responsible for lung cancer in non-smokers living or not with smokers. The magnitude of the risk is in the order of at least 15-20% (Hackshaw 1997). Occupational exposure to carcinogens such as asbestos, radon, polycyclic aromatic hydrocarbons, chromium, nickel and inorganic arsenic compounds has been recognised to be a risk factor. Occupational exposure has been associated with an increased risk of lung cancer more than for any other tumour type (Stewart 2003). (repeat of first sentence). The risk is increased multiplicatively amongst persons who both smoke and are exposed to asbestos. Such phenomenon has been noted also in relation to other occupational lung cancers (Stewart 2003). Atomic bomb survivors and patients treated with radiotherapy are at an increased risk of lung. The magnitude of risk is 1.5 to 2 for cumulative exposure in excess of 100 rads (Stewart 2003). Underground miners exposed to radioactive radon and its decay products have found to be at an increased risk of lung cancer (repeat of previous paragraph) (Samet 1989). Lung cancer incidence rates are higher in cities than in a rural setting (Dockery 1993) Urban air pollution is a risk factor for lung cancer and the excess risk may be in order of 50% (Stewart 2003). There is no conclusive evidence about genetic increased susceptibility to the effect of certain carcinogens, in particular tobacco carcinogens. Chromosomal abnormalities are present in lung cancer, but it is unclear whether these changes are responsible for cancer or whether they result from instability during malignant transformation. However, epidemiological studies show that:
•  only 15% of heavy smokers will eventually develop lung cancer
•  • females are more susceptible to the carcinogenic effects of tobacco smoke than men (van Zandwijk 2000a)
•  Ex-smokers are at elevated risk for lung cancer for many years (Peto 2000)
•  Smoking seems to interact with increased familial risk for lung cancer.

This means that genetically determined factors may modulate the individual susceptibilty to develop lung cancer (van Zandwijk 2002). From recent advances on our understanding of the molecular and the biologic basis of lung cancer, it is nowadays generally accepted that carcinogenesis is a multistep event and that lung cancer develops as the result of multiple genetic events. Some of these lesions are closely associated with exposure to tobacco smoke, but there is a wide variation in individual susceptibility to develop lung cancer (Hirsch 20011, van Zandwijk 2002).

1.5 Cancer Prevention

Some epidemiological studies have suggested that higher intakes of vitamin E and beta-carotene with yellow and green leafy vegetables may play a protective role against the effects of carcinogens. None of the big randomized chemoprevention trials evaluating the role of dietary supplement with antioxidant micronutrients such as vitamin A, vitamin E, carotenoids, N-acetylcysteine or 4-HPR have shown a decrease in lung cancer incidence. On the contrary, beta-carotene may have a detrimental effect, primarily on smokers Further investigations are ongoing (Albanes 1996; ATBCCPSG 1994; Kurie 1999; Omenn 1996; Van Zandwijk 2000b; Lippman 2001; Cohen 2003). Peto (Peto 2000) and Khuder (Khuder 2001) strengthen that smoking cessation is the most important preventive measure.

1.6 Screening

Currently, there are no practicable and effective procedures available to provide population-based screening for lung cancer. Five randomized trials failed to demonstrate a disease-specific mortality reduction with periodic chest sputum cytology and or chest radiography in the screened group (Brett 1968; Marcus 2000; Kubik 1990; Melamed 1987; Tockman 1986) because of the low sensitivity of these tests. The results of the Early Lung Cancer Action Project (Henschke 1999; Henschle 2002) showed that spiral CT can identify very small lung cancers in a high-risk population: more than 80% of the screen-detected tumors were stage I disease, the resectability rate was 96% and the estimated 10-year survival was 88% in this subgroup; therefore, the authors concluded that annual spiral CT screening can detect lung cancer that is curable (Henschle 2006). The demonstration project by Pastorino et al (Pastorino 2003) aimed to assess the efficacy of repeated yearly spiral CT and selective use of positron emission tomography (PET) in a large cohort of high-risk volunteers (aged 50 years or older with a history of 20 pack-years or more). This study confirmed the promising results for accuracy and sensitivity of low-dose spiral CT with a 95% resectability in screening-detected lung cancers, and 77% of stage I disease. Adenocarcinoma was overrepresented in these studies, which may suggest that CT can detect peripheral lesions and miss some central lesions, probably squamous tumours. A major concern for the use of spiral CT screening is the high frequency of false-positive findings for benign nodules, that is related to the number of the slices of the scanner and the incidence of fungal or other pulmonary infections. Most of these lesions are very small and may not require immediate investigastion (PET scan and/or fine-needle aspiration biopsy). In the ELCAP study , only 23% of the volunteers had noncalcified nodules at baseline screening that needed further evaluation. However, as more data on the behavior of these nodules become available, it is possible that the smaller nodules, especially those <5.0 mm, could be evaluated during annual follow-up scans (Henschke 2004: Pastorino 2003). In order to try to minimize the number of invasive procedures required to confirm (or exclude) malignancy and the inherent risk for complications therein, Libby et al. created an algorithm based on the ELCAP data and the medical literature from 1993–2003 for nodules discovered incidentally on CT (Libby 2004). Although the perioperative mortality in the Mayo Clinic experience was only 1.7%, there is a real concern that, if screening is made widely available to the population, smaller centers with lesser expertise may not be able to duplicate the low complication rates achieved at the Mayo Clinic. Currently there is a 3.8% incidence of mortality with wedge resection of pulmonary nodules in community hospitals in the U.S. (Crestanello 2004). The most intriguing argument against screening is the possibility of overdiagnosis of lung cancer. Although more than 80% of the screen-detected tumors were stage I disease, there was no true stage shift (Swensen 2004). No difference in the incidence of advanced-stage disease between the low-dose CT studies and the chest radiographic trials (~3/1,000 patients) were detected. An obvious limitation of these kinds of analyses, however, is that the two populations chosen at different time periods in different studies may not be comparable. However, autopsy studies suggest that overdiagnosis may not be a significant problem, with lung cancer diagnosed for the first time in only 0.8% of all autopsies (McFarlane 1986). Recently, Bach et al (Bach 2007) compared the predicted with the observed lung cancers in a longitudinal analysis of 3246 asymptomatic smokers: they reported that screening for lung cancer with annual low-dose CT scans may increase the rate of lung cancer diagnosis (RR 3.2) and treatment (RR 10.0), but may not reduce the risk of advanced lung cancer or death from lung cancer. Bianchi et al. compared the gene-expression profile of screen-detected lung carcinomas with those of a matched case-control population of patients presenting with symptomatic lung cancer and found that all the tumors detected by screening had tha same biochemical gene-expression patterns (Bianchi 2004). Although there are no mature randomized clinical trials that have addressed this specific issue, observational studies from Japan have demonstrated a decrease in 5-year mortality with screening using CT scans, as opposed to chest radiographs (Mulshine 2005). The significant results in Japan with lung cancer screening has been of considerable importance for the U.S. Preventive Services Task Force who modifies the screening recommendations from discouraging screening to making no recommendation either for or against the use of CT scans (Humphrey 2004). Randomised trials are ongoing to measure the efficacy of low-dose spiral CT in reducing lung cancer mortality. Screening is investigational, but annual low-dose spiral CT may be investigational on a type 3 level of evidence in high risk individuals, (Pastorino 2003; Henschke 2006).

2. PATHOLOGY AND BIOLOGY

2.1 Biological data

Several chromosomal mutations have been identified. Some of them, being associated with tobacco exposure, have elucidated the mechanisms of malignant transformation. Biological data have been studied particularly as prognostic factors. Their usefulness in developing new treatment strategies, mainly targeted immunotherapy, is under evaluation in phase I clinical trials.

2.2 Histological types

Non-small cell lung carcinoma accounts for around 80% of all bronchogenic carcinomas. The World Health Organization classification of malignant tumours, which has been recently updated in 2004. includes between non-small-cell lung tumors squamous cell carcinoma, adenocarcinoma, large cell carcinoma, adenosquamous carcinoma, sarcomatoid carcinoma, carcinoid tumours and salivary gland tumours (Travis 2004; Franklin 2000). The most common types are adenocarcinoma, squamous cell carcinoma and large cell carcinoma. As regards histogenesis, it seems that lung cancer derives from a pluripotent stem cell which is able to differentiate in different phenotypes. For this reason the tumour may exhibit mixed histological patterns.

2.2.1 ICD-O codes

Morphology codes of the ICD-O (“International Classification of Diseases for Oncology”) are provided in brackets (ICD-O 2000; Travis 2004).

2.2.2 Squamous cell carcinoma [M-8070/3]

It accounts for approximately 30% of all cases of lung cancer. Within squamous cell carcinoma there are several variants like small cell variant, clear cell type, well differentiated papillary-verrucous type, and basaloid type. It is more frequent in the proximal bronchi. It is composed of epithelial cells with different grades of differentiation frequently associated with metaplasia. Squamous tumors with < 10% of cells containing mucin are to be classified as squamous carcinoma. A variant of both squamous and large-cell carcinoma, for which a unique biological behaviour is not yet documented, is termed basaloid carcinoma. It is a slow growing tumour and the estimated time required to become clinically evident is 3 to 4 years. Its frequency is decreasing relatively to adenocarcinoma.

2.2.3 Adenocarcinoma [M-8140/3]

It represents approximately 45% of all lung cancers. There is a tendency to increase in incidence. It derives from the gland cells producing mucin and it is more frequently located in the periphery of the lung. Bronchioloalveolar carcinoma (BAC) is a variant of adenocarcinoma; it is a distinct clinical entity frequently behaving in an aggressive fashion, with multifocal disease rapidly spreading from lobe to lobe including the contralateral lung. BAC is more likely to occur in women and nonsmokers. It has been reported that survival is better in patients with BAC than in patients with other histological types (Breathnach 1999; BrBreathnach 2000).

2.2.4 Large-cell carcinoma [M-8012/3]

It is the least common tumourtype (15%). The majority presents as a large, peripheral mass with poorly defined margins; rapid growth occurs frequently. Large cell carcinoma comprises the following variants: basaloid carcinoma, large cell neuroendocrine carcinoma, Large cell carcinoma with rhabdoid phenotype, clear cell carcinoma and lymphoepithelioma-like carcinoma. In the recent past, immunohistochemical staining provided greater accuracy in the diagnosis of this entity by more correctly classifying part of them as adenocarcinoma. Their clinical behaviour is similar to that of adenocarcinoma.

2.2.5 Preinvasive lesions, either squamous or nonsquamous

The 2004 WHO tumor classification (Travis 2004) has included four histologic types of squamous preinvasive lesions: mild or moderate or severe dysplasia and carcinoma in situ. Not included in the classification and reported elsewhere is a lesion classified as angiogenic squamous dysplasia. Nonsquamous preinvasive lesions include atypical adenomatous hyperplasia and diffuse idiopathic pulmonary neuroendocrine cell hyperplasia; both lesions are rare. ICD-O morphology code will end up with /2.

2.3 Grading

Grading has no relevance in defining different prognostic subgroups in patients with lung cancer.

2.4 Accuracy and reliability of pathological diagnosis

Sputum cytological analysis has a greater accuracy for squamous (93%) or small cell (89%) histotypes than for adenocarcinoma (25%) and large cell carcinoma (54%). Overall agreement regarding subtypes and grading within adenocarcinoma is approximately 40% (Sorensen 1993).

3. DIAGNOSIS

3.1 Signs and symptoms

Approximately 95% of patients presenting with lung cancer have symptoms, although frequently attributed initially to the side effects of smoking. The most frequent symptoms are cough, productive sputum and shortness of breath. Each of them can be attributed to smoking, for underlying bronchitis or chronic obstructive lung disease. Weight loss, hoarseness and hemoptysis are seen in patients presenting with more advanced disease. Paraneoplastic syndromes are frequently reported in patients with lung cancer. Hypertrophic pulmonary osteoarthropathy is one of the most common and almost exclusively observed in adenocarcinoma. Clinical characteristics of this condition are clubbing of fingers and toes and symmetric periostitis of the distal long bones. Patients may complain of pain, tenderness and swelling. Non steroidal antiinflammatory agents associated to the treatment of the underlying disease are recommended.

3.2 Diagnostic strategy

A chest X-ray, spiral CT and sputum cytology are recommended on a type C basis when lung cancer is suspected. A normal chest X-ray rules out the diagnosis of cancer in most cases; however, 19% of NSCLC presenting as a nodular lesion are missed on the chest-X ray (Quekel 1999). In the case of normal chest X-ray with sputum cytology positive, a bronchoscopy is recommended on a type C basis. When a chest X-ray abnormality smaller than 3 cm is detected, a comparison with old radiograph is recommended on a type R basis, since absence of growth over a 2-year period strongly suggests a benign process and an observational approach with serial radiographs can be recommended on a type C basis (Liptay 1999; Patz 2000). If no old radiograph is available or if the chest X-ray abnormality is new, a thoracic CT scan is recommended on a type C basis. A major concern for the use of CT scans is the false-positive rate, that is related to the number of the slices of the scanner and the incidence of fungal or other pulmonary infections. In the ELCAP study , only 23% of the volunteers had noncalcified nodules at baseline screening that needed further evaluation. However, as more data on the behavior of these nodules become available, it is possible that the smaller nodules, especially those <5.0 mm, could be evaluated during annual follow-up scans (Henschke CI 2004). In order to try to minimize the number of invasive procedures required to confirm (or exclude) malignancy and the inherent risk for complications therein, Libby et al. created an algorithm based on the ELCAP data and the medical literature from 1993–2003 for nodules discovered incidentally on CT (Libby 2004). A positron emission tomography (PET) using F-18-fluorodeoxyglucose (FDG) has 83% to 100% sensitivity, 77% to 100% specificity and 82% to 94% accuracy in distinguishing between benign and malignant lesions larger than 1 cm, while in lesions smaller than 1 cm a negative PET is less reliable. False-positive results are mainly found in benign inflammatory lesions. False-negative results have been observed in primary pulmonary carcinoid tumors and bronchoalveolar cell cancer (Berman 2000; Haberkorn 2001). The accuracy of PET examination for diagnosis of pulmonary nodules and mass lesions has been recently reported in a meta-analysis including 1474 focal pulmonary lesions of any size. The authors conclude that FDG-PET has a high sensitivity (97%) and intermediate specificity (78%) for malignancy. Few data exist for nodules smaller than 1 cm in diameter (Gould 2001). Its use is at present optional, for instance evaluation of lung nodules in patients at risk for complications during surgery (Hellwig 2001). History and physical examination are essential. Elicitation of symptoms like weight loss, respiratory complaints, bone or abdominal pain and central nervous system is important. Abnormal laboratory results, such as alkaline phosphatase, serum calcium and LDH are often predictive of metastatic disease.

3.3 Pathological diagnosis

The easiest and least expensive method is to obtain sputum. The probability of a diagnostic sputum is proportional to the number of pecimens and reaches a plateau at 6-7. If this approach is non diagnostic, a bronchoscopic examination with bronchial biopsy and bronchial washing is recommended on a type C basis. Accuracy of bronchoscopy with bronchial biopsy and bronchial washing is approximately 85% for visible masses. Washing and brushing of bronchi in cases without visible lesion may result in a diagnostic procedure. The addition of endobronchial needle aspiration (EBNA) to biopsy and washing increases the sensitivity, especially for patients with submucosal abnormalities or lesions causing extrinsic compression (Govert 1999). If the lesion is peripheral a CT-guided fine needle biopsy is recommended on a type C basis. Successful examination may be related to the diameter of the lesion: a diagnosis can be made in about 90% of patients with lesions greater than 2 cm and in only 60% of patients with lesions greater than 1 cm. The main risk of the procedure is pneumothorax which has been reported in approximately 15-30% of cases. Only in 5 to 20% of affected patients a chest tube for lung re-expansion is required (Berman 2000). Hemoptysis is rare. Although the diagnostic ability depends on the radiologist’s and cytologist’s expertise, the expected accuracy of this procedure may reach 90%. Closed thoracoscopy or video assisted thoracoscopic surgery (VATS) is useful in reaching small peripheral nodules and lesions that approximate diaphragmatic areas.

4. STAGING

4.1 Staging Classification

4.1.1 TNM classification (UICC 2002)
primary Tumor (T)

TX Primary tumour cannot be assessed, or tumour 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: Tumour 3 cm or less in greatest dimension, surrounded by lung or visceral pleura, without bronchoscopic evidence of invasion more proximal than the lobar bronchus (i.e., not in the main bronchus)*
T2: Tumour with any of the following features of size or extent:
•  More than 3 cm in greatest dimension
•  Involving main bronchus, 2 cm or more distal to the carina
•  Invading the visceral pleura
•  Associated with atelectasis or obstructive pneumonitis that extends to the hilar region but does not involve the entire lung
T3: Tumour of any size:
Invading directly any of the following: chest wall (including superior sulcus tumours), diaphragm, mediastinal pleura, parietal pleura or parietal pericardium
Involving main bronchus less than 2 cm distal to the carina but without involvement of the carina
Associated with atelectasis or obstructive pneumonitis of the entire lung
T4: Tumour of any size:
Invading any of the following: mediastinum, heart, great vessels, trachea, esophagus, vertebral body, carina
Or separate tumour nodules in the same lobe
or tumour with malignant pleural effusion**

*Note: The uncommon superficial tumour of any size with its invasive component limited to the bronchial wall, which may extend proximal to the main bronchus, is also classified T1.
**Note: Most pleural effusions associated with lung cancer are due to tumour. However, there are a few patients in whom multiple cytopathologic examinations of pleural fluid are negative for tumour. In these cases, fluid is non-bloody and is not an exudate. When these elements and clinical judgement dictate that the effusion is not related to the tumour, the effusion should be excluded as a staging element and the patient should be staged T1, T2, or T3.

Regional lymph node metastasis (N)
NX: Regional lymph nodes cannot be assessed
N0: No regional lymph node metastasis
N1: Metastasis to ipsilateral peribronchial and/or ipsilateral hilar lymph nodes, and intrapulmonary nodes including involvement by direct extension of the primary tumour.
N2: Metastasis to ipsilateral mediastinal and/or subcarinal lymph node(s)
N3: Metastasis to contralateral mediastinal, contralateral hilar, ipsilateral or contralateral scalene, or supraclavicular lymph node(s)

Distant metastasis (M)
MX: Presence of distant metastases cannot be assessed
M0: No distant metastasis
M1: Distant metastasis present
Note: M1 includes separate tumour nodule(s) in a different lobe (ipsilateral or contralateral).

4.1.2 Stage grouping (UICC 2002)
Occult carcinoma TX N0 M0
Stage 0 Tis N0 M0
Stage IA T1 N0 M0
Stage IB T2 N0 M0
Stage IIA T1 N1 M0
Stage IIB T2 N1 M0
T3 N0 M0
Stage IIIA T1 N2 M0
T2 N2 M0
T3 N1 M0
T3 N2 M0
Stage IIIB Any T N3 M0
T4 Any N M0
Stage IV Any T Any N M1
4.1.3 Histopathologic grade (G)

GX Grade cannot be assessed
G1 Well differentiated
G2 Moderately differentiated
G3 Poorly differentiated
G4 Undifferentiated
4.2 Controversies of the staging classification

“T” Category
Controversy concerning the relation between tumor size and patient prognosis persists, and the appropriate cut-off for tumor size, i.e. 2, 3, 4, 5 or 7 cm to classify T1 and T2 diseases continues to be debated. Ginsberg (Ginsberg 1998) proposed that tumors invading the phrenic nerve or vagus nerve in the aortic orsubaortic region, now classified as T3, have extremely poor prognoses and probably should be upgraded to aT4. More precise definitions to identify the Tstatus of the superior sulcus tumor (T3 vs. T4) are required. For example, the presence of Horner’s syndrome, motor (vs. sensory) dysfunction of the lower brachial plexus (C8 involvement), or involvement of the subclavian vessels inall likelihood should designate this tumor as T4.

“N” Category
To date, there are three kinds of maps, i.e. Japan LungCancer Society (JLCS) map (so-called Naruke-map, 2000), The American Thoracic Society (ATS) map (1983), and the recently proposed Mountain-map (1997) JLCS-map is based on the bronchial tree, thoracotomy findings and resected specimen. ATS-map is based on major anatomic structures and mediastinoscopic identification. The Mountain map is based on mediastinal pleura and mediastinoscopic identification. After proposal of the Mountain map, there was greatconfusion regarding N category, especially concerning the boundary between #7 (subcarinal) and #10 (hilar) lymph nodes. In the JLCS-map, the #7 lymph node is defined as the lymph node in contact with the subcarina. However, the Mountain-map defines all subcarinal area nodes within the pleural reflection as #7 nodes, including part of the nodes designated as #10 nodes on the JLCSmap. Lymph node metastasis to the #7 lymph node is an N2 lesion, whereas metastasis to #10 is an N1 lesion. This confusion is exacerbated by the difference in survival rates between N1 and N2 lesions. Ginsberg pointed out that the definition of N3 disease within the mediastinum is quite vague and depends on the nodal map used. The lymphatic drainage of the various lobes to the superior mediastinum should be considered in designating N3 disease. Left-sided tumors,for example, drain ipsilaterally in the superior mediastinum,along only the left tracheoesophageal groove.Any lymph node drainage to the right of the leftparatracheal border should be considered contralateral or N3 disease for these left-sided tumors. In contrast, right-sided disease drains to lymph nodes in the superior mediastinum,anterior to the trachea as far as the left trachealborder. These should all be considered ipsilateral (right)paratracheal lymph nodes. Because of these anatomic features, the left anterior border of the trachea and not the midline of the trachea should be designated as the dividing point between ispilateral and contralateral. By this definition, contralateral N3 nodes from a right-sided tumor would include only those lymph nodes along the left tracheoesophageal groove and along the lateral border of the left mainstem bronchus.

Separate Tumor Nodule
The greatest controversy regarding the definition of M1 disease arises when ipsilateral satellite lesions (separate tumor nodule, STN) are present. In the last edition of TNM classification, STN in the same lobe is defined as T4 and STN in a different lobe is M1. Patients with STN in the primary lobe may behave more favorably than patients with other subgroup of T4 stage IIIB disease. As a result, patients with stages IIIB show favorable prognoses because a moderate number of patients with T4 from STN are included. From these facts, there are some proposals, that STN in the primary lobe should be T3.

4.3 Staging procedures

4.3.1 Staging examinations

Staging is aimed at defining the extend of disease as accurately as possible in order to define the most appropriate treatment, be it surgery, radiotherapy, chemotherapy, a combination of the previous or best supportive care for the individual patient.

4.3.2 T staging

Either chest X-ray and multi-slice thoracic CT scan are recommended on a type C basis. The extent of the primary lesion is assessed by chest X-ray and CT scan, even if CT is generally considered inaccurate to predict either chest wall or mediastinal (T3 vs T4) invasion (overall accuracy from 40 to 85%). Thoracic MRI is not recommended in most cases since it has a sensitivity and specificity similar to CT scan. MRI is superior to CT scan in delineating thetumor from adjacent connective tissues (desmoplastic reaction). MRI is more accurate than CT scan in evaluating superior sulcus tumors, particularly the extension to the brachial plexus, neural foramina, vertebral body and subclavian vessels and is therefore recommended in such cases on a type C basis (Patz 2000; Haberkorn 2001). Bronchoscopy is recommended in order to determine endobronchial T status, particularly tracheal invasion. VATS procedure is appropriate for evaluating pleural effusion and pleural abnormalities. The role of PET examination for diagnosis of pulmonary nodules and mass lesions has been recently reported in a meta-analysis. The authors conclude that FDG-PET has a high sensitivity ( 97%) and intermediate specificity (78%) in predicting malignancy (Gould 2001).

4.3.3 N staging

CT is recommended on a type C basis because it is critical for the evaluation of mediastinal lymph node involvement, permitting assessment of the size of lymphnodes. Lymphnodes are considered clinically positive when the minor axis is larger than 1-1,5 cm, or when multiple 1 cm nodes are contiguous, even if there is little correlation between nodal size and their pathological status. The cut-off of 1 cm has only an accuracy of 70-80%, a positive predictive value of nearly 60% and a negative predictive value of approximately 90% (which means that mediastinoscopy is less necessary in patients with a negative CT scan). Thoracic MRI is not recommended since it has a sensitivity and specificity similar to CT scan. In the absence of extrathoracic disease in patients with enlarged nodes, mediastinoscopy is recommended on a type R basis, unless a PET can be performed In cases of peripheral lesions and normal mediastinum, mediastinoscopy is not recommended on a type R basis. Cervical mediastinoscopy provides bioptic material from right and left, paratracheal areas,carineal nodes and subcarinal space. Anterior mediastinoscopy provides access to the aortic pulmonary window. This area can be accessed even through VATS procedure. Mediastinoscopy is recommended on a type R basis if PET scan of the mediastinum is positive. A transtracheal fine needle biopsy in conjunction with bronchoscopy may be diagnostic in some selected cases. Several studies (Berman 2000; Gupta 1999; Gupta 2001; Kernstine 1999; Lloyd 2001; Saunders 1999a; Vansteenkiste 1998, Pieterman 2000; Gupta 2000) and three recent meta-analysis (Dwamena 1999; Hellwig 2001; Gould 2003) have shown that PET is more accurate than CT scan for identifying mediastinal node involvement. Median sensitivity was around 85% for PET (only 60% for CT), while median specificity was around 90% for PET (80% for CT scan). PET is highly sensitive but less specific when CT showed enlarged lymph nodes (median sensitivity, 100%; median specificity 78%) (Gould 2003) PET has been shown to change N staging in 13-41% of patients and to change and improve patient manegement in 15-30% of cases (Salminem 2002; Dwamena 1999). A negative PET scan of the mediastinum suggests that mediastinoscopy can be avoided (Haberkorn 2001). Moreover, a recent randomized Dutch study has shown that addition of whole-body FDP-PET to conventional workup prevents unnecessary surgery in 20% of patients (van Tinteren 2002). Therefore, when available, whole-body FDG-PET is recommended for N staging on a type C basis (Salminem 2002; Hellwig 2001; O’Doherty 2000). PET has also been found cost-effective in the assesment of pulmonary nodules and in the staging of lung cancer, primarly from the avoidance of unnecessary surgery (Salminen 2002; Coleman 2002; Dietlein 2000; Gambhir 1998; Gambhir 1996).

4.3.4 M staging

History, elicitation of symptoms, physical examination and routine blood tests are recommended on a type C basis. A meta-analysis and a recent review of the current evidence have shown that the negative predictive value of the clinical evaluations for brain, abdominal and bone metastases are >or=90%. Nevertheless, there was great variation in the methodology of individual studies (Hillers 1994; Silvestri 1995; Toloza 2003). Abnormal physical findings or abnormal laboratory results are often predictive of metastatic disease and should dictate additional staging procedures, such as bone scan, brain CT scan, abdominal CT scan. Extrathoracic staging is not recommended for T1-T2 N0 patients with negative clinical evaluation considering that silent metastasis are found in <1% of cases (Tanaka 1999). Extratoracic investigation foroccult metastases is appropriate on a type R basis in potentially operable asymptomatic patients with higher T or N stages, where a higher incidence of occult metastases are reported (Deslauriers 2000b). If available, whole-body FDG-PET or PET-TC scan is recommended on a type C basis for M staging (except brain) (Salminem 2002; Hellwig 2001; O’Doherty 2000). It has been reported that whole-body FDP-PET is more accurate than conventional imaging in staging NSCLC and that PET can change M stage in 10-25% of patients. The highest yield of unexpected distant metastases was observed in pre-PET stage III (Berman 2000; BeGupta 1999; Marom 1999; Weder 1998; Pieterman 2000; Mac Manus 2001; Kalff 2001). The addition of whole-body FDP-PET to conventional staging in NSCLC patients changed or influenced therapy management in up to 67% of patients (Haberkorn 2001; Kalff 2001) and prevented unnecessary surgery in 20% of patients (van Tinteren 2002). If PET is negative, additional brain CT scan or brain MR is recommended on a type C basis. If PET or PET-CT scan is not available, conventional imaging for for M staging (brain CT scan, contrast-enhanced thoracic CT scan through the adrenal glands and liver, bone scan) is recommended on a type C basis. CT scan should be performed with slice thickness of 5 mm or less. With the new generation of multi-slice CT system, a thickness of 2-3 mm can be obtained (Haberkorn 2001). Magnetic resonance imaging (MRI) has shown a tendency toward a higher preoperative detection rate of brain metastases than CT scan in asymptomatic patients (3.4% vs 0.6%), but it does not influence prognosis (Yokoi 1999). Brain PET is not recommended since the high FDP uptake seen in normal brain makes the detection of small lesions difficult (Berman 2000). For the detection of bone metastases, both PET and bone scanning have 90% sensitivity, but the 98% specificity of PET is superior to the 61% specificity of bone scan (Berman 2000; Haberkorn 2001). PET has a 100% sensibility and a 90% specificity in evaluation of adrenal massess detected on CT scan (Yun 2001). PET may be useful to characterise additional lesions found on routine preoperative CT scan (lesions on lung, adrenal gland, liver, kidney, spleen and pleura), with a 100% specificity and a 93% sensitivity (Kutlu 1998). CT guided biopsy of adrenal gland is recommended in patients with operable NSCLC and adrenal mass on a type R basis. Accuracy of percutaneous CT guided biopsy of adrenal gland is 80 to 100%. PET has 100% sensitivity and 80% specificity for the detection of lung metastases to the adrenal gland, thus adrenal biopsy may be optional in case of normal PET (Berman 2000; Porte 1999).

4.3.5 Presurgical medical assessment

After having completed staging, the patient must be evaluated for operability by determining whether there is sufficient cardio-pulmonary reserve to withstand the sublobar, lobar or lung resection. The usual surgical procedure is lobectomy in 70% of cases, pneumonectomy in 25%, bilobectomy, segmentectomy or wedge resection are performed in the remainder cases. Both short-term or operative risk (which refers to perioperative mortality and reversibile morbidity) and long-term fixed complications (activity limited to bed to chair movement, the need for complete assistance with activities of daily living and twentyfour-hour oxygen dependence) must be assessed. (Cykert S 2000) Respiratory reserve and cardiac function are evaluated through a careful history and physical examination in order to assess the patient’s daily performance. Pulmonary function testing is recommended in all patients on a type C basis to determine forced expiratory volume in 1 second (FEV1), forced vital capacity (FVC), FEV1/FVC, maximum voluntary ventilation (MVV), oxygen diffusion capacity (DLCO) and arterial blood gas components. Predicted postoperative FEV1 (ppoFEV1) after lobectomy/segmentectomy is calculated by the following formula: ppoFEV1=FEV1-[(FEV1/19)*number of functional segments to be resected]. PpoFEV1 after pneumonectomy is predicted by the FEV1* % of radionuclide perfusion of the controlateral lung (obtained from quantitative radionuclide perfusion scanning with Xenon 133 and tecnetium). Patients are considered at “low risk” if the predicted postoperative FEV1 is greater than 40% of predicted normal and the preoperative MVV and DLCO are greater than 50% of predicted normal values. As the normal FEV1 decline with age, the crue value is also important, value <800 ml is a relative controindication to surgery. A decreased postoperative morbidity and mortality has been observed as well in patients having a PCO2 less than 45 mm Hg and a PO2 greater than 60 mm Hg. Patients with obstructive disease (FEV1/ FVC < 70%) without emphysema or restrictive disease, must be carefull evaluated specially if upper lobectomy is planned. Standard ppoFEV1 overestimates the true post-operative FEV1 if Copd index [FEV1%+ (FEV1/FVC)] is <120. Upper lobectomy reduces the FVC but enhances the FEV1/FVC like bronchodilatator effect (Korst 1998). Patients with significant obstructive disease (preoperative FEV1<60%) or with borderline resectable disease should also have quantitative radionuclide perfusion scanning with Xenon 133 and technetium in order to allow accurate prediction of postoperative function. In selected patients, considered at “high risk” on the basis of the ppoFEV<40%, formal cardiopulmonary test (exercise oxygen consumption test with expired gas analysis-MVO2) must be performed: an MVO2 <10-15 mL/kg/min or a predicted postoperative MVO2<10 mL/kg/min identifies patients at unacceptably high risk for complications and mortality (Bolliger 1995). Limited available data support the use of preoperative risk indices (ASA class, pulmonary index or Goldman CRI) to identify patients at high risk (Reilly 1999). One old-fashioned test is the evaluation of the number of stairs the patient is able to climb before stopping because of breath shortness. In one study it was found that the successful climbing of 44 steps predicts uneventful surgical outcome for lobectomy (Holden 1992). Cardiac evaluation is based on an exercise electrocardiogram to evaluate coronary artery disease. A list of risk factors that strongly suggest the need for a careful cardiac evaluation has been worked up: previous cardiac surgery, prior hospitalisation for cardiac disease, cardiac symptoms, abnormal resting ECG, presence of peripheral vascular disease, presence of cardiac calcification seen on chest CT and presence of ischemia during pulmonary testing. Further workup may comprise myocardial scan, echocardiogram and angiography in selected cases. The rationale guiding all these evaluations is to avoid surgery in patients at excessive surgical risk. No consistent data are available for demonstrating that postoperative complications are fewer in patients who stopped smoking before surgery. Other factors may increase operability risk, such as obesity, alcohol and drug abuse, neurologic deficits, difficult swallowing, psychiatric illness and immune disorders. Age is associated with acceptable surgical risk and in itself should not constitute a contraindication to surgical lung resection. Reported operative mortality for carefully selected elderly patients ranges from 3 to 7% (Ginsberg 1983; Jaklitsch 1999). Improvement of pulmonary functions has been reported in carefully selected patients with heterogeneous emphysema after lung reduction operation combined with tumour resection (Carretta 1999; DeRose 1998; Korst 1998; Mentzer 1999). Patients undergoing preoperative chemo(radio)therapy, especially elderly patients, may require special perioperative care. The most important complications affecting subsequent resection include pulmonary and cardiac toxicities due to the administration of certain drugs such as doxorubicin. These can be potentiated by preoperative radiation.

4.3.6 Restaging examinations

Small trials have shown that the evaluation of response to therapy seems to be more accurate with PET than with CT scan, and that response on PET scan is strongly predictive for survival. Patients with post-therapeutic positive PET scans have a worse prognosis than patients with negative results (Patz 2000; Vansteeniste 1998; Young 1999). PET seems even more accurate than CT scan for detecting recurrent tumors. Its use in therapy monitoring and follow up is at present investigational.

5. PROGNOSIS

5.1 Natural history

The tumour tends to spread, after a variable period of time, invading vascular and lymphatic channels resulting in nodal and distant metastases. The lymphatic spreading follows the bronchoarterial branching system. Lower lobe lymphatics drain to the posterior mediastinum and to the subcarinal nodes. Right upper lobe drains to the superior mediastinum, left upper lobe to the anterior and superior mediastinum. The tumour may spread contiguously in peritumoral structures (pleura, chest wall, vessels etc.) or through retrograde lymphatic spreading to the pleural surface. The most frequent sites of metastatic involvement are bone, liver, adrenals and brain. Only 20% of patients present with stage I disease and 5% with stage II. Most patients present with locally advanced disease (stage III) or metastatic (stage IV). Late stage presentation influences prognosis. The 5-year survival rate for all patients with a non-small cell lung cancer is approximately 10-15% and the median time from diagnosis to death is 6 months. Socioeconomic factors and race appear to influence survival in early-stage NSCLC in the United States; it has been reported that patients with the highest socioeconomic status and whites were more likely to receive surgery and to attain 5-year survival than those poorer and blacks. Five year survival rate was 34% for whites and 26% for blacks; up to 77% of white patients received surgery, while only 64% of blacks received surgery (Bach 1999; Greenwald 1998).

5.2 Prognostic and predictive factors

5.2.1 Clinical prognostic factors

Performance status is a cornerstone of prognosis in advanced NSCLC. In fact, the relevance of performance status in lung cancer was ushered in by Karnofsky et al (Karnofsky 1948) who treated NSCLC with nitrogen mustards. The prognostic value of performance status has been supported in an International Association for the Study of Lung Cancer (IASLC) consensus meeting (Feld 1994). For stage I , severe or moderate comorbitities according to Feinstein classification adversely impact only overall survival without affecting free disease interval (Battafarano 2002). Comorbidity classification according to the Charlson index shows the same impact on survival for index >=3 (Birim 2005). Stage has been highlighted as second main clinical prognostic factor primarily in Europe, where chemotherapy trials quite often include stage III and IV patients together. Other putative prognostic factors which are not so unanimously recognized are weight loss (more than 10% of body weight), gender, LDH, albumin, but probably not age. However, their value on survival is difficult to demonstrate in multivariate analysis. The strong adverse influence of bone metastases on chemotherapy response and survival has been noted in several studies (Green 1971; Lanzotti 1977; O’Connell 1986; Ruckdeschel 1986; Stanley 1980). Dismal survival is observed in patients having the following features: low performance status (60% or 70%), serum LDH level above normal and presence of bone metastases or two or more non-bony extrathoracic metastatic sites (Kosmidis 1994; O’Connell 1986; Rosell 1990; Ruckdeschel 1986). PET may be useful as a prognostic indicator because patients with increased FDP uptake in the primary lesion have a worse survival rate than patients with relatively less uptake, and this prognostic information is independent from lesion size and clinical stage. The use of FDP uptake as prognostic marker in the decision on adjuvant treatment protocols is investigational (Ahuja 1998; Vansteenkiste 1999). Most patients who are free from progression 5 years after radical radiotherapy or surgery for NSCLC have a good probability to remain well for 10 or more years (MacMannus 2000; Martini 1999). Known clinical prognostic factors in surgically resected stage I and II patients are tumor size (T1 vs T2 vs T3), age ( 70 years), gender (women vs men), completeness of resection, histologic type (squamous vs nonsquamous histology) and the number and location of nodes. Metastases to the hilar nodes carry a worse prognosis than metastases to the lobar and segmental nodes (Deslauriers 2000a). Based on large series of radically resected stage I and stage II NSCLC, the 5-year survival rates are 60 to 80% for stage I and 40 to 50% for stage II disease. Prognosis of stage IIIA disease depends on nodal disease extension (the number and nodal levels involved), ranging at 5 years, from 5% in patients with mediastinoscopy positive N2 disease to 20%-50% in patients with limited stage IIIA (Suzuki 1999). When lymph node metastases have progressed beyond the ipsilateral hemithorax (N3 or stage IIIB), the outcome is very poor (only 3% of patients survive at five years). Patients with metastases to multiple distant sites have a worse prognosis than patients with single-site metastases, which may be responsive to available treatments (for example, surgical resection of solitary brain or hepatic lesions).

5.2.2 Biological prognostic factors

The IASLC 1993 consensus meeting recommended looking for biological tumour data in tumour samples and normal tissue. Often cited are: the overexpression of dominant oncogenes such as the ras, bcl-2, HER-1, and HER-2/neu; the lost of suppressor genes such as p53, and p16; expression of blood group antigens, and neuroendocrine markers; overexpression of growth factor receptors; production of matrix metalloproteinase (MMPs); DNA aneuploidy, and tumour cell line from biopsy, among others (Bunn 2000; Feld 1994; Rozengurt 1999). In a multivariate analysis, performance status and neuron specific enolase tissue expression were independent prognostic factors in predicting survival in cisplatin-treated patients (Carles 1993). Recent advances in molecular genetics of cancer have led to the development of a model which characterizes the multiple genetic changes involving the activation of dominant oncogenes and the inactivation of tumour suppressor genes. Nevertheless, some investigators point out that despite the large number of gene mutations (ten to twenty) present in a given NSCLC tumour sample, few critical molecular events are actually crucial in disease progression and metastases (Silini 1994). Overexpression of dominant oncogenes plays a role in lung cancer progression. Mutations in K-ras gene (found in 20 to 40% of adenocarcinomas) may increase the malignant potential of human lung cancer cells (Rosell 1993). A strong association between K-ras gene mutations and survival in NSCLC has been demonstrated in several studies mainly in resected tumours, though not so clearly demonstrated in metastatic disease (Mitsudomi 1991; Silini 1994). However, the analysis of K-ras mutations in 488 patients with completely resected non-small lung cancer, has shown that K-ras may be a weak prognostic marker (Schiller 2001) . Additional questions should be addressed to further define the predictive value of K-ras on survival in NSCLC. Bcl-2 is a tumor oncogene that inhibits apoptosis; its overexpression is associated with a poor prognosis and drug resistance (Bunn 2000).On a multivariate analysis, the overexpression of HER-2/neu and extent of tumor emerged as independent factors for mortality in a group of 130 consecutive patients with radically resected non-small cell lung cancer (Selvaggi 2002). There is frequent loss of tumor suppression genes during the pathogenesis and progression of lung cancer. p53 mutations are present in about 50% of NSCLC (Johnson 1993; Salgia 1998). P53 gene may play a role in tumour progression although controversial findings have been reported regarding its predictive value in decreasing survival in surgically resectable NSCLC patients (Carbone 1994; Schiller 2001). It is envisaged that loss of heterozygosity (LOH) of the p53 gene might promote cell divisions more intensively than point mutations. Furthermore, frequent dramatic genetic changes in cells cause telomeric repeat length shortening and lung cancer cells with altered telomeric repeat length are often linked to LOH of p53 and retinoblastoma genes, thereby constituting a hallmark of metastatic disease (Hiyama 1995). Alteration in telomeric repeat length may be a prognostic marker suggesting a higher malignant potential.Tumor growth of NSCLC is mediated by polypeptide growth factors that act through tyrosine kinase receptors. In particular, the epidermal growth factor (EGP) and its ligands, TGF-alpha and amphiregulin (AR), are thought to function as an autocrine loop in NSCLC; the overexpression of AR and receptors correlates with survival in completely resected stage I-IIIA NSCLC (Fontanini 1998). Plateled-derived growth factor (PDGF) B-chain has been detected in a significant proportion of NSCLC and has been associated with poor prognosis (Kawai 1997). Neovascularization plays a critical role in tumor growth, early invasion, and metastases. Vascular endothelial growth factor (VEGF) is a promoter of angiogenesis. VEGF expression by NSCLC as well as microvessel count (as a measure of neovascularization) have been identified as independent prognostic factors (Fontanini 1997; Fontanini 1998). Microsatellite instability and LOH of chromosomal regions harboring tumour suppressor genes involving 3p, 5q, 8p, 9p, 11p, 13q, 17p, 18q are under evaluation (Fong 1995; Sekido 1994; Shridhar 1994; Washimi 1995). No such markers are used as yet for routine staging or for determination of prognosis of resected non-small cell lung cancer and for treatment decisions (such as the use of adjuvant/neoadjuvant chemotherapy).

5.2.3 Clinical predictive factors

On the basis of multivariate analyses, initial performance status of 80-100% has been linked to a greater probability of objective response rate and prolonged survival. Conversely, bone metastases are adversely predictive of response and survival (O’Connell 1986). Stage also correlates with response, with stage III patients responding better to chemotherapy than stage IV patients (Rosell 1990). In regionally advanced disease radiation therapy dose correlates with response while cisplatin dose has not been associated to a higher response rate or survival gain (Klastersky 1986). Current data indicate that there is a dose/response relationship between radiation dose and loco-regional control (Choi 2001).

5.2.4 Biological predictive factors

Neuroendocrine differentiation in NSCLC may well delineate a relative chemoresponsive subset of patients (Gazdar 1992) but the benefit on survival has not yet been confirmed conclusively (Carles 1993). Also, experimental evidence indicate that low levels of topoisomerase II gene expression, and possibly mutations, may predict a reduced sensitivity of unselected human lung cancer cell lines to several drugs, such as etoposide and doxorubicin, however its translation to clinical practice has not yet been fully developed (Giaccone 1992). Multidrug resistance seems caused by a non-P-glycoprotein (multidrug-resistant protein 1, MRP-1) encoded by the MRP-1 gene (Nishio 1999). The frequency of MRP-1 overexpression in clinical lung cancer and the relationship between chemoresistance and MRP-1 expression both remain unclear. In a small study, K-ras gene mutations were linked to lower chemotherapy response rate (Feld 1994), although this finding should be regarded with caution, as other researchers have experimentally proven that chemoresistance is a phenomenon independent of ras mutations in NSCLC cell lines (Tsai 1993). However, the establishment of a cell line from tumour tissue is in itself an independent prognostic factor for survival of NSCLC patients (Stevenson 1990), and the transfection of an activated ras gene has been shown to induce cisplatin resistance (Sklar 1988). It is foreseeable that in the future some genetic perturbations such as: ras oncogene activation, p53 gene mutations and genomic instability in some microsatellite sequences might serve as molecular prognostic tools predictive of chemoresistance. At present, the relation between p53 status and chemosensitivity has not been defined. It has been reported that bcl-2 expression causes the resistance to chemotherapeutic agents such as CPT-11 and MMC (Nishio 1999). The new drug gefitinib is an inhibitor of the epidermal growth factor receptor (EGFTR) tyrosine kinase. About 10% of treated patients show a rapid and often dramatic clinical response, but clinical remissions are observed only in female, non-smoking patients, with adenocarcinoma, bronchioloalveolar carcinoma (BAC) variant (Fukuoka 2003; Kris 2003). Some recent studies have clarified some molecular mechanisms underlying sensitivity to gefitinib. Specific mutations in the EGFR gene correlate with clinical responsiveness to the tyrosine kinase inhibitor gefinitib: these mutations are observed more frequently in Japan and in female, non-smoking patients, with adenocarcinoma, bronchioloalveolar carcinoma (BAC) variant. These results suggest that EGFR mutations may predict sensitivity to gefitinib (Lynch 2004; Paez 2004).

6. TREATMENT

6.1 Stage 0 (Tis)

6.1.1 Treatment strategy

Surgery is recommended on a type of C basis if consistent positive cytology derives from a specific lobe. Five-year survival is 100% after resection. If cytological examination is not localising the tumour site, bronchoscopy and chest X-ray every 3 months are recommended on a type R basis. Fluorescence bronchoscopy or low-dose spiral CT scan may represent a diagnostic alternative.

6.2 Operable stage I

6.2.1 Treatment strategy

Stage I disease includes T1-T2 tumours with no evidence of nodal involvement. For patients who are surgically staged, only 10% will have stage I disease. 5-year survival with optimal surgery is 70% (75-80% for patients with T1N0/stage IA and 60-70% for patients with T2N0/stage IB) (Deslauriers 2000a; Martini 1995; Mountain 1997). Aim of treatment is therefore cure. Known clinical prognostic factors in surgically resected stage I patients are tumor size (T1 vs T2), age ( 70 years), gender (women vs men), completeness of resection, histologic type (squamous vs nonsquamous histology). (Deslauriers 2000a).

6.2.2 Stage I

Recommended treatment is optimal surgery on a type C basis. Complete resection can be achieved with lobectomy, removal of the hilar nodes and completed with omolateral mediastinal lymphnode dissection on a type C basis. The role of radical systematic mediastinal lymphadenectomy is debated (Asamura 1999; Izbicki 1994; Izbicki 1998; Okada 1998). Lobectomy is recommended on a type C basis basis in stage I tumors, since it is superior in terms of local control and cancer-related mortality in comparison with wedge resections and segmentectomies (Landreneau 1997; Ginsberg 1995; Warren 1994). In patients who can not withstand lobectomy because of cardiopulmonary physiologic impairment, especially in T1N0 patients, a segmentectomy or a wedge resection is suitable for individual clinical use on a type 3 level of evidence (55-60% 5-year survival has been reported) (Landreneau 1997; Yano 1995). Nodal status has been reported in patients with periferal clinical T1N0M0, 2 cm or less in diameter, who had undergone surgical resection: lymph-node metastasis were significantly more common in tumours 1.5-2 cm in diameter (22%) than in those 1.5 cm or less in diameter (14%), while there was no nodal metastases only in tumors smaller than 1 cm (Konaka 1998). VATS procedure (video assisted thoracoscopy surgery) has not been proven superior to standard thoracotomy and it is at present investigational. Two small randomised trials have compared muscle-sparing thoracotomy and lobectomy versus VATS lobectomy or video-assisted minithoracotomy (Giudicelli 1994; Kirby 1995). Another randomized trial including 100 patients with clinical stage IA NSCLC has compared VATS lobectomy with conventional lobectomy: 5-year survival rates were similar in the two groups (85-90%), no postoperative data were provided (Sugi 2000).The limited incisions preserve respiratory muscle functions and avoid rib fractures and therefore VATS procedure may be associated with less pain, less respiratory failure, stronger cough, and shorter hospital stay. VATS is safe and with complication rates similar to that of open lobectomy (Jaklitsch 1999; McKenna 2006; Giudicelli 1994; Landreneau 1993; Ohbuchi 1998; Walker 1998). Large series have recently reported VATS lobectomy can achieve cure rates similar to those performed via thoracotomy (McKenna 2006). Closed thoracoscopy (2-cm incisions) or VATS procedures (incisions of 8 cm or less) are suitable for individual clinical use in patients with stage I NSCLC on a type 3 level of evidence, in institutions with expertise in such surgical technique. McKenna et al. (McKenna 2006; Swanson 2007). Preoperative radiotherapy is not recommended (Granone 2000; Warram 1975). Postoperative thoracic radiotherapy (PORT) is not recommended in radically resected stage I NSCLC on a type 1 level of evidence (PORT 1998; Burdett 2005; Lally 2006), since it has a detrimental effect on survival. PORT is standard option on a type C basis in R2 patients and in stage I with in adverted pN2 disease. Adjuvant chemotherapy is not recommended in radically resected stage IA NSCLC on a type 1 level of evidence (Pignon 2006). Adjuvant chemotherapy in radically resected stage IB NSCLC is investigational (Pignon 2006). The Lung Adjuvant Cisplatin Evaluation (LACE) Collaborative Group (Pignon 2006) has collected and pooled individual patient data from five largest recent trials: among the 347 stage IA NSCLC patient subset, there was no benefit on survival from adjuvant cisplatin- based chemotherapy; among the 1371 stage IB patient subset, only a trend toward improvement in survival has been observed.

6.3 Operable stage II
6.3.1 Treatment strategy

Mostly stage II disease is diagnosed only after pathological examination and account for around 20% of all NSCLC patients. The 5-year survival rate, if resection is complete, is of 34-55% in T1N1 and 24-40% in T2N1 (Mountain 1997; Baas 2002). Tumor size (T1 vs T2), histology (squamous vs nonsquamous histology) and the number and location of nodes are significant prognostic variables after complete resection (Deslauriers 2000a). In patients with N1 involvement the presence of lobar lymphnode or hilar N1 disease seems to influence 5-year survival, being 65% in the first case and only 39% in the latter (Yano 1994). Surgery is cornerstone for T3 tumours, where extended resection is possible. Tumours invading parietal pleura or chest wall (T3) are placed in stage IIB or stage IIIA according to nodal involvement (T3N0 are placed in stage IIB, T3N1 or T3N2 are placed in stage IIIA). Chest wall infiltrating disease, including rib involvement, is potentially considered resectable. Such resections include chest wall, diaphragm, pericardium. Survival of completely resected (R0) patients is dependent on the extent of nodal involvement and much less so on the depth of chest wall invasion (parietal pleural invasion only rather than invasion of chest wall musculature or ribs): the 5-year survival of patients with completely resected T3N0 ranges from 22% to 38-50% (Downey 1999; Gould 1999; McCaughan 1985; Piehler 1982; Baas 2002).

6.3.2 Stage II

Recommended treatment is optimal surgery on a type C basis. Complete resection is achievable with lobectomy, removal of the hilar nodes and mediastinal lymph node dissection (link 6.C) on a type C basis. The role of radical systematic mediastinal lymphadenectomy (link 6.C) is debated (Asamura 1999; Izbicki 1994; Izbicki 1998; Okada 1998). Postoperative thoracic radiotherapy (PORT) (link 6.B2) is not recommended in radically resected stage II NSCLC on a type 1 level of evidence (PORT 1998; Burdett 2005; Lally 2006), since it has a detrimental effect on survival. PORT is standard option on a type C basis in R1 patients and in stage II with in adverted pN2 disease, after adjuvant chemotherapy. Adjuvant cisplatin-based chemotherapy (link 6.A2) is standard option in radically resected stage II NSCLC in good performance status on a type 1 level of evidence (Pignon 2006). The Lung Adjuvant Cisplatin Evaluation (LACE) Collaborative group (Pignon 2006) has collected and pooled individual patient data from five largest recent trials: among the 1616 stage II patients subset, they reported a 27% reduction in the risk of death (HR: 0.83) from chemotherapy. Induction chemotherapy before surgery is investigational.

6.4 Inoperable, unfit, stage I and stage II

In patients with stage I/II resectable disease, inoperable because of non-tumour related co-morbidity, radiotherapy is recommended on a type C basis. Radiotherapy appears to result in a better survival, even if no randomized trials have addressed this issue ((Rowell 2001; Sirzen 2003). With standard radiotherapy, reported data from Cochrane Database (Rowell 2001) for overall survivals are 17-55% at 3 years and 0-42% at 5 years, while for cancer specific survivals are 22-56% at 3 years and 13-39% at 5 years. Large differences are due to comorbidity, poor correlation between clinical and pathological staging and underestimation of the clinical (N and M) stage. In general, better results are obtained with smaller lesions and in patients receiving higher doses. Continuous hyperfractionated accelerated radiotherapy, CHART, (54 Gy in 12 days) is associated with increased 2 year survival (37%) compared to conventional RT, 60 Gy in 6 weeks, (24%) and is therefore suitable for individual clinical use on a type 2 level of evidence (Saunders 1999b; Bentzen 2000). Hyperfractionated radiotherapy as well as stereotactic hypofractionated high-dose irradiation are investigational.

6.5 Stage IIIA

6.5.1 Treatment strategy

Stage IIIA non-small cell lung cancer is a heterogeneous group including patients with T1-T2-T3 lesions with metastatic disease to the ipsilateral mediastinal nodes (N2) as well as T3N1 patients. This stage ranges from apparently resectable tumors to Bulky or fixed multistation N2 disease. Difficulties on treatment strategy are due both to the large heterogeneity of clinical presentations in this broad stage and to the myriad of treatment options and targets (from “curative” to palliation). Patients with stage IIIA and IIIB (locally advanced disease) at initial presentation represent around 30% of all patients with NSCLC; of those, one third (10% of the total) have stage IIIA. Factor affecting survivals is mediastinal nodal involvement. Published 5-years survival rate is only 23% (Mountain 1997). Surgery is the recommended treatment on a type C basis for completely resectable stage IIIA patients, which means those with T3 tumors and carefully selected cases with ipsilateral mediastinal nodal involvement (N2). The 5-year survival of surgery alone in patients with negative mediastinoscopy but intraoperative detection of multiple mediastinal stations is approximately 5-10%, while survival rate for patients with negative mediastinoscopy and limited intraoperative N2 disease or microscopic nodal involvement ranges from 20 to 30% (Suzuky 1999). In patients with bulky N2-N3 involvement probability of cure is 0%. Multimodality therapy is either standard option on a type C basis or suitable for individual clinical use on a type 3 level of evidence in all subsets of stage IIIA patients.

6.5.2 Resectable stage III A, incidental N2 disease

Although uncommon with current preoperative staging (including CT scan, PET-TC and mediastinoscopy), incidental (occult) single station N2 metastases may be recognized intraoperatively. If complete resection is technically possible, recommended treatment is surgery on a type C basis. Systematic mediastinal lymph node sampling or complete mediastinal lymph node dissection is recommended on a type R basis, since in approximately one third of patients metastatic tumor cells bypass the N1 hilar lymph nodes. In some patients, occult nodal metastases are found only on final pathologic examination. Adjuvant cisplatin-based chemotherapy is standard option in radically resected patients in good performance status on a type 1 level of evidence (Pignon 2006). The Lung Adjuvant Cisplatin Evaluation (LACE) Collaborative group (Pignon 2006) has collected and pooled individual patient data from five largest recent trials (ALPI, ANITA, IALT, BLT and JBR10) of cisplatin-based adjuvant chemotherapy. At five years, the absolute benefit on survival was 4.2% with chemotherapy (HR of death: 0.89). Four of these trials included from 30% to 39% stage IIIA patients (ALPI, BLT, ANITA and IALT). The benefit varied with stage, being greater in patients with stage II and IIIA (HR of death: 0.83%). Adjuvant postoperative mediastinal radiation (PORT 1998, after adjuvant chemotherapy, is suitable for individual clinical use on a type 2 level of evidence to reduce the risk of local relapse, particularly for patients with higher risk of local recurrence (involvement of multiple nodal stations, extra capsular tumor spread). PORT is standard option on a type C basis in patients with close or R1-R2 margins. The Lung Cancer Study Group demonstrated a striking effect of RT to significantly reduce the risk of local relapse, but it failed to demonstrate a significant survival benefit (LCSG 1986). The PORT metha-analysis concluded that postoperative radiation was associated with a highly significant increase in the risk of death (RR 1.21), but the increased risk of death was most marked in stage I patients and was not significant for patients with N2 disease (PORT 1998). A later review from a Canadian group (Okawara 2004) concluded that no survival benefit was found with PORT in completely resected stage IIIA disease and that the data for improved local control were conflicting. Lally (Lally 2006) has recently confirmed that, in a large population-based cohort of over 7000 patients, from 1988 to 2002, PORT did not have a significant impact on survival overall. However, in subset analysis, PORT was associated with a significant increase in survival for N2 patients (HR=0.85). In general, modern RT techniques will lead, in selected cases, to a better local control, without excess deaths due to treatment. The risk of heart disease mortality associated with PORT has declined in more recent years (Lally 2007). Combined postoperative concurrent chemo-radiotherapy is experimental. Trials are ongoing.

6.5.3 Potentially resectable stage III A, prethoracotomy N2 disease

Nodal metastases are recognized prethoracotomy by nodal biopsy in mediastinoscopy or PET scan. Although resectability criteria are not uniformly accepted, for most surgeons, the involved nodes should be discrete and not adherent to the trachea, subcarinal airway or great vessels (Pearson 1999). Although resectable, the rate of long-term survival after surgery alone or followed by adjuvant therapy is marginal or poor, therefore surgical resection alone is not recommended on a type C basis and primary surgical resection followed by adjuvant therapy is experimental. Postoperative platinum-based chemoradiotherapy is standard option on a type C basis in R1-R2 patients Small randomized phase III trials have compared neoadjuvant chemotherapy including cisplatin followed by surgery and PORT to surgery alone (Elias 1997; Rosell 1999; Roth 1998; Depierre 2002; Nagai 2003); although conflicting results have been shown, a survival benefit from induction therapy has been reported in some studies (Elias 1997; Rosell 1999; Roth 1998). A Cochrane systematic review and meta-analysis was carried out to assess the effectiveness of preoperative chemotherapy in NSCLC: from 12 eligible Randomized Controlled Trials including 988 pts, pre-operative chemotherapy increased survival with a hazard ratio of 0.82, equivalent to an absolute benefit of 6%, increasing overall survival across all stages of disease from 14% to 20% at 5 years (Burdett 2006). The authors say that this analysis is currently the best estimate of the effectiveness of pre-operative chemotherapy, but this is based on a small number of trials and patients. More recent trials have compared induction chemotherapy (with or without radiotherapy) followed by surgery versus chemoradiotherapy alone. The larger studies were EORTC 08941 (van Meerbeeck 2007) and RTOG 9309 (Albain 2005). In the EORTC study, 579 patients with histologic proven stage IIIA disease were treated with three cycles of cisplatin-based chemotherapy (mainly cisplatn/gemcitabine); 332 responding patients were subsequently randomly allocated to resection (+/- PORT) or sequential radiotherapy (60 Gy). In the surgical arm, only 50% of patients had a radical resection, 42% had a pathologic downstaging, 5% had a pathologic complete response, 4% died after surgery. Morbidity and mortality from radiotherapy were low, only one patient died of radiation pneumonitis. Median, overall survival (16% vs 14% at 5 years) and progression-free survivals were similar in both groups (van Meerbeeck 2007). In the RTOG study (Albain 2005), 396 patients with histologic proven stage IIIA disease, technically resectable, were randomized to concurrent chemo-radiotherapy (two cycles cisplatin/etoposide and 45 Gy RT) followed by surgery (and two cycles postoperative chemotherapy) versus concomitant chemoradiotherapy alone (two cycles cisplatin/etoposide and 61 Gy RT). In the surgical arm, 46% had a pathologic downstaging, 18% had a pathologic complete response, 8% died after surgery (26% after pneumonectomy), In the radiotherapy arm, treatment-related mortality was only 2%. Progression-free survival was better in the surgical arm, but overall survival was similar (27% vs 20% at 5 years). Platinum-based induction chemotherapy (with or without radiotherapy) before surgery is feasible. After induction chemoradiotherapy, pneumonectomy is not recommended for high mortality rate (Albain 2005). Given survival curves and low morbidity and mortality, radiotherapy is suitable for individual clinical use on a type 2 level of evidence as locoregional treatment (van Meerbeeck 2007; Albain 2005). Therefore, three cycles of platinum-based chemotherapy (platinum/gemcitabine) followed by sequential radiotherapy (60 Gy) or concomitant chemoradiotherapy (two cycles cisplatin/etoposide and 61 Gy RT) are suitable for individual clinical use on a type 2 level of evidence (van Meerbeeck 2007; Albain 2005).

6.5.4 Unresectable stage III A, (Bulky or fixed N2 disease)

Most trials include NSCLC patients with locally advanced unresectable disease, without distinguishing between stage IIIA and stage IIIB disease. The same recommendations apply to both unresectable stage IIIA and stage IIIB disease. Combination platinum-based chemotherapy and radiotherapy is standard option on a type C basis for patients with good performance status. Concurrent platinum-based chemoradiotherapy is suitable for individual clinical use on a type 2 level of evidence for patients with very good performance status and minimal weight loss (<5%). Otherwise, sequential chemo-radiotherapy (induction platinum-based chemotherapy followed by full dose radiotherapy) is standard option on a type C basis.

6.5.5 Resectable stage III A, T3 N1

The T3 tumours are tumors of any size invading directly chest wall (including superior sulcus tumours), or diaphragm, or mediastinal pleura, or parietal pleura or parietal pericardium or proximal airway (less than 2 cm distal to the carina). Most of them are resectable and the T3N1 recommendations are the same as for stage II disease . Surgery is standard option on a type C basis. Surgery is cornerstone for T3 tumours, where extended resection is possible. Tumors invading parietal pleura or chest wall (T3) are placed in stage IIB or stage IIIA according to nodal involvement (T3N0 are placed in stage IIB, T3N1 or T3N2 are placed in stage IIIA). Chest wall infiltrating disease, including rib involvement, is potentially considered resectable. Such resections include chest wall, diaphragm, pericardium. Survival of completely resected (R0) patients is dependent on the extent of nodal involvement and much less so on the depth of chest wall invasion (parietal pleural invasion only rather than invasion of chest wall musculature or ribs): the 5-year survival of T3N0 may reach 38-50%, while it is around 30% for T3N1 disease and 15% for T3N2 disease (Downey 1999; Gould 1999; McCaughan 1985; Piehler 1982; Baas 2002). Adjuvant cisplatin-based chemotherapy is standard option in radically resected patients in good performance status on a type 1 level of evidence (Pignon 2008). PORT is standard option on a type C basis in R1-R2 resections, after adjuvant chemotherapy.

6.6 Superior sulcus tumors, T3-4, N0-1

For resectable superior sulcus tumors (Pancoast tumours) preoperative radiation (40 Gy) is suitable for individual clinical use on a type 3 level of evidence (Arcasoy 1997; Hagan 1999). This approach has yielded 5-year survival in the range of 20-35%. If resectable, induction chemoradiotherapy followed by surgery and adjuvant chemotherapy is suitable for individual clinical use on a type 3 level of evidence. In the SWOG- Intergroup Trial 0160, 110 patients received two cycles of cisplatin and etoposide concurrently with 45 Gy radiotherapy: 80% underwent thoracotomy, 76% had complete resection, 56% had pathologic complete response (CR). Five-year survival was 44% for all patients and 54% after complete resection (Rusch 2007). In the Japan Clinican Oncology Group trial 9806, 76 patients received two cycles of mitomycin, cisplatin and vindesine concurrent to radiotherapy, 45 Gy: 76% underwent resection, 68% had complete resection, 12 patients had pathologic CR. The disease-free and overall survival rates were 45% and 56% at 5 years (Kunitoh 2008). Similarly to other site locally advanced unresectable stage IIIA and stage IIIB disease, combination platinum-based chemotherapy and radiotherapy is standard option on a type C basis for patients with good performance status. Concurrent platinum-based chemoradiotherapy (link 6.A) is suitable for individual clinical use on a type 2 level of evidence for patients with very good performance status and minimal weight loss ( <5%). Otherwise, sequential chemo-radiotherapy (induction platinum-based chemotherapy followed by full dose radiotherapy) is standard option on a type C basis.

6.7 Stage III B

6.7.1 Treatment strategy
Stage IIIB include T4, any N lesions and any T,N3 disease; most stage IIIB are unresectable.
6.7.2 Unresectable stage III B

Most trials include NSCLC patients with locally advanced unresectable disease, without distinguishing between stage IIIA and stage IIIB disease. The same recommendations apply to both unresectable stage IIIA and stage IIIB disease. Combination platinum-based chemotherapy and radiotherapy is standard option on a type C basis for patients with good performance status. Concurrent platinum-based chemoradiotherapy is suitable for individual clinical use on a type 2 level of evidence for patients with very good performance status and minimal weight loss ( <5%). Otherwise, sequential chemo-radiotherapy (induction platinum-based chemotherapy followed by full dose radiotherapy) is standard option on a type C basis. In 1995-1996 three meta-analysis reviewing over 50 small trials have concluded that the addition of chemotherapy to radiotherapy, either concurrently or sequentially administered, offers a small but significant survival benefit in patients with locally advanced, unresectable NSCLC (10% to 20% decrease in the risk of death, mean gain in life expectancy of about 2 months), but at a price, namely the increased toxicity associated with combined treatment (Pritchard 1996; Marino 1995; NSCLC-CG 1995). Other subsequent large randomized trials, testing chemotherapy (such as cisplatin and vinblastine or MIC) before standard radiotherapy vs radiotherapy alone have showed small but significant improvement on median, 2-year and 5-year survivals, with acceptable toxicity, but only for patients with good PS and minimal weight loss (<5%). Patterns of failure are similar for RT and CT/RT group.(Cullen 1999; Sause 2000). A few subsequent phase III trials have compared sequential vs concurrent radiation and chemotherapy. A large Japanese randomized trial, including over 300 patients, most stage IIIB disease, has compared chemotherapy (two cycles mitomycin C, cisplatin and vindesine) concurrent with RT (56Gy) to the same chemotherapy followed by the same RT: concurrent CT/RT yields a significantly better median survival (16 months vs 13 months) and 5-year survival (16% vs 9%) (Furuse 1999; Furuse 2000). The RTOG 9410 trial, including over 600 patients, compared sequential chemotherapy with Cisplatin/vinblastine followed by 63-Gy radiotherapy to concurrent CT/RT: concurrent CT/RT yields a significantly better median survival (17 months vs 15 months) and 4-year survival (21% vs 12%) (Curran 2000). A French study (178 patients) compared cisplatin/vinorelbine for 3 cycles followed by 66-Gy RT to concurrent cisplatin/etoposide for 2 cycles and RT followed by cisplatin/vinorelbine for 2 cycles: again, concurrent CT/RT yields a significantly better median survival (16.3 months vs 14.5 months) and 4-year survival (21% vs 14%) Acute toxicity (myelosuppression and esophagitis ) was greater among patients on the concurrent arms, but concurrent therapy did non increase the number of treatment-related deaths. Therefore, concurrent platinum-based chemoradiotherapy is suitable for individual clinical use on a type 2 level of evidence for patients with very good performance status and minimal weight loss (suitable for individual clinical use on a type 2 level of evidence (Auperin 2006). No phase III trials have proved that chemotherapy plus multiple daily fraction RT yields superior survival than chemotherapy plus once-daily thoracic RT: once-daily thoracic RT plus chemotherapy is recommended on a type C basis. Induction full-dose chemotherapy before concurrent chemoradiation show high response rate (over 70%) at the price of a higher incidence of acute severe esophagitis (10-27%) and severe late lung toxicity (around 20%). However, no benefit in any survival and failure pattern has been observed for induction CT followed by concurrent CT/RT over concurrent chemo-radiotherapy alone in three randomized trials from CALGB/ECOG (Clamon 1999), French Lung Cancer Study Group (Gervais 2005) and CALGB 39801 (Vokes 2004) which tested this approach.

6.7.3 Potentially resectable stage III B

Surgery may be indicated for carefully selected patients with T4 solely on the basis of a satellite tumor nodule(s) within the same lobe. A 5-year survival rate of around 20% has been reported from retrospective case series. Adjuvant chemotherapy is standard option on a type R basis.

6.8 Unfit stage IIIA and IIIB patients

Palliative radiotherapy alone, up to 50 Gy, is suitable for individual clinical use on a type R basis for unfit patients with symptoms as a result of chest disease (dyspnea, cough, hemoptysis and pain. Radiotherapy can only be considered in patients where the tumor can be encompassed by a volume not prohibitive for radiation complications and when there is no risk for esophageal fistulisation. In addition, patient’s PS should be 0-2 and pulmonary function should be adequate (FEV1>1L/s). Results are however dismal, with 5-year survival rate less than 5% and nearly all patients dying of distant disease, while local progression occurs in more than 70% of patients. In the palliative setting, a variety of dose/fraction schedules have been used, either conventional RT up to 30 Gy (10x3Gy in 2 weeks) or 50 Gy (25 x 2 Gy in 5 weeks) or hypofractionated RT (e.g. 2 x 8 Gy with 1 week interval, or 1 x 10 Gy, or 5 x 4 Gy). The general trend from randomized trials with positive results were that higher dose conventional regimens resulted in better palliation and longer survival. However, two studies show that 16 Gy/2fr/8days is equal to 20Gy/5fr/5days (Senkus-Konefka 2005) and 17Gy/2fr/8days is as good as 42Gy/15fr/19days (Sundstrom 2004), Therefore, either conventional schedules or hypofractionated schedules are suitable for individual clinical use on a type 2 level of evidence, depending on patient’s PS and estimated survival.

6.9 Stage IV (metastatic disease)

6.9.1 Treatment strategy

Since at two years the vast majority of patients have died from disseminated lung cancer, treatment strategy should be individualised according to clinical feature and patients’ preferences.

6.9.2 Oligometastatic disease

Tailored treatment, including surgery of the primary tumour and of a single metastasis, is suitable for individual clinical use on a type 2 level of evidence (Burt 1992; DeMeester 1989; Nakahara 1989; Patchell 1990). Surgical resection may provide benefit for solitary metastases found either synchronously or metachronously in brain, ipsilateral lung and/or adrenal gland. In a retrospective study the overall 5-year survival of patients with isolated synchronous or metachronous metastases was found to be 7,5% (Naruke 1988).

6.9.3 Advanced disease in good performance status

Although survival benefit is very small and prognosis poor, palliative chemotherapy is standard treatment on a type 1 level of evidence, in patients with good performance status (PS 0-1) (Cullen 1999; Grilli 1993; Marino 1994; NSCLC-CG 1995; Souquet 1993). Palliative chemotherapy is able to improve symptoms, quality of life and survival in fit patients. Median survival is around 8-10 months and 1-year survival is 30-40% in more recent trials. A retrospective analysis of phase III trials conducted in North America over the last two decades, involving over 8000 patients with advanced NSCLC, has shown that the prolongation in median survival was rarely in excess of 2 months (Breathnach 2001). One of the meta-analyses performed, reported a 27% reduction in the risk of death equivalent to an absolute improvement in 1-year survival of 10% or an increased median survival of 1,5 months for cisplatin-based trials (NSCLC-CG 1995). Furthermore, a Canadian study showed a decrease in costs in chemotherapy-treated patients because of a lower incidence of disease-related complications (Jaakkimainen 1990). Two randomized European studies and one randomized Asian support a similar small beneficial effect of cisplatin-based chemotherapy (such as MIC or MVP) or carboplatin-based chemotherapy on survival in advanced NSCLC, PS 0-1, when compared to best supportive care (BSC) only (Cullen 1999; Helsing 1998; Thongprasert 1999; Billingham 2001). Similar findings have been repeatedly confirmed in recent trials comparing newer single agent chemotherapy (gemcitabine, taxanes) with BSC (Ranson 2000; Roszkowski 2000; Anderson 2000). In a small group of NSCLC patients previously treated with cisplatin, around 70% of patients would chose chemotherapy if this would result in a substantial reduction of symptoms, even without life prolongation (Silvestri 1998). standard chemotherapy in PS 0-1 advanced NSCLC patients is a two drug combination regimen containing cisplatin and a newer agent (gemcitabine, vinorelbine, or taxanes) on a type 1 level of evidence. Adding a third cytotoxic chemotherapeutic drug has a weak effect on response, no effect on survival and may be harmful (Delbaldo 2004; Booton 2002; Hotta 2004). The combination of newer drugs with platinum demonstrates equivalent survival to traditional regimens, such as MVP (mitomycin-vinblastine or vindesine-cisplatin), MIC (mitomycin-ifosfamide-cisplatin) or EC (etoposide-cisplatin) (Crinò 1999; Cardenal 1999). However, a better toxic profile and stronger clinical benefit have been reported with newer combinations. The optimal association as well as the optimal number of chemotherapy courses are controversial yet (Booton 2002). Chemotherapy (carboplatin and paclitaxel or cisplatin and gemcitabine) plus bevacizumab is suitable for individual clinical use on a type 2 level of evidence in a clinically selected subset of PS 0-1 patients with stage IV NSCLC (non-squamous histology, lack of brain metastases, no hemoptysis, no severe hypertension, no central tumours) (Sandler 2006; Manegold 2007). Radiotherapy is standard treatment on a type C basis for isolated symptomatic lesions (such as bone metastases, spinal cord compression).

6.9.4 Advanced disease in elderly patients

NSCLC is typical of advanced age, since more than 50% of patients are diagnosed over the age of 65 and more than two-thirds of patients dying of lung cancer are over 65 years old. A cut-off of 70 years seems to be the most appropriate for definition of elderly population (Balducci 2000). To plan appropriate treatment, it is mandatory to practice a comprehensive geriatric assessment (CGA) including evaluation of comorbidity as well as functional, mental and nutritional status, and socio-economic conditions. However a standard score has not yet been defined. A retrospective study of 6232 elderly patients not included in clinical trials showed that chemotherapy for advanced NSCLC seems to have the same effectiveness as that seen in younger patients included in randomized trials (Earle 2001). The meta-analysis of chemotherapy versus best supportive care, reports a 27% reduction in the risk of death equivalent to an absolute improvement in 1-year survival of 10% or an increased median survival of 1,5 months for cisplatin-based trials. No difference related to age was observed (NSCLC-CG 1995). Therefore, palliative chemotherapy is standard option on a type R basis in elderly patients with good performance status . Vinorelbine has shown a 20% response rate, mild toxicity, a small survival benefit (from 21 to 28 weeks) and possible better QOL in elderly patients with advanced NSCLC and good performance status, when compared to best supportive care (Gridelli 2001). Gemcitabine is the most widely investigated agent. In phase II studies, gemcitabine has shown response rate of 16% to 33% and median survival of 29 to 33 weeks (Ricci 2000; Gridelli 2001; Altavilla 2000; Martoni 2001). Both weekly paclitaxel and weekly docetaxel have been tested in small phase II trials with similar results (18- 20% response rate, 5 to 11 months of median survivals) (Fidias 2001; Hainsworth 2000). A randomized phase III trial from Japan (Takeda 2005) compared single-agent docetaxel vs vinorelbine in 180 elderly patients with good PS: response rates and PPS were better with docetaxel, whereas median and 1-year survival rates showed only a trend in favour of docetaxel. A large randomized phase III trial including about 700 patients has compared single agent chemotherapy with vinorelbine or gemcitabine to the gemcitabine plus vinorelbine combination MILES Study): polychemotherapy with gemcitabine plus vinorelbine does not improve outcomes (Response rate, time to progression, OS and QOL). Although QOL was similar across the three treatment arms, the combination treatment was more toxic than the two single drug regimens (Gridelli 2003) Therefore, single agent chemotherapy with a third generation drug (either gemcitabine, or vinorelbine, or docetaxel) is standard option in elderly patients with good performance status on a type C basis; their choise should be based on the toxicity profile and type of comorbid conditions (Gridelli 2002; Gridelli 2005). Clinical benefit (in term of objective response and symptom relief) has been observed in elderly patients treated with cisplatin-based doublets (Hickish 1998). Retrospective data analysis has been kept in randomized, phase III trials of platinum-based chemotherapy, in order to compare outcomes in older patients. Different groups conclude that response rate, toxicity and survivals are similar in younger and older patients, with good performance status. More leukopenia and neuropsychiatric toxicity can be expected in patients 70 years old or older. (Langer 2002; Rocha Lima 2002). A similar retrospective analysis was conducted in TAX 326 (docetaxel/cisplatin vs docetaxel/carboplatin vs cisplatin/vinorelbine): again response rate, toxicity and survivals are similar in younger and older patients; overall, carboplatin/docetaxel had a more favorable therapeutic index (Belani 2005). The authors conclude that advanced age alone should not preclude appropriate/aggressive NSCLC treatment. Nevertheless, given the small benefit showed on survival and the possible selection bias of trials, platinum-based or carboplatin-based doublets should be considered at present either investigational or suitable for individual clinical use in “fit elderly” patients (PS 0-1, adequate organ function) on a type 3 level of evidence (Gridelli 2005). Palliative care is standard treatment on a type R basis in elderly patients with advanced NSCLC and poor performance status (Gridelli 2005).

6.9.5 Thoracic symptomatic disease and patients in poor general conditions

In symptomatic patients due to intrathoracic tumour – i.e. cough, haemoptysis and chest pain – short course palliative radiotherapy is considered standard treatment on a type R basis for palliation of symptoms. Massive bleeding is rare in lung cancer patients and these patients are more at risk of asphyxia, due to blood in the airways, than of exsanguination. Relief of symptoms can be obtained in 60 to 80% of patients, with a medium duration of 3 to 5 months, with minimal side-effects for the patient (MRC 1991). In patients with symptoms due to endobronchial or endotracheal tumour, a single fraction of intraluminal brachy-radiotherapy to a dose of 15 to 20 Gy at 1 cm from the source results in similar palliation rates (Gollins 1994). Such treatment is appropriate even in symptomatic patients with intraluminal relapse after external beam radiotherapy. Serious complications of this procedure (fistulization, trachea perforation, pneumonitis) are rare except for bleeding which has been reported in several series as ranging from 0 to 36%. Obstructive disease may even be palliated with laser treatment or with bronchoscopic photodynamic therapy. Patients in poor general conditions (PS 2) can present improvements in quality of life and symptoms control after chemotherapy, while a survival improvement has not been demonstrated (Booton 2002). In an English study comparing mitomycin/ifosfamide/cisplatin (MIC) to BSC, PS2 patients gained no survival benefit from chemotherapy, but they experienced the greatest improvement in QOL (Billingham 2001). Another English study has shown that symptomatic advanced NSCLC patients treated with Gemcitabine experienced better QOL and reduced symptoms compared with patients receiving BSC alone, even if no difference in survival was reported (Anderson 2000). In A French study comparing vinorelbine to cisplatin+vinorelbine to cisplatin+vindesine, survival in PS 2 patients was similar, whatever the treatment. Therefore, PS 2 patients might not benefit from cisplatin combination chemotherapy (Soria 2001). Either single agent chemotherapy (vinorelbine or gemcitabine or docetaxel) or palliative care are suitable for individual clinical use on a type R basis (Soria 2001; Anderson 2000; Billingham 2001).

6.9.6 Malignant pleural effusion

Pleural effusion is a poor prognostic sign. Mean survival of these patients is only 3 to 6 months. Five-year survival is negligible. Patients in good general conditions may benefit from sclerosis of pleural surface which requires complete drainage and full reexpansion of the lung. The pleural sclerosing effect is obtained by injecting agents like talc, tetracycline, bleomycin into the drainage tube. No agent is superior to the others, even if talc has been reported to have minimal complications with 90-100% success rate in preventing recurrent pleural effusion. Randomised trials are ongoing. With the other agents the procedure has a success rate of approximately 60-70%. In cases of not full re-expansion of the lung, a pleural decortication under VATS is suitable for individual clinical use in patients with good performance status on a type 3 level of evidence. Complications of this procedure are blood loss and prolonged air leaks. For these reasons this procedure is not recommended on a type R basis in patients with short life expectancy. Repeated thoracenteses are recommended in these cases. Palliative chemotherapy is standard treatment on a type 1 level of evidence, in patients with good performance status (PS 0-1).

6.9.7 Brain metastases

Palliative whole brain radiotherapy (WBRT) is standard treatment for multiple brain metastases on a type C basis. WBRT is associated with high symptomatic response but survival is poor (median survival 3-5 months) (Ryan 1995; Sen 1998). Only a limited number of small studies have assessed the effects of chemotherapy in patients with multiple brain metastases from NSCLC. In general, the efficacy against brain metastases is similar to the overall activity in patients with stage IV NSCLC (Postmus 1999). Among 43 patients with brain metastases from NSCLC treated with cisplatin/etoposide, response rate was 30%, median survival was about 7 months. Chemotherapy with a two-drug regimen containing cisplatin or a platinum analogue and a newer agent (gemcitabine, vinorelbine or taxans) is suitable for individual clinical use on a type 3 level of evidence in patients with multiple brain metastases (Franciosi 1999; Schuette 2004, Kim 2005). Gefitinib is active in patients with brain metastases from NSCLC (Chiu 2005); at present its use is investigational. Surgical resection of single brain metastasis, found either synchronously or metachronously, followed by WBRT is suitable for individual clinical use on a type 2 level of evidence when resection is technically feasible, for patients in good performance status and stable extracranial disease (Patchell 1990; Vecht 1993). The combined treatment led to a longer survival and better quality of life than radiotherapy alone. In patients with synchronous metastases, complete resection of primary tumour is the primary determinant of survival (Burt 1992). Reported median and 1-year survivalrates were 40 weeks and 55%. Stereotactic radiosurgery of few lesions in the brain is suitable for individual clinical use on a type 3 level of evidence. The major advantage of this approach is the delivery of high-dose RT to the lesions, sparing the surrounding brain. Local control is observed in 65 to 94% of patients, median survival after radiosurgery is from 8 to 14 months (Phillips 1994; Williams 1998; Gerosa 2005). Prophylactic cranial irradiation (PCI) for preventing brain metastases is investigational (Lester 2005).

6.10 Progressive disease after first-line chemotherapy

Patients with primary lung cancer have a higher risk of developing synchronous primary lung tumours. Synchronous tumours are defined by the presence of more than one tumour mass in the lung, by differences in histological subtype, by the presence of separate bronchial origins, or by differences in DNA stemlines. The incidence of patients presenting with more than one primary lung tumour at the time of diagnosis is lower than 2%. Synchronous neoplasms are commonly found at the time of surgical resection without preoperative radiological evidence. Synchronous lung neoplasm should be distinguished from pulmonary metastases and from satellite nodules, the latter being defined as well circumscribed accessory foci of carcinoma adjacent to the primary tumour but clearly separated from it by normal parenchyma and considered as a subcategory of stage IIIA disease (Deslauriers 1989). Recommended treatment, on a type C basis, is surgical resection, especially when both primaries are in the same lung, the presence of satellite nodules is also a criterion of pneumonectomy. Preoperative chemotherapy is suitable for individual clinical use on a type 2 level of evidence when N2 disease is present (Rosell 1999; Roth 1998). If a sole synchronous lesion is discovered in a different lobe from the primary tumour, resection of both lesions is recommended on a type R basis. Prognosis for synchronous tumours has been reported as poor, but is significantly better for patients with synchronous squamous carcinomas (Carey 1993). Treatment of synchronous tumours located in other sites depends on individual disease presentation and extension.

6.A Chemotherapy and targeted therapy

standard chemotherapy in PS 0-1 advanced or recurrent NSCLC patients is a two drug combination regimen containing cisplatin and a newer agent (gemcitabine, vinorelbine, or taxanes) on a type 1 level of evidence. Adding a third cytotoxic chemotherapeutic drug has a weak effect on tumor response, no effect on survival and may be harmful (Delbaldo 2007; Booton 2002; Hotta 2004). The combination of newer drugs with platinum demonstrates equivalent survival to traditional regimens, such as MVP (mitomycin-vinblastine or vindesine-cisplatin), MIC (mitomycin-ifosfamide-cisplatin) or EC (etoposide-cisplatin) (Crinò 1999; Cardenal 1999). However, a better toxic profile and stronger clinical benefit have been reported with newer combinations. The optimal association as well as the optimal number of chemotherapy courses are controversial yet (Booton 2002). Large randomized phase III trials have shown that three-drug cisplatin combinations have response rates and survival similar to cisplatin/vinorelbine or cisplatin/gemcitabine, while toxicity is higher for the triplet (Alberola 2003; Souquet 2002). A recent published meta-analysis has evaluated the clinical benefit of adding a drug to a single-agent or 2-agent chemotherapy regimen in terms of tumor response rate, survival and toxicity. Sixty-five trials (including 13601 patients) published between 1/1980 and 10/2003 were eligible. Meta-analysis has concluded that a 2-drug regimen provides a higher response rate and longer survival rates than single agent cisplatin, while adding a third drug has a weaker effect on tumor response and no effect on survival. A 2-drug combination is standard option on a type 1 level of evidence(Delbaldo 2004). Another meta-analysis of eight randomized trials (published between 1994-2003 and including 2374 patients) comparing cisplatin to carboplatin, plus a new agent, in patients with advanced NSCLC, has shown that cisplatin plus a new agent yelds 11% longer survival than carboplatin plus the same new drug. A 2-drug combination containing cisplatin rather than carboplatin plus a new agent is standard option on a type 1 level of evidence (Hotta 2004). Rosell compared paclitaxel /CBDCA with paclitaxel /cisplatin in 618 patients with advanced NSCLC: although paclitaxel/CBDCA and paclitaxel /cisplatin yelded similar response rates, a significantly longer median survival was obtained with paclitaxel /cisplatin (median survival 8.2 months in the paclitaxel/CBDCA arm and 9.8 months in the paclitaxel /cisplatin; the 2-year survival rates were 9% and 15% respectively) (Rosell 2002). Carboplatin is suitable for individual clinical use on a type 2 level of evidence. A number of phase III studies and one meta-analysis have tried to answer the question: which is the best 2-drug combination? However, no particular 2-drug, platinum based combination seems superior in terms of efficacy. The SWOG 9505 trial has compared paclitaxel/carboplatin (PC) to vinorelbine/cisplatin/ (VC) on 408 advanced (mainly stage IV) NSCLC. Equivalent response rates (28% vs 25%) and survivals (1-year OS 36% vs 38%, MS 8 months) have been observed. PC is less toxic and better tolerated: vomiting and leukopenia were higher in the VC group, while peripherial neurophaty was higher on the PC arm. No difference in QOL was observed. PC is also associated with higher drug costs (Kelly 2001; Ramsey 2002). The ECOG 1594 trial has compared cisplatin/gemcitabine to cisplatin/docetaxel to cisplatin/paclitaxel to carboplatin/paclitaxel on 1207 patients, either stage IIIB or stage IV or recurrent. The response rate was 19%, with a median survival of 8 months and a 1-year survival rate of 33% for all patients. None of the four CT regimens offered a significant advantage over the others, although the combination carboplatin and paclitaxel was less toxic and better tolerated than the other regimens. Farmaco-economic evaluation is lacking (Schiller 2002). Both studies confirm that the benefits of chemotherapy among good performance status patients are marginal, since response and survival rates were lower than those reported by single institution trials. Both group, SWOG and ECOG, have chosen PC as reference regimen. The TAX 326 trial has compared docetaxel/cisplatin (DC) or docetaxel/carboplatin (DCb) to vinorelbine/cisplatin/ (VC) on 1218 stage IIIB or stage IV NSCLC . The DC combination has shown a better response rate (32% vs 25%) and a better 2-year survival rate (21% vs 14%) than the VC combination Grade 3 to 4 anemia, nausea and vomiting were more common with VC than with DC or DCb. (Fossella 2003). The ILCP trial has compared three platinum-based doublets (gemcitabine/cisplatin, GC arm, vs vinorelbine/cisplatin, VC arm, vs paclitaxel/caboplatin, PCb arm) on 612 patients. Efficacy end points were not significatly different between arms, although toxicities showed differences: neutropenia, nausea and vomiting were significatly higher in the VC arm, while thrombocitopenia was more common on the GC arm and alopecia and peripheral neurotoxicity were most common on the PCb arm (Scagliotti 2002) GC arm had the lowest overall mean costs (Novello 2005) Another Italian study, comparing GC to VC on 285 patients, with the same dose and schedule of cisplatin, produced similar overall response, clinical benefit and overall survival, while only mild differences in toxicity were observed. On the contrary, pharmaco-economical evaluation favoured the VC doublet (Martoni 2005). Analysis of third-generation agent plus platinum regimens has shown a non-significant trend favoring gemcitabine-platinum regimens, HR 0.93%. This means an absolute benefit at 1 year of 4%, a really modest clinical benefit (Le Chevalier 2005). All these findings suggest that the choice between combinations could be done evaluating efficacy, toxicities, personal experience as well as patient’s preferences. Nonplatinum based regimens have been evaluated, as well. The combinations gemcitabine-docetaxel (GD) and cisplatin-docetaxel have comparable activity (response rate around 30%, median survival 10 months, 1-year survival 40%), but gemcitabine-docetaxel is less toxic (Georgoulias 2001) Efficacy end points were not significant different between gemcitabine/docetaxel (GD) and vinorelbine/cisplatin, however the VC regimen was more myelotoxic (Pujol 2005). A number of phase II studies have shown that Gemcitabine plus vinorelbine (GV) is an active and well tollerated regimen. A recent meta-analysis has compared platinum-based vs non-platinum-based chemotherapy in 37 trials, including 7633 patients. The 1-year survival rate was increased by 5% with platinum-based regimens vs nonplatinum therapies (34% vs 29%). However, when platinum-based therapy were compared with third-generation-based doublet combinations (such as GD or GV) only, no statistically significant increase in 1-year survival was found (D’Addario 2005). Therefore, a third-generation-based combination regimen, such as gemcitabine/docetaxel or gemcitabine/vinorelbine is suitable for individual clinical useon a type 2 level of evidence if a platinum-based CT is contraindicated. The optimal number of chemotherapy courses is controversial. Only one randomized trial has compared 3 vs 6 courses of MVP, demonstrating no clinical benefit for continuing MVP chemotherapy beyond 3 courses; however, these results may not apply to newer combinations of drugs (Smith 2001). Moreover, a composite of dose intensity and treatment duration may have some impact on clinical outcome (Booton 2002). Recent randomized trials of newer combinations have shown that, in practice, patients receive a median of no more than 3-4 courses (Booton 2002). A recent published trail compared four cycles of carboplatin+paclitaxel versus continuous treatment until progression: no overall benefit in survival, QOL, response rate has been observed continuing treatment beyond 4 cycles. A trend to increased neuropathy has been reported at cycle 8 (Socinski 2002) At present, a maximum of 6 courses in responding patients is suitable for individual clinical use on a type R basis. Bevacizumab has shown survival benefit when combined with chemotherapy in a clinically selected subset of PS 0-1 patients with stage IV NSCLC (non-squamous histology, lack of brain metastases, no hemoptysis, no severe hypertension, no central tumours). The ECOG study randomized 878 patients with recurrent or advanced non-squamous NSCLC to carboplatin and paclitaxel +/- bevacizumab 15 mg/Kg every 21 days: median survival (12.3 vs 10.3 months) and response rates (35% vs 15%) were better in the chemotherapy plus bevacizumab group compared with chemotherapy-alone group. There were 15 toxic death in the chemotherapy-plus-bevacizumab group (Sandler 2006). The AVAiL study (Manegold 2007) compared cisplatin and gemcitabine +/- Bevacizumab 7.5 mg/Kg or 15 mg/Kg every 21 days in 1043 patients with recurrent or advanced non-squamous NSCLC: both doses of bevacizumab significantly improved response rates (34% vs 20%) as well as progression free survival (6.7 months vs 6.1 months). Therefore, chemotherapy (carboplatin and paclitaxel or cisplatin and gemcitabine) plus bevacizumab 7.5 mg/kg every 21 days is suitable for individual clinical use on a type 2 level of evidence in a clinically selected subset of PS 0-1 patients with stage IV NSCLC (non-squamous histology, lack of brain metastases, no hemoptysis, no severe hypertension, no central tumours) (Sandler 2006; Manegold 2007). Two oral epidermal growth factor receptors (EGFR) inhibitors, gefitinib and erlotinib, are small-molecule agents that selectively inhibit the intracellular tyrosine kinase activity of the EGFR. Either oral erlotinib 150 mg daily or oral Gefitinib 250 mg/mq/die are suitable for individual clinical use on a type 2 level of evidence as second or third line therapy for patients with relapsing NSCLC, women, never smokers, adenocarcinoma and bronchioloalveolar carcinomas .

Some standard chemotherapy regimens
1) GC regimen
Cisplatin 75-100 mg/m2 day 1
Gemcitabine 1000-1250 mg/m2 day 1, 8
Every 21 days

2) CV regimen
Cisplatin 75-100 mg/m2 day 1
Vinorelbine 25 mg/m2 day 1, 8
Every 21 days

3) Paclitaxel and cisplatin
Paclitaxel 135 mg/m2 day 1 as 24-hour infusion
Cisplatin 75 mg/m2 day 2
Every 21 days

4) Docetaxel plus platinum
Docetaxel 75 mg/mq day 1
Cisplatin 75 mg/mq day 1
Every 21 days

5) Paclitaxel and carboplatin
Paclitaxel 225 mg/m2 day 1 as 3-hour infusion
Carboplatin , AUC 6.0 mg/ml/min on day 1
Every 21 days

6) GD
Gemcitabine 1000 mg/mq day 1,8
Docetaxel 85 mg/mq day 8
Every 21 days

Concurrent platinum-based chemoradiotherapy
1) Cisplatin and etoposide
Cisplatin 50 mg/mq day 1, 8 and day 29,36
Etoposide 50 mg/mq/day from day 1 to 5 and from day 29 to 36 plus once-daily thoracic RT

6.A1 Adjuvant Chemotherapy

Randomized trials of adjuvant CT have shown conflicting results. Small randomised trials failed to demonstrate a clear survival gain in patients receiving postoperative chemotherapy, although this observation may reflect both the small sample and the use of suboptimal chemotherapy regimens (Feld 1993; Holmes 1986; LCSG 1988; Keller 2000). Moreover, only 70% of patients received the planned chemotherapy, given the poor compliance (Keller 2000). In 1995, the NSCLC collaborative group published a meta-analysis on chemotherapy: eight trials comparing surgery with surgery plus cisplatin-based chemotherapy gave a 5-year survival improvement of 5% (NSCLC-CG 1995). It has been reported that some biological markers (p53 mutation or K-ras mutation) can be predictive of survival and they could be used in the future to select individualized adjuvant therapy (Keller 2000; Wagner 2000). Another meta-analysis on 11 trials, published after 1995, including 5716 patients, has demonstrated a small benefit from cisplatin-based or single-agent UFT adjuvant CT in the treatment of resected NSCLC (Hotta 2004). In 2006-2008, the Lung Adjuvant Cisplatin Evaluation (LACE) Collaborative group has reported a new meta-analysis: individual patient data were collected and pooled from five randomized largest recent trials including 4584 patients (ALPI, ANITA, BLT, IALT and JBR10). The overall HR of death was 0.89, corresponding to a 5-year absolute benefit of 5.4%% with adjuvant cisplatin-based chemotherapy (Pignon 2008). This benefit depends on stage and is greatest with stage II and III (HR of death was 0.83), while chemotherapy may not benefit in stage IA patients and only a trend toward improvement in survival has been found for stage IB patients. The effect of chemotherapy did not vary significantly with associated drugs (vinorelbine, etoposide, vinca alkaloid); chemotherapy benefit was higher in patients with better performance status. In the ALPI/EORTC study 1209 completely resected stage I, II or IIIA patients have been randomized to receive 3 cycles of MVP vs no treatment. No difference between the 2 groups has been observed in OS, but only 70% of patients received the planned chemotherapy, given the poor compliance (Scagliotti 2003). The BLT trial, on 381 stage I-IIIA patients, confirmed ALPI findings. In contrast to the ALPI/EORTC study and BLT trial, the IALT study has shown that 3 or 4 cycles of cisplatin-based adjuvant chemotherapy improves survival among 1867 patients with completely resected stage I-II-IIIA NSCLC: 5-year survival rate was 44.5% in the CT arm versus 40.4% in the control arm (HR of death= 0.86). These results were similar to those reported by the 1995 meta-analysis (NSCLC-CG 1995). Again, only 70% of patients received the planned chemotherapy, given the poor compliance (Arriagada 2004). As well as the IALT study, even the recent reports of NCIC and JBR.10 (Winton 2005) CALGB 9633 (Strauss 2006) and ANITA (Douillard 2006) support a role for platinum-based combination chemotherapy as adjuvant therapy in resected NSCLC. All three trials demonstrated an improvement in overall survival: NCIC-JBR.10 (stage IB or stage II, 482 patients) 15% at 5 years, CALGB 9633 (only stage IB, 344 pts) 9% at 3 years, and ANITA (stage IB to IIIA, 840 patients) 8.6% at 5 years, 8.4 % at 7 years. A number of factors may account for the lack of benefit from adjuvant therapy in ECOG 3590 and ALPI, as compared to IALT, NCIC-JBR.10, CALGB 9633 and ANITA. These include the potentially detrimental effect of post-operative radiotherapy, the impact of newer chemotherapy agents, and the total dose of chemotherapy delivered. IALT, NCIC-JBR.10, CALGB 9633 and ANITA provide compelling evidence in favour of adjuvant chemotherapy, although appropriate selection of patients for treatment is highlighted by the 0.8% risk in IALT of chemotherapy related adverse events resulting in death. Both NCIC-JBR.10 and ANITA also reported treatment-related deaths, accounting for 0.8% and 2% of those treated with chemotherapy, respectively, while no toxic deaths were seen in CALGB 9633. IALT enrolled five times as many subjects, and on this basis may better reflect treatment outcomes in the general population of NSCLC patients.

Some chemotherapy regimens for adjuvant therapy
1) GC regimen
Cisplatin 75-100 mg/m2 day 1
Gemcitabine 1000-1250 mg/m2 day 1, 8
Every 21 days for four cycles

2) CV regimen
Cisplatin 75-100 mg/m2 day 1
Vinorelbine 25-30 mg/m2 day 1, 8
Every 21 days for four cycles

6.B Radiotherapy

Modern radiotherapy techniques should be always applied. Various recent national and international recommendations are available for high precision radiotherapy of lung cancer (Senan 2004; Ortholan 2008; NCCN 2009). All patients shoud have a CT planning scan in reproducible treatment position to define the target volume. Thin CT slice (2-3 mm), and intravenous contrast use are recommended. The gross target volume (GTV) should be generated taking into account the gross tumor volume visible on the CT scans but including also the data derived from all imaging modalities, especially CT/PET. A margin must be added to pass from GTV to clinical target volume (CTV). The margins required for microscopic tumor extension in radiotherapy planning of NSCLC are no less than 5–6 mm and may be 8 mm for adenocarcinoma. Whenever appropriate, nodal chains should be included in CTV. When generating target volumes, accounting for tumor motion is of paramoun relevance and any available tool to include movements in outlining a correct PTV should be used. Unfortunately, fluoroscopy checks, addition of “standard” margins, and slow CT scans are all useful but insufficient tools. On the other hand, respiration-gated radiotherapy, decreasing the impact of tumor mobility, is not routinely available and is still regarded as investigational. Furthermore, breath holding manoeuvers may not be well tolerated by lung cancer patients. Two-dimensional treatment planning is no more considered acceptable for lung cancer patients candidate to curative radiotherapy.Three-dimensional (3-D) radiotherapy planning, which is essential for ensuring both optimal target coverage and the optimal sparing of normal tissues, is nowadays considered standard. Intensity modulated radiation therapy (IMRT) may confer some dosimetric advantage in terms of dose escalation, and may be most appropriate for individual patient; however IMRT increases the volume of lung receiving a low dose of RT. Therefore, the choice between 3-D conformal radiotherapy and IMRT must be evaluated through the evaluation of rival plans. Several constraints must be considered when planning radiotherapy in lung cancer concerning normal lung, heart, esophagus, spinal cord, and less often, live and kidney. This is due to the risk of both acute and late damage, leading to potentially dangerous complications (e.g. lung fibrosis and pneumonitis, esophageal strictures etc.). Constraints may vary according to treatment strategy, whether radiotherapy is performed alone, or combined with chemotherapy and/or surgery, with more restrictive values for combined modalities. An accurate evaluation of the dose volume histograms for the various organs is crucial. Unability to respect constraints may indicate a higher than acceptable risk of normal tissue damage and may dictate a dose modulation. While it is standard to work out a treatment plan considering the covering of the tumor volumes and the healthy organs’ constraints, there is no general consensus on which dosimetric parameters should be used. A variety of such parameters can be found in recommendations and general overviews (Milano 2007; (Senan 2004; Ortholan 2008; NCCN 2009). A maximum dose of 35 Gy and 45 Gy are suggested for the heart and for the spinal cord, respectively. The risk of radiation pneumonitis can be estimated from the V20 (volume of both lungs minus the PTV which receives a dose of 20 Gy) or the V30, and by the mean lung dose (MLD). V20 should be less than 30 Gy and V30 should be less than 10-15 Gy; a MLD of <10-15 Gy is recommended.. The length of esophagus that is irradiated should be limited in order to reduce the incidence of high-grade toxicity especially during concurrent chemo-radiotherapy or altered fractionation schemes. Treatment interruptions or dose reductions for acute toxicities which are otherly manageable are to be discouraged as could jeopardize cure chances. A variety of agents have been used to mitigate the effects of radiation on normal tissue. The most widely tested agent is amifostine (Ethyol, WR-2721), Presently, given the acute toxicity associated with amifostine(nausea/vomiting, hypotension, infection, rash), and the mixed clinical results, amifostine is not supported as a standard option for patients receiving thoracic RT. Although standard for several years, the policy of electively irradiating uninvolved mediastinal lymph nodes and ipsilateral hilum to 40 to 45 Gy followed by a boost to gross disease to 60 to 66 Gy has been challenged in recent years. There are both opponents and supporters of elective nodal irradiation (ENI) In the absence of randomized data, firm recommendations cannot be made as a standard option . However, omitting ENI could provide better tolerance, and better survival come at the expense of a low nodal relapse, on a type 2 level of evidence. Obviously, omitting the ENI, requires a previous full staging procedure (including PET/CT) (Yuan 2007; Rosenzweig 2007). The dose that for many years has been regarded as standarddose (60 Gy in 2 Gy daily fractions) stemmed from the Perez et al. studies in the eighties (RTOG 7301) (Perez 1980; Perez 1987). Nowadays 66 to 70 Gy in 2 daily fractions are increasingly considered a standard radiotherapy schedules for locally advanced NSCLC. Local failures are, nevertheless, frequent, even with the addition of chemotherapy, making dose escalation an appealing approach, although this approach should still be considered investigational. In fact, there seems to be a faded border between improvement of tumor control and increase of late toxicities. Actually, for larger tumors, to get the same complications rate, dose has to be decreased (Bradley 2005). Altered fractionation trials have lead to mixed results. Only 1 of 6 randomized trials comparing cnventional fractionation versus altered fractionation (1.2 bid1.5 tid) have showed a statistically significant survival improvement (Saunders 1999). Therefore, altered fractionation cannot be considered a standard option for lung cancer patients. There is a small group of medically inoperable stage I patients to which dose limitations apply less and to which stereotactic body radiation therapy (SBRT) delivers a few very large fractions (e.g. 48 Gy in four fractions, 45 Gy in three fractions, and 60 Gy in three fractions). These large daily doses are feasible because only small volumes are treated with conformal techniques, which minimizes dose to surrounding critical structures. Appropriate patient immobilization, accurate daily setup, and some method to account for respiratory motion are critical. SBRT may be a reasonable option for selected stage I lung cancer patients, that cannot be operated on, and are peripherically located, on a type 3 level of evidence. Prophylactic cranial irradiation (PCI) for locally advanced NSCLC at present, remains investigational and cannot be recommended off-study.

6.C Surgery

Lobectomy, removal of the hilar nodes and completed with omolateral mediastinal lymphnode dissection represents the recommended surgical procedure on a type C basis, when a complete excision can be achieved. Other lung-preserving operations like segmentectomy and sleeve lobectomy are to be preferred only in selective cases. Pneumonectomy is performed when the primary tumour involves the proximal bronchus or the pulmonary artery or crosses the major fissure. In such patients with small centrally located cancers, especially in those with compromised lung function, an extended sleeve lobectomy with bronchial and vascular reconstruction is suitable for individual clinical use on a type 3 level of evidence since it seems safer than pneumonectomy (Okada 1999; Rendina 2000). Today postoperative mortality rate is age-related and can be expected to be 6-10% with pneumonectomy, 3-5% with lobectomy and 1% with minor resections.As always, reported mortality is less for patients operated by experienced thoracic surgeons (Silvestri 1998; Goodney 2005). Since the most common complications are cardiopulmonary, optimal patient selection is recommended . The role of radical systematic mediastinal lymphadenectomy is debated (Izbicki 1998). It is effective to achieve a complete nodal staging, but its prognostic impact (improvement of local control and postoperative survival) has yet to be determined. The radical approach is associated with a longer operation time, but the rate of morbidity and mortality are probably only slightly influenced by the type of lymphadenectomy (Izbicki 1994). A small randomized trial has suggested that radical systematic lymphadenectomy may improve the prognosis in patients with limited lymph node metastases (pN1 disease or pN2 disease with involvement of only one lymph node level), but these results require confirmation (Izbicki 1998). Other authors propose that the extent of lymph node dissection should be based on the prevalence of metastases to each mediastinal station and on the prognosis. The prevalence in turn depends on the location of the tumor (Asamura 1999; Okada 1998). In a 2005 Cochrane review, in a pooled analysis of three trials (420 patients), Manser reported that four-year survival was superior in patients with resectable stage I to IIIA NSCLC who underwent resection and complete mediastinal lymph node dissection compared with those undergoing resection and lymph node sampling ( P = 0.005). Therefore, both nodal sampling and radical systematic lymphadenectomy are suitable for individual clinical use on a type 3 level of evidence. Closed thoracoscopy (2-cm incisions) or VATS procedures (incisions of 8 cm or less) are suitable for individual clinical use only in patients with stage I NSCLC on a type 3 level of evidence, in institutions with expertise in such surgical technique (McKenna 2006; Swanson 2007).

7. LATE SEQUELAE

7.1 Treatment late sequelae

The most important side-effect of treatment is pulmonary toxicity due to radiation treatment. Radiation pneumonitis is characterised by cough, dyspnea, rarely fever or chest pain. On chest X-ray, lung infiltrate is normally limited to the radiation portals. Two waves of radiopneumonitis can be distinguished, probably the expression of damage to different ‘target’ tissues: a first wave between 6 to 10 weeks, a second one at around 6 months. Early onset pneumonitis is often reversible and should be treated with steroids. Late onset pneumonitis is often irreversible and can lead to permanent dyspnea. The most significant treatment-related factors associated with radiation pneumonitis are dose per fraction, especially with fraction doses above 2Gy, total dose and volume treated (Roach 1995).

8. FOLLOW-UP

8.1 General principles and objectives

Early detection of relapse is of potential benefit if recurrent disease is curable with further treatment or at least if salvage treatment is more effective in presence of smaller disease burden. Follow-up examinations may be directed to the early detection of second primaries, as well.

8.2 Suggested protocols

In patients with progressive disease, follow-up examinations are to be performed within a good palliative care program. In completely resected patients the probability of a second primary is about 10%. About half of these will be in the aerodigestive tract. The median time to recurrence varies from 8 months to 24 months depending on stage disease presentation. Approximately 30% of patients will have an asymptomatic recurrence. From the study of Walsh GL et al (Walsh 1995) it has been observed that an intensive follow-up program will alter treatment approach in 3% of patients and that the most important determinant of survival after recurrence is disease free interval from first operation. A recent retrospective evaluation of 130 completely resected patients who had a complete follow-up, either strict or symptom-oriented, for at least 2 years, has shown that metastatic disease was diagnosed on the basis of symptoms in most patients and that there were no significant differences in the disease-free interval or in the control rate for either group. The costs of strict follow-up were very high (Younes 1999). Another group has reported that, despite clinical follow-up by the surgeon, 70% of recurrences were detected by the family physician (Gilbert 2000). In patients with completely resected disease a routine chest X-ray is recommended on a type R basis every 3-6 months for the first two years in order to maximise the probability of an early detection of a chest relapse or a second primary, which may both be successfully treated with surgery in highly selected cases. Thereafter a physical examination and a chest radiograph is suitable for individual clinical use on a type R basis every 6-12 months, since this strategy could be efficient in detecting health problems other than cancer recurrence (Younes 1999). Other evaluations can be performed only for symptomatic patients.

INDEX

Adelstein DJ, Rice TW, Rybicki LA, Larto MA, Koka A, Taylor ME, et al. Mature results from a phase II trial of accelerated induction chemoradiotherapy and surgery for poor prognosis stage III non-small-cell lung cancer. Am J Clin Oncol 1999; 22: 237-242 [Medline]

Ahuja V, Coleman RE, Herndon J, Patz EFJ. The prognostic significance of fluorodeoxyglucose positron emission tomography imaging for patients with nonsmall cell lung carcinoma. Cancer 1998; 83: 918-924 [Medline]

Alam N, Darling G, Evans WK, Mackay JA, Shepherd FA. Adjuvant chemotherapy for completely resected non-small cell lung cancer: a systematic review. Crit Rev Oncol Hematol 2006; 58: 146-155 [Medline]

Albain KS, Swann RS, Rusch VR, Turrisi AT, Shepherd FA, Smith CJ, et al. Phase III study of concurrent chemotherapy and radiotherapy (CT/RT) vs CT/RT followed by surgical resection for stage IIIA(pN2) non-small cell lung cancer (NSCLC): Outcomes update of North American Intergroup 0139 (RTOG 9309). ASCO Annual Meeting Proceedings 2005; 23, No. 16S: 7014

Albanes D, Heinonen OP, Taylor PR, Virtamo J, Edwards BK, Rautalahti, et al. Alpha-Tocopherol and beta-carotene supplements and lung cancer incidence in the alpha-tocopherol, beta-carotene cancer prevention study: effects of base-line characteristics and study compliance. J Natl Cancer Inst 1996; 88: 1560-1570 [Medline]

Alberola V, Camps C, Provencio M, Isla D, Rosell R, Vadell C, et al. Cisplatin plus gemcitabine versus a cisplatin-based triplet versus nonplatinum sequential doublets in advanced non-small-cell lung cancer: a Spanish Lung Cancer Group phase III randomized trial. J Clin Oncol 2003; 21: 3207-3213 [Medline]

Altavilla G, Adamo V, Buemi B, Marabello G, Maisano R, Lupo G, et al. Gemcitabine as single agent in the treatment of elderly patients with advanced non small cell lung cancer. Anticancer Res 2000; 20: 3675-3678 [Medline]

Anderson H, Hopwood P, Stephens RJ, Thatcher N, Cottier B, Nicholson M, et al. Gemcitabine plus best supportive care (BSC) vs BSC in inoperable non-small cell lung cancer–a randomized trial with quality of life as the primary outcome. UK NSCLC Gemcitabine Group. Non-Small Cell Lung Cancer. Br J Cancer 2000; 83: 447-453 [Medline]

Arcasoy SM, Jett JR. Superior pulmonary sulcus tumors and Pancoast’s syndrome. N Engl J Med 1997; 337: 1370-1376 [Medline]

Arriagada R, Bergman B, Dunant A, Le CT, Pignon JP, Vansteenkiste J. Cisplatin-based adjuvant chemotherapy in patients with completely resected non-small-cell lung cancer. N Engl J Med 2004; 350: 351-360 [Medline]

ARS. American Thoracic Society. Medical section of the American Lung Association. Clinical staging of primary lung cancer. Am Rev Respir Dis 1983; 127: 659-664 [Medline]

Asamura H, Nakayama H, Kondo H, Tsuchiya R, Naruke T. Lobe-specific extent of systematic lymph node dissection for non-small cell lung carcinomas according to a retrospective study of metastasis and prognosis. J Thorac Cardiovasc Surg 1999; 117: 1102-1111 [Medline]

ATBCCPSG. The effect of vitamin E and beta carotene on the incidence of lung cancer and other cancers in male smokers. The Alpha-Tocopherol, Beta Carotene Cancer Prevention Study Group. N Engl J Med 1994; 330: 1029-1035 [Medline]

Auperin A, Le PC, Pignon JP, Koning C, Jeremic B, Clamon G, et al. Concomitant radio-chemotherapy based on platin compounds in patients with locally advanced non-small cell lung cancer (NSCLC): a meta-analysis of individual data from 1764 patients. Ann Oncol 2006; 17: 473-483 [Medline]

Baas P. Inductive and adjuvant treatment strategies for localized nonsmall cell lung cancer in operable and inoperable patients. Curr Opin Oncol 2002; 14: 180-184 [Medline]

Bach PB, Cramer LD, Warren JL, Begg CB. Racial differences in the treatment of early-stage lung cancer. N Engl J Med 1999; 341: 1198-1205 [Medline]

Bach PB, Jett JR, Pastorino U, Tockman MS, Swensen SJ, Begg CB. Computed tomography screening and lung cancer outcomes. JAMA 2007; 297: 953-961 [Medline]

Balducci L. Geriatric oncology: challenges for the new century. Eur J Cancer 2000; 36: 1741-1754 [Medline]

Ball D, Bishop J, Smith J, O’Brien P, Davis S, Ryan G, et al. A randomised phase III study of accelerated or standard fraction radiotherapy with or without concurrent carboplatin in inoperable non-small cell lung cancer: final report of an Australian multi-centre trial. Radiother Oncol 1999; 52: 129-136 [Medline]

Battafarano RJ, Piccirillo JF, Meyers BF, Hsu HS, Guthrie TJ, Cooper JD, et al. Impact of comorbidity on survival after surgical resection in patients with stage I non-small cell lung cancer. J Thorac Cardiovasc Surg 2002; 123: 280-287 [Medline]

Bedini AV, Tavecchio L, Gramaglia A, Villa S, Palazzi M. Radiotherapy and concurrent continuous infusion of cisplatin with adjuvant surgery in nonresectable Stage III lung carcinoma: short- and long-term results of a Phase II study. Int J Radiat Oncol Biol Phys 1999; 45: 613-621 [Medline]

Belani CP, Fossella F. Elderly subgroup analysis of a randomized phase III study of docetaxel plus platinum combinations versus vinorelbine plus cisplatin for first-line treatment of advanced nonsmall cell lung carcinoma (TAX 326). Cancer 2005; 104: 2766-2774 [Medline]

Bentzen SM, Skoczylas JZ, Bernier J. Quantitative clinical radiobiology of early and late lung reactions. Int J Radiat Biol 2000; 76: 453-462 [Medline]

Berman CG, Clark RA. Positron emission tomography in initial staging and diagnosis of persistent or recurrent disease. Curr Opin Oncol 2000; 12: 132-137 [Medline]

Berrino F, Capocaccia R, Coleman MP, Esteve J, Gatta G, Hakulinen T, et al. Survival of cancer patients in Europe: the EUROCARE-3 Study. Oncol. 2003; 14 Suppl 5:v128-49. [Medline]

Bezjak A, Tu D, Seymour L, Clark G, Trajkovic A, Zukin M, et al. Symptom improvement in lung cancer patients treated with erlotinib: quality of life analysis of the National Cancer Institute of Canada Clinical Trials Group Study BR.21. J Clin Oncol 2006; %20;24: 3831-3837 [Medline]

Bianchi F, Hu J, Pelosi G, Cirincione R, Ferguson M, Ratcliffe C, et al. Lung cancers detected by screening with spiral computed tomography have a malignant phenotype when analyzed by cDNA microarray. Clin Cancer Res 2004; 10: 6023-6028 [Medline]

Billingham LJ, Cullen MH. The benefits of chemotherapy in patient subgroups with unresectable non-small-cell lung cancer. Ann Oncol 2001; 12: 1671-1675 [Medline]

Birim O, Kappetein AP, Bogers AJ. Charlson comorbidity index as a predictor of long-term outcome after surgery for nonsmall cell lung cancer. Eur J Cardiothorac Surg 2005; 28: 759-762 [Medline]

Blanke C, Ansari R, Mantravadi R, Gonin R, Tokars R, Fisher W, et al. Phase III trial of thoracic irradiation with or without cisplatin for locally advanced unresectable non-small-cell lung cancer: a Hoosier Oncology Group protocol. J Clin Oncol 1995; 13: 1425-1429 [Medline]

Bolliger CT, Wyser C, Roser H, Soler M, Perruchoud AP. Lung scanning and exercise testing for the prediction of postoperative performance in lung resection candidates at increased risk for complications. Chest 1995; 108: 341-348 [Medline]

Bonner JA. The role of postoperative radiotherapy for patients with completely resected nonsmall cell lung carcinoma: seeking to optimize local control and survival while minimizing toxicity. Cancer 1999; 86: 195-196 [Medline]

Bonomi P, Kim K, Fairclough D, Cella D, Kugler J, Rowinsky E, et al. Comparison of survival and quality of life in advanced non-small-cell lung cancer patients treated with two dose levels of paclitaxel combined with cisplatin versus etoposide with cisplatin: results of an Eastern Cooperative Oncology Group trial. J Clin Oncol 2000; 18: 623-631 [Medline]

Bonomi PD, Finkelstein DM, Ruckdeschel JC, Blum RH, Green MD, Mason B, et al. Combination chemotherapy versus single agents followed by combination chemotherapy in stage IV non-small-cell lung cancer: a study of the Eastern Cooperative Oncology Group. J Clin Oncol 1989; 7: 1602-1613 [Medline]

Booton R, Thatcher N. Chemotherapy in advanced nonsmall cell lung cancer: indication, intensity, and duration. Curr Opin Oncol 2002; 14: 191-198 [Medline]

Bradley J, Graham MV, Winter K, Purdy JA, Komaki R, Roa WH, et al. Toxicity and outcome results of RTOG 9311: a phase I-II dose-escalation study using three-dimensional conformal radiotherapy in patients with inoperable non-small-cell lung carcinoma. Int J Radiat Oncol Biol Phys 2005; 61: 318-328 [Medline]

Breathnach OS, Freidlin B, Conley B, Green MR, Johnson DH, Gandara DR, et al. Twenty-two years of phase III trials for patients with advanced non-small-cell lung cancer: sobering results. J Clin Oncol 2001; 19: 1734-1742 [Medline]

Breathnach OS, Ishibe N, Williams J, Linnoila RI, Caporaso N, Johnson BE. Clinical features of patients with stage IIIB and IV bronchioloalveolar carcinoma of the lung. Cancer 1999; 86: 1165-1173 [Medline]

Breathnach OS, Kwiatkowski DJ, Godleski JJ, Finkelstein D, Sugarbaker DJ, Johnson BE, et al. Bronchioloalveolar carcinoma of the lung: recurrences and survival in patients with stage I disease. Proc ASCO 2000; 19: 502a

Brett GZ. The value of lung cancer detection by six-monthly chest radiographs. Thorax 1968; 23: 414-420 [Medline]

Bunn PAJ, Soriano A, Johnson G, Heasley L. New therapeutic strategies for lung cancer: biology and molecular biology come of age. Chest 2000; 117: 163S-168S [Medline]

Burdett S, Stewart L. Postoperative radiotherapy in non-small-cell lung cancer: update of an individual patient data meta-analysis. Lung Cancer 2005; 47: 81-83 [Medline]

Burdett S, Stewart LA, Rydzewska L. A systematic review and meta-analysis of the literature: chemotherapy and surgery versus surgery alone in non-small cell lung cancer. J Thorac Oncol 2006; 1: 611-621 [Medline]

Burkes RL, Ginsberg RJ, Shepherd FA, Blackstein ME, Goldberg ME, Waters PF, et al. Induction chemotherapy with mitomycin, vindesine, and cisplatin for stage III unresectable non-small-cell lung cancer: results of the Toronto Phase II Trial. J Clin Oncol 1992; 10: 580-586 [Medline]

Burris HA, Hainsworth JD, Erland JB, Morrissey LH, Kalman LA, Hon JK, et al. Phase II trial evaluating triplet chemotherapy using gemcitabine, paclitaxel, and carboplatin in the treatment of patients with advanced non-small cell lung cancer. Semin Oncol 2000; 27: 9-13 [Medline]

Burt M, Wronski M, Arbit E, Galicich JH. Resection of brain metastases from non-small-cell lung carcinoma. Results of therapy. Memorial Sloan-Kettering Cancer Center Thoracic Surgical Staff. J Thorac Cardiovasc Surg 1992; 103: 399-410 [Medline]

Byhardt RW, Scott C, Sause WT, Emami B, Komaki R, Fisher B, et al. Response, toxicity, failure patterns, and survival in five Radiation Therapy Oncology Group (RTOG) trials of sequential and/or concurrent chemotherapy and radiotherapy for locally advanced non-small-cell carcinoma of the lung. Int J Radiat Oncol Biol Phys 1998; 42: 469-478 [Medline]

Carbone DP, Mitsudomi T, Chiba I, Piantadosi S, Rusch V, Nowak JA, et al. p53 immunostaining positivity is associated with reduced survival and is imperfectly correlated with gene mutations in resected non-small cell lung cancer. A preliminary report of LCSG 871. Chest 1994; 106: 377S-381S [Medline]

Cardenal F, Lopez-Cabrerizo MP, Anton A, Alberola V, Massuti B, Carrato A, et al. Randomized phase III study of gemcitabine-cisplatin versus etoposide-cisplatin in the treatment of locally advanced or metastatic non-small-cell lung cancer. J Clin Oncol 1999; 17: 12-18 [Medline]

Carey FA, Donnelly SC, Walker WS, Cameron EW, Lamb D. Synchronous primary lung cancers: prevalence in surgical material and clinical implications. Thorax 1993; 48: 344-346 [Medline]

Carles J, Rosell R, Ariza A, Pellicer I, Sanchez JJ, Fernandez-Vasalo G, et al. Neuroendocrine differentiation as a prognostic factor in non-small cell lung cancer. Lung Cancer 1993; 10: 209-219 [Medline]

Carretta A, Zannini P, Puglisi A, Chiesa G, Vanzulli A, Bianchi A, et al. Improvement of pulmonary function after lobectomy for non-small cell lung cancer in emphysematous patients. Eur J Cardiothorac Surg 1999; 15: 602-607 [Medline]

Chiu CH, Tsai CM, Chen YM, Chiang SC, Liou JL, Perng RP. Gefitinib is active in patients with brain metastases from non-small cell lung cancer and response is related to skin toxicity. Lung Cancer 2005; 47: 129-138 [Medline]

Choi N, Baumann M, Flentjie M, Kellokumpu-Lehtinen P, Senan S, Zamboglou N, et al. Predictive factors in radiotherapy for non-small cell lung cancer: present status. Lung Cancer 2001; 31: 43-56 [Medline]

Clamon G, Herndon J, Cooper R, Chang AY, Rosenman J, Green MR. Radiosensitization with carboplatin for patients with unresectable stage III non-small-cell lung cancer: a phase III trial of the Cancer and Leukemia Group B and the Eastern Cooperative Oncology Group. J Clin Oncol 1999; 17: 4-11 [Medline]

Cohen V, Khuri FR. Progress in lung cancer chemoprevention. Cancer Control 2003; 10: 315-324 [Medline]

Coleman MP, Babb P, Damiecki P, et al. Cancer survival trends in England and Wales, 1971-1995: deprivation and NHS Region. Studies in medical and population subjects. London: The Stationary Office. 1999;

Coleman RE. Value of FDG-PET scanning in management of lung cancer. Lancet 2002; 359: 1361-1362 [Medline]

Comella P, Frasci G, Panza N, Manzione L, De Cataldis G, Cioffi R, et al. Randomized trial comparing cisplatin, gemcitabine, and vinorelbine with either cisplatin and gemcitabine or cisplatin and vinorelbine in advanced non-small-cell lung cancer: interim analysis of a phase III trial of the Southern Italy Cooperative Oncology Group. J Clin Oncol 2000; 18: 1451-1457 [Medline]

Cox JD, Azarnia N, Byhardt RW, Shin KH, Emami B, Pajak TF. A randomized phase I/II trial of hyperfractionated radiation therapy with total doses of 60.0 Gy to 79.2 Gy: possible survival benefit with greater than or equal to 69.6 Gy in favorable patients with Radiation Therapy Oncology Group stage III non-small-cell lung carcinoma: report of Radiation Therapy Oncology Group 83-11. J Clin Oncol 1990; 8: 1543-1555 [Medline]

Crestanello JA, Allen MS, Jett JR, Cassivi SD, Nichols FC, III, Swensen SJ, et al. Thoracic surgical operations in patients enrolled in a computed tomographic screening trial. J Thorac Cardiovasc Surg 2004; 128: 254-259 [Medline]

Crino L, Clerici M, Figoli F, Carlini P, Ceci G, Cortesi E, et al. Chemotherapy of advanced non-small-cell lung cancer: a comparison of three active regimens. A randomized trial of the Italian Oncology Group for Clinical Research (G.O.I.R.C.). Ann Oncol 1995; 6: 347-353 [Medline]

Crino L, Mosconi AM, Scagliotti GV, Selvaggi G, Rinaldi M, Della GM, et al. Gemcitabine as second-line treatment for relapsing or refractory advanced non-small cell lung cancer: a phase II trial. Semin Oncol 1998; 25: 23-26 [Medline]

Crino L, Scagliotti GV, Ricci S, De Marinis F, Rinaldi M, Gridelli C, et al. Gemcitabine and cisplatin versus mitomycin, ifosfamide, and cisplatin in advanced non-small-cell lung cancer: A randomized phase III study of the Italian Lung Cancer Project. J Clin Oncol 1999; 17: 3522-3530 [Medline]

Crosignani P, Piffer S. Respiratory tract cancers: lung and mesothelioma. Epidemiol Prev 2004; 28: 48-56 [Medline]

Cullen MH, Billingham LJ, Woodroffe CM, Chetiyawardana AD, Gower NH, Joshi R, et al. Mitomycin, ifosfamide, and cisplatin in unresectable non-small-cell lung cancer: effects on survival and quality of life. J Clin Oncol 1999; 17: 3188-3194 [Medline]

Curran WJ, Scott C, Langer C, Komaki R, Lee J, Hauser S, et al. Phase III Comparison of Sequential vs Concurrent Chemoradiation for Patients (Pts) with Unresected Stage III Non-Small Cell Lung Cancer (NSCLC): Initial Report of Radiation Therapy Oncology Group (RTOG) 9410. Proc ASCO 2000; 19: 484a

Cykert S, Kissling G, Hansen CJ. Patient preferences regarding possible outcomes of lung resection: what outcomes should preoperative evaluations target? Chest 2000; 117: 1551-1559 [Medline]

D’Addario G, Pintilie M, Leighl NB, Feld R, Cerny T, Shepherd FA. Platinum-based versus non-platinum-based chemotherapy in advanced non-small-cell lung cancer: a meta-analysis of the published literature. J Clin Oncol 2005; 23: 2926-2936 [Medline]

Darwish S, Minotti V, Crino L, Rossetti R, Maranzano E, Checcaglini F, et al. Neoadjuvant cisplatin and etoposide for stage IIIA (clinical N2) non-small cell lung cancer. Am J Clin Oncol 1994; 17: 64-67 [Medline]

Dautzenberg B, Arriagada R, Chammard AB, Jarema A, Mezzetti M, Mattson K, et al. A controlled study of postoperative radiotherapy for patients with completely resected nonsmall cell lung carcinoma. Groupe d’Etude et de Traitement des Cancers Bronchiques. Cancer 1999; 86: 265-273 [Medline]

Delbaldo C, Michiels S, Rolland E, Syz N, Soria JC, Le CT, et al. Second or third additional chemotherapy drug for non-small cell lung cancer in patients with advanced disease. Cochrane Database Syst Rev 2007; CD004569 [Medline]

DeMeester TR, Albertucci M, Dawson PJ, Montner SM. Management of tumor adherent to the vertebral column. J Thorac Cardiovasc Surg 1989; 97: 373-378 [Medline]

Depierre A, Milleron B, Moro-Sibilot D, Chevret S, Quoix E, Lebeau B, et al. Preoperative chemotherapy followed by surgery compared with primary surgery in resectable stage I (except T1N0), II, and IIIa non-small-cell lung cancer. J Clin Oncol 2002; 20: 247-253 [Medline]

DeRose JJJ, Argenziano M, El-Amir N, Jellen PA, Gorenstein LA, Steinglass KM, et al. Lung reduction operation and resection of pulmonary nodules in patients with severe emphysema. Ann Thorac Surg 1998; 65: 314-318 [Medline]

Deslauriers J, Brisson J, Cartier R, Fournier M, Gagnon D, Piraux M, et al. Carcinoma of the lung. Evaluation of satellite nodules as a factor influencing prognosis after resection. J Thorac Cardiovasc Surg 1989; 97: 504-512 [Medline]

Deslauriers J, Gregoire J. Clinical and surgical staging of non-small cell lung cancer. Chest 2000b; 117: 96S-103S [Medline]

Deslauriers J, Gregoire J. Surgical therapy of early non-small cell lung cancer. Chest 2000a; 117: 104S-109S [Medline]

Deslauriers J. Medical complications of combined surgical and nonsurgical therapy. Curr Opin Oncol 2000c; 12: 127-131 [Medline]

Dickman PW, Hakulinen T, Luostarinen T, Pukkala E, Sankila R, Soderman B, et al. Survival of cancer patients in Finland 1955-1994. Acta Oncol 1999; 38 Suppl 12:1-103. [Medline]

Dietlein M, Weber K, Gandjour A, Moka D, Theissen P, Lauterbach KW, et al. Cost-effectiveness of FDG-PET for the management of potentially operable non-small cell lung cancer: priority for a PET-based strategy after nodal-negative CT results. Eur J Nucl Med 2000a; 27: 1598-1609 [Medline]

Dietlein M, Weber K, Gandjour A, Moka D, Theissen P, Lauterbach KW, et al. Cost-effectiveness of FDG-PET for the management of solitary pulmonary nodules: a decision analysis based on cost reimbursement in Germany. Eur J Nucl Med 2000b; 27: 1441-1456 [Medline]

Dillman RO, Herndon J, Seagren SL, Eaton WLJ, Green MR. Improved survival in stage III non-small-cell lung cancer: seven-year follow-up of cancer and leukemia group B (CALGB) 8433 trial. J Natl Cancer Inst 1996; 88: 1210-1215 [Medline]

Dillman RO, Seagren SL, Propert KJ, Guerra J, Eaton WL, Perry MC, 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 [Medline]

Dockery DW, Pope CA, III, Xu X, Spengler JD, Ware JH, Fay ME, et al. An association between air pollution and mortality in six U.S. cities. N Engl J Med 1993; 329: 1753-1759 [Medline]

Dosoretz DE, Katin MJ, Blitzer PH, Rubenstein JH, Galmarini DH, Garton GR, et al. Medically Inoperable Lung Carcinoma: The Role of Radiation Therapy. Semin Radiat Oncol 1996; 6: 98-104 [Medline]

Douillard JY, Rosell R, De LM, Carpagnano F, Ramlau R, Gonzales-Larriba JL, et al. Adjuvant vinorelbine plus cisplatin versus observation in patients with completely resected stage IB-IIIA non-small-cell lung cancer (Adjuvant Navelbine International Trialist Association [ANITA]): a randomised controlled trial. Lancet Oncol 2006; 7: 719-727 [Medline]

Downey RJ, Martini N, Rusch VW, Bains MS, Korst RJ, Ginsberg RJ. Extent of chest wall invasion and survival in patients with lung cancer. Ann Thorac Surg 1999; 68: 188-193 [Medline]

Dwamena BA, Sonnad SS, Angobaldo JO, Wahl RL. Metastases from non-small cell lung cancer: mediastinal staging in the 1990s–meta-analytic comparison of PET and CT. Radiology 1999; 213: 530-536 [Medline]

Earle CC, Tsai JS, Gelber RD, Weinstein MC, Neumann PJ, Weeks JC. Effectiveness of chemotherapy for advanced lung cancer in the elderly: instrumental variable and propensity analysis. J Clin Oncol 2001; 19: 1064-1070 [Medline]

Edelman MJ, Gandara DR, Roach M, Benfield JR. Multimodality therapy in stage III non-small cell lung cancer. Ann Thorac Surg 1996; 61: 1564-1572 [Medline]

ELCVISG. The Elderly Lung Cancer Vinorelbine Italian Study Group. Effects of vinorelbine on quality of life and survival of elderly patients with advanced non-small-cell lung cancer. J Natl Cancer Inst 1999; 91: 66-72 [Medline]

Elias AD, Herndon J, Kumar P, Sugarbaker D, Green MR. A phase III comparison of “best local-regional therapy” with or without chemotherapy (CT) for stage IIIA T1-3N2 non-small cell lung cancer (NSCLC): preliminary results. Proc ASCO 1997; 16: 448a

Elias AD, Skarin AT, Gonin R, Oliynyk P, Stomper PC, O’Hara C, et al. Neoadjuvant treatment of stage IIIA non-small cell lung cancer. Long-term results. Am J Clin Oncol 1994; 17: 26-36 [Medline]

Feld R, Borges M, Giner V, Ginsberg R, Harper P, Klastersky J, et al. Prognostic factors in non-small cell lung cancer. Lung Cancer 1994; 11 Suppl 3:S19-23 [Medline]

Feld R, Rubinstein L, Thomas PA. Adjuvant chemotherapy with cyclophosphamide, doxorubicin, and cisplatin in patients with completely resected stage I non-small-cell lung cancer. The Lung Cancer Study Group. J Natl Cancer Inst 1993; 85: 299-306 [Medline]

Ferlay J, Bray F, Pisani P, Parkin DM. GLOBOCAN 2000. Cancer incidence, mortality and prevalence worldwide, version 1.0. Lyon: IARC Press. IARC Cancer Base No. 5. book 2001;

Ferlay J, Bray F, Sankila R, Parkin DM. EUCAN: Cancer incidence, mortality and prevalence in the European Union.Lyon: IARC Press. 1999;

Fidias P, Supko JG, Martins R, Boral A, Carey R, Grossbard M, et al. A phase II study of weekly paclitaxel in elderly patients with advanced non-small cell lung cancer. Clin Cancer Res 2001; 7: 3942-3949 [Medline]

Fong KM, Zimmerman PV, Smith PJ. Tumor progression and loss of heterozygosity at 5q and 18q in non-small cell lung cancer. Cancer Res 1995; 55: 220-223 [Medline]

Fontanini G, De Laurentiis M, Vignati S, Chine S, Lucchi M, Silvestri V, et al. Evaluation of epidermal growth factor-related growth factors and receptors and of neoangiogenesis in completely resected stage I-IIIA non-small-cell lung cancer: amphiregulin and microvessel count are independent prognostic indicators of survival. Clin Cancer Res 1998; 4: 241-249 [Medline]

Fontanini G, Vignati S, Boldrini L, Chine S, Silvestri V, Lucchi M, et al. Vascular endothelial growth factor is associated with neovascularization and influences progression of non-small cell lung carcinoma. Clin Cancer Res 1997; 3: 861-865 [Medline]

Fossella FV, DeVore R, Kerr R, Crawford J, Natale R, Dunphy F, et al. Phase III trial of docetaxel 100 mg/m2 vs vinorelbine/ifosfamide for non-small cell lung cancer (NSCLC) previously treated with platinum-based chemotherapy (PBC). Proc ASCO 1999; 18: 460 a

Fossella FV, DeVore R, Kerr RN, Crawford J, Natale RR, Dunphy F, et al. Randomized phase III trial of docetaxel versus vinorelbine or ifosfamide in patients with advanced non-small-cell lung cancer previously treated with platinum-containing chemotherapy regimens. The TAX 320 Non-Small Cell Lung Cancer Study Group. J Clin Oncol 2000; 18: 2354-2362 [Medline]

Fossella FV, Lee JS, Shin DM, Calayag M, Huber M, Perez-Soler R, et al. Phase II study of docetaxel for advanced or metastatic platinum-refractory non-small-cell lung cancer. J Clin Oncol 1995; 13: 645-651 [Medline]

Franciosi V, Cocconi G, Michiara M, Di Costanzo F, Fosser V, Tonato M, et al. Front-line chemotherapy with cisplatin and etoposide for patients with brain metastases from breast carcinoma, nonsmall cell lung carcinoma, or malignant melanoma: a prospective study. Cancer 1999; 85: 1599-1605 [Medline]

Franklin WA. Diagnosis of lung cancer: pathology of invasive and preinvasive neoplasia. Chest 2000; 117: 80S-89S [Medline]

Frasci G, Lorusso V, Panza N, Comella P, Nicolella G, Bianco A, et al. Gemcitabine plus vinorelbine versus vinorelbine alone in elderly patients with advanced non-small-cell lung cancer. J Clin Oncol 2000; 18: 2529-2536 [Medline]

Frasci G, Panza N, Comella P, Nicolella GP, Natale M, Manzione L, et al. Cisplatin, gemcitabine, and paclitaxel in locally advanced or metastatic non-small-cell lung cancer: a phase I-II study. Southern Italy Cooperative Oncology Group. J Clin Oncol 1999; 17: 2316-2325 [Medline]

Fukuoka M, Yano S, Giaccone G, Tamura T, Nakagawa K, Douillard JY, et al. Multi-institutional randomized phase II trial of gefitinib for previously treated patients with advanced non-small-cell lung cancer (The IDEAL 1 Trial) [corrected]. J Clin Oncol 2003; 21: 2237-2246 [Medline]

Furuse K, Fukuoka M, Kawahara M, Nishikawa H, Takada Y, Kudoh S, 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 [Medline]

Furuse K, Hosoe S, Masuda N, Sugiura T, Yokota S, Ohbayashi K, et al. Impact of tumor control on survival in unresectable stage III non-small cell lung cancer (NSCLC) treated with concurrent thoracic radiotherapy (TRT) and chemotherapy (CT). Proc ASCO 2000; 19: 484a

Gambhir SS, Hoh CK, Phelps ME, Madar I, Maddahi J. Decision tree sensitivity analysis for cost-effectiveness of FDG-PET in the staging and management of non-small-cell lung carcinoma. J Nucl Med 1996; 37: 1428-1436 [Medline]

Gambhir SS, Shepherd JE, Shah BD, Hart E, Hoh CK, Valk PE, et al. Analytical decision model for the cost-effective management of solitary pulmonary nodules. J Clin Oncol 1998; 16: 2113-2125 [Medline]

Gandara DR, Valone FH, Perez EA, Deisseroth AB, Roach M, Ahn DK, et al. Rapidly alternating radiotherapy and high dose cisplatin chemotherapy in stage IIIB non-small cell lung cancer: results of a phase I/II study. Int J Radiat Oncol Biol Phys 1991; 20: 1047-1052 [Medline]

Gandara DR, Vokes E, Green M, Bonomi P, DeVore R, Comis R, et al. Activity of docetaxel in platinum-treated non-small-cell lung cancer: results of a phase II multicenter trial. J Clin Oncol 2000; 18: 131-135 [Medline]

Gandhi S, Walsh GL, Komaki R, Gokaslan ZL, Nesbitt JC, Putnam JBJ, et al. A multidisciplinary surgical approach to superior sulcus tumors with vertebral invasion. Ann Thorac Surg 1999; 68: 1778-1784 [Medline]

Garfinkel L, Stellman SD. Smoking and lung cancer in women: findings in a prospective study. Cancer Res 1988; 48: 6951-6955 [Medline]

Garg K, Keith RL, Byers T, Kelly K, Kerzner AL, Lynch DA, et al. Randomized controlled trial with low-dose spiral CT for lung cancer screening: feasibility study and preliminary results. Radiology 2002; 225: 506-510 [Medline]

Gazdar AF, Kadoyama C, Venzon D, Park JG, Tsai CM, Linnoila RI, et al. Association between histological type and neuroendocrine differentiation on drug sensitivity of lung cancer cell lines. J Natl Cancer Inst Monogr 1992; 191-196 [Medline]

Georgoulias V, Papadakis E, Alexopoulos A, Tsiafaki X, Rapti A, Veslemes M, et al. Platinum-based and non-platinum-based chemotherapy in advanced non-small-cell lung cancer: a randomised multicentre trial. Lancet 2001; 357: 1478-1484 [Medline]

Gerosa M, Nicolato A, Foroni R, Tomazzoli L, Bricolo A. Analysis of long-term outcomes and prognostic factors in patients with non-small cell lung cancer brain metastases treated by gamma knife radiosurgery. J Neurosurg 2005; 102 Suppl:75-80 [Medline]

Gervais R, Ducolone A, Le Chevalier T, Legroumellec A, Lemarie E, Quoix E, et al. Conventional radiation (RT) with daily carboplatin (Cb) compared to RT alone after induction chemotherapy (ICT) [vinorelbine (Vr)-cisplatin (P)]: Final results of a randomized phase III trial in stage III unresectable non small cell lung (NSCLC) cancer. Study CRG/BMS/NPC/96 of the French Lung Cancer Study Group FNCLCC and IFCT. ASCO Annual Meeting Proceedings 2005; 23, No. 16S: 7016

Giaccone G, Gazdar AF, Beck H, Zunino F, Capranico G. Multidrug sensitivity phenotype of human lung cancer cells associated with topoisomerase II expression. Cancer Res 1992; 52: 1666-1674 [Medline]

Giaccone G, Splinter TA, Debruyne C, Kho GS, Lianes P, Van Zandwijk N, et al. Randomized study of paclitaxel-cisplatin versus cisplatin-teniposide in patients with advanced non-small-cell lung cancer. The European Organization for Research and Treatment of Cancer Lung Cancer Cooperative Group. J Clin Oncol 1998; 16: 2133-2141 [Medline]

Gilbert S, Reid KR, Lam MY, Petsikas D. Who should follow up lung cancer patients after operation? Ann Thorac Surg 2000; 69: 1696-1700 [Medline]

Gillis CR, Hole DJ, Lamont DW, Graham AC, Ramage S. The incidences of lung cancer and breast cancer in women in Glasgow. BMJ 1992; 305: 1331 [Medline]

Ginsberg RJ, Hill LD, Eagan RT, Thomas P, Mountain CF, Deslauriers J, et al. Modern thirty-day operative mortality for surgical resections in lung cancer. J Thorac Cardiovasc Surg 1983; 86: 654-658 [Medline]

Ginsberg RJ, Rubinstein LV. Randomized trial of lobectomy versus limited resection for T1 N0 non-small cell lung cancer. Lung Cancer Study Group. Ann Thorac Surg 1995; 60: 615-622 [Medline]

Ginsberg RJ. Continuing controversies in staging NSCLC: an analysis of the revised 1997 staging system. Oncology (Williston Park) 1998; 12: 51-54 [Medline]

Giudicelli R, Thomas P, Lonjon T, Ragni J, Morati N, Ottomani R, et al. Video-assisted minithoracotomy versus muscle-sparing thoracotomy for performing lobectomy. Ann Thorac Surg 1994; 58: 712-717 [Medline]

Gollins SW, Burt PA, Barber PV, Stout R. High dose rate intraluminal radiotherapy for carcinoma of the bronchus: outcome of treatment of 406 patients. Radiother Oncol 1994; 33: 31-40 [Medline]

Gonzalez BM, Feliu J, Espinosa E, Garcia GC, Blanco E, Garrido P, et al. Comparison of two chemotherapeutic regimens–mitomycin + vindesine + cisplatin (MVP) vs. mitomycin + ifosfamide + cisplatin (MIP)–in advanced non-small-cell lung cancer. ONCOPAZ Cooperative Group. Ann Oncol 1994; 5: 323-327 [Medline]

Goodney PP, Lucas FL, Stukel TA, Birkmeyer JD. Surgeon specialty and operative mortality with lung resection. Ann Surg 2005; 241: 179-184 [Medline]

Gould MK, Kuschner WG, Rydzak CE, Maclean CC, Demas AN, Shigemitsu H, et al. Test performance of positron emission tomography and computed tomography for mediastinal staging in patients with non-small-cell lung cancer: a meta-analysis. Ann Intern Med 2003; 139: 879-892 [Medline]

Gould MK, Maclean CC, Kuschner WG, Rydzak CE, Owens DK. Accuracy of positron emission tomography for diagnosis of pulmonary nodules and mass lesions: a meta-analysis. JAMA 2001; 285: 914-924 [Medline]

Gould PM, Bonner JA, Sawyer TE, Deschamps C, Lange CM, Li H. Patterns of failure and overall survival in patients with completely resected T3 N0 M0 non-small cell lung cancer. Int J Radiat Oncol Biol Phys 1999; 45: 91-95 [Medline]

Govert JA, Dodd LG, Kussin PS, Samuelson WM. A prospective comparison of fiberoptic transbronchial needle aspiration and bronchial biopsy for bronchoscopically visible lung carcinoma. Cancer 1999; 87: 129-134 [Medline]

Graham MV, Pajak TE, Herskovic AM, Emami B, Perez CA. Phase I/II study of treatment of locally advanced (T3/T4) non-oat cell lung cancer with concomitant boost radiotherapy by the Radiation Therapy Oncology Group (RTOG 83-12): long-term results. Int J Radiat Oncol Biol Phys 1995; 31: 819-825 [Medline]

Granone P, Trodella L, Margaritora S, Cesario A, Corbo GM, Mantini G, et al. Radiotherapy versus follow-up in the treatment of pathological stage Ia and Ib non-small cell lung cancer. Early stopped analysis of a randomized controlled study. Eur J Cardiothorac Surg 2000; 18: 418-424 [Medline]

Green N, Kuroara SS, George FW. Cancer of the lung. An in-depth analysis of prognostic factors. Cancer 1971; 28: 1229-1233 [Medline]

Greenwald HP, Polissar NL, Borgatta EF, McCorkle R, Goodman G. Social factors, treatment, and survival in early-stage non-small cell lung cancer. Am J Public Health 1998; 88: 1681-1684 [Medline]

Gridelli C, Aapro M, Ardizzoni A, Balducci L, De Marinis F, Kelly K, et al. Treatment of advanced non-small-cell lung cancer in the elderly: results of an international expert panel. J Clin Oncol 2005; 23: 3125-3137 [Medline]

Gridelli C, Cigolari S, Gallo C, Manzione L, Ianniello GP, Frontini L, et al. Activity and toxicity of gemcitabine and gemcitabine + vinorelbine in advanced non-small-cell lung cancer elderly patients: Phase II data from the Multicenter Italian Lung Cancer in the Elderly Study (MILES) randomized trial. Lung Cancer 2001; 31: 277-284 [Medline]

Gridelli C, Maione P, Barletta E. Individualized chemotherapy for elderly patients with nonsmall cell lung cancer. Curr Opin Oncol 2002; 14: 199-203 [Medline]

Gridelli C, Perrone F, Gallo C, Cigolari S, Rossi A, Piantedosi F, et al. Chemotherapy for elderly patients with advanced non-small-cell lung cancer: the Multicenter Italian Lung Cancer in the Elderly Study (MILES) phase III randomized trial. J Natl Cancer Inst 2003; 95: 362-372 [Medline]

Gridelli C, Perrone F, Gallo C, Rossi A, Barletta E, Barzelloni ML, et al. Single-agent gemcitabine as second-line treatment in patients with advanced non small cell lung cancer (NSCLC): a phase II trial. Anticancer Res 1999; 19: 4535-4538 [Medline]

Gridelli C. The ELVIS trial: a phase III study of single-agent vinorelbine as first-line treatment in elderly patients with advanced non-small cell lung cancer. Elderly Lung Cancer Vinorelbine Italian Study. Oncologist 2001; 6 Suppl 1: 4-7 [Medline]

Grilli R, Oxman AD, Julian JA. Chemotherapy for advanced non-small-cell lung cancer: how much benefit is enough? J Clin Oncol 1993; 11: 1866-1872 [Medline]

Gupta NC, Graeber GM, Bishop HA. Comparative efficacy of positron emission tomography with fluorodeoxyglucose in evaluation of small (3 cm) lymph node lesions. Chest 2000; 117: 773-778 [Medline]

Gupta NC, Graeber GM, Rogers JS, Bishop HA. Comparative efficacy of positron emission tomography with FDG and computed tomographic scanning in preoperative staging of non-small cell lung cancer. Ann Surg 1999; 229: 286-291 [Medline]

Gupta NC, Tamim WJ, Graeber GG, Bishop HA, Hobbs GR. Mediastinal lymph node sampling following positron emission tomography with fluorodeoxyglucose imaging in lung cancer staging. Chest 2001; 120: 521-527 [Medline]

Haberkorn U, Schoenberg SO. Imaging of lung cancer with CT, MRT and PET. Lung Cancer 2001b; 34 Suppl 3:S13-23 [Medline]

Haberkorn U. Positron emission tomography (PET) of non-small cell lung cancer. Lung Cancer 2001; 34 Suppl 2:S115-21 [Medline]

Hackshaw AK, Law MR, Wald NJ. The accumulated evidence on lung cancer and environmental tobacco smoke. BMJ 1997; 315: 980-988 [Medline]

Hagan MP, Choi NC, Mathisen DJ, Wain JC, Wright CD, Grillo HC. Superior sulcus lung tumors: impact of local control on survival. J Thorac Cardiovasc Surg 1999; 117: 1086-1094 [Medline]

Hainsworth JD, Burris HA, III, Billings FT, III, Bradof JE, Baker M, Greco FA. Weekly docetaxel with either gemcitabine or vinorelbine as second-line treatment in patients with advanced nonsmall cell lung carcinoma: Phase II trials of the Minnie Pearl Cancer Research Network. Cancer 2001; 92: 2391-2398 [Medline]

Hainsworth JD, Burris HA, Litchy S, Erland JB, Hon JK, Brierre JE, et al. Gemcitabine and vinorelbine in the second-line treatment of nonsmall cell lung carcinoma patients: a minnie pearl cancer research network phase II trial. Cancer 2000; 88: 1353-1358 [Medline]

Hellwig D, Ukena D, Paulsen F, Bamberg M, Kirsch CM. [Meta-analysis of the efficacy of positron emission tomography with F-18-fluorodeoxyglucose in lung tumors. Basis for discussion of the German Consensus Conference on PET in Oncology 2000]. Pneumologie 2001; 55: 367-377 [Medline]

Helsing M, Bergman B, Thaning L, Hero U. Quality of life and survival in patients with advanced non-small cell lung cancer receiving supportive care plus chemotherapy with carboplatin and etoposide or supportive care only. A multicentre randomised phase III trial. Joint Lung Cancer Study Group. Eur J Cancer 1998; 34: 1036-1044 [Medline]

Henschke CI, McCauley DI, Yankelevitz DF, Naidich DP, McGuinness G, Miettinen OS, et al. Early Lung Cancer Action Project: overall design and findings from baseline screening. Lancet 1999; 354: 99-105 [Medline]

Henschke CI, Yankelevitz DF, Libby DM, Pasmantier MW, Smith JP, Miettinen OS. Survival of patients with stage I lung cancer detected on CT screening. N Engl J Med 2006; 355: 1763-1771 [Medline]

Henschke CI, Yankelevitz DF, Naidich DP, McCauley DI, McGuinness G, Libby DM, et al. CT screening for lung cancer: suspiciousness of nodules according to size on baseline scans. Radiology 2004; 231: 164-168 [Medline]

Henschke CI, Yankelevitz DF, Smith JP, Miettinen OS. Screening for lung cancer: the early lung cancer action approach. Lung Cancer 2002; 35: 143-148. [Medline]

Herrero CC, Martinez EN, Jaime AB. Second-line treatment with gemcitabine and vinorelbine in non-small-cell lung cancer (NSCLC) cisplatin failures: a pilot study. Lung Cancer 2000; 27: 47-53 [Medline]

Herse B, Dalichau H, Wormann B, Hemmerlein B, Schmidberger H, Hess CF, et al. Induction combination chemotherapy with docetaxel and carboplatin in advanced non-small-cell lung cancer. Thorac Cardiovasc Surg 1998; 46: 298-302 [Medline]

Hickish TF, Smith IE, O’Brien ME, Ashley S, Middleton G. Clinical benefit from palliative chemotherapy in non-small-cell lung cancer extends to the elderly and those with poor prognostic factors. Br J Cancer 1998; 78: 28-33 [Medline]

Hillers TK, Sauve MD, Guyatt GH. Analysis of published studies on the detection of extrathoracic metastases in patients presumed to have operable non-small cell lung cancer. Thorax 1994; 49: 14-19 [Medline]

Hirsch FR, Franklin WA, Gazdar AF, Bunn PA, Jr. Early detection of lung cancer: clinical perspectives of recent advances in biology and radiology. Clin Cancer Res 2001; 7: 5-22 [Medline]

Hiyama K, Ishioka S, Shirotani Y, Inai K, Hiyama E, Murakami I, et al. Alterations in telomeric repeat length in lung cancer are associated with loss of heterozygosity in p53 and Rb. Oncogene 1995; 10: 937-944. [Medline]

Holden DA, Rice TW, Stelmach K, Meeker DP. Exercise testing, 6-min walk, and stair climb in the evaluation of patients at high risk for pulmonary resection. Chest 1992; 102: 1774-1779 [Medline]

Holmes EC, Gail M. Surgical adjuvant therapy for stage II and stage III adenocarcinoma and large-cell undifferentiated carcinoma. J Clin Oncol 1986; 4: 710-715 [Medline]

Hotta K, Matsuo K, Ueoka H, Kiura K, Tabata M, Tanimoto M. Addition of platinum compounds to a new agent in patients with advanced non-small-cell lung cancer: a literature based meta-analysis of randomised trials. Ann Oncol 2004; 15: 1782-1789 [Medline]

Huisman C, Smit EF, Giaccone G, Postmus PE. Second-line chemotherapy in relapsing or refractory non-small-cell lung cancer: a review. J Clin Oncol 2000; 18: 3722-3730 [Medline]

Huisman C, Smit EF, Giaccone G, Postmus PE. Second-line chemotherapy in relapsing or refractory non-small-cell lung cancer: a review. J Clin Oncol 2000; 18: 3722-3730 [Medline]

Humphrey LL, Teutsch S, Johnson M. Lung cancer screening with sputum cytologic examination, chest radiography, and computed tomography: an update for the U.S. Preventive Services Task Force. Ann Intern Med 2004; 140: 740-753 [Medline]

IARC. Tobacco smoking. IARC monogeaphy on the evaluation of the carcinogenetic risk of chemicals to humans. Vol 38. Lyon: IARC Press. 1986;

ICD-O. International Classification of Diseases for Oncology. Fritz A, Percy C, Jack A, Shanmugaratnam K, Sobin L, Parkin DM, Whelan S, editors. 3rd ed. Geneva: World Health Organization. 2000;

Izbicki JR, Passlick B, Pantel K, Pichlmeier U, Hosch SB, Karg O, et al. Effectiveness of radical systematic mediastinal lymphadenectomy in patients with resectable non-small cell lung cancer: results of a prospective randomized trial. Ann Surg 1998; 227: 138-144 [Medline]

Izbicki JR, Thetter O, Habekost M, Karg O, Passlick B, Kubuschok B, et al. Radical systematic mediastinal lymphadenectomy in non-small cell lung cancer: a randomized controlled trial. Br J Surg 1994; 81: 229-235 [Medline]

Jaakkimainen L, Goodwin PJ, Pater J, Warde P, Murray N, Rapp E. Counting the costs of chemotherapy in a National Cancer Institute of Canada randomized trial in nonsmall-cell lung cancer. J Clin Oncol 1990; 8: 1301-1309 [Medline]

Jaklitsch MT, Bueno R, Swanson SJ, Mentzer SJ, Lukanich JM, Sugarbaker DJ. New surgical options for elderly lung cancer patients. Chest 1999; 116: 480S-485S [Medline]

Janssen-Heijnen ML, Gatta G, Forman D, Capocaccia R, Coebergh JW. Variation in survival of patients with lung cancer in Europe, 1985-1989. EUROCARE Working Group. Eur J Cancer 1998; 34: 2191-2196 [Medline]

Jeremic B, Shibamoto Y, Acimovic L, Milisavljevic S. Hyperfractionated radiation therapy with or without concurrent low-dose daily carboplatin/etoposide for stage III non-small-cell lung cancer: a randomized study. J Clin Oncol 1996; 14: 1065-1070 [Medline]

JLCS. Japan Lung Cancer Society, editors. Classification of lung cancer. Tokyo: Kanehara. 2000;

Johnson BE, Kelley MJ. Overview of genetic and molecular events in the pathogenesis of lung cancer. Chest 1993; 103: 1S-3S [Medline]

Kalff V, Hicks RJ, MacManus MP, Binns DS, McKenzie AF, Ware RE, et al. Clinical impact of (18)F fluorodeoxyglucose positron emission tomography in patients with non-small-cell lung cancer: a prospective study. J Clin Oncol 2001; 19: 111-118 [Medline]

Kaneda H, Tamura K, Kurata T, Uejima H, Nakagawa K, Fukuoka M. Retrospective analysis of the predictive factors associated with the response and survival benefit of gefitinib in patients with advanced non-small-cell lung cancer. Lung Cancer 2004; 46: 247-254 [Medline]

Kaneko M, Eguchi K, Ohmatsu H, Kakinuma R, Naruke T, Suemasu K, et al. Peripheral lung cancer: screening and detection with low-dose spiral CT versus radiography. Radiology 1996; 201: 798-802 [Medline]

Karnofsky DA, Abelmann WH, Craver LF, Burchenal JH. The use of the nitrogen mustards in the palliative treatment of carcinoma. With particular reference to bronchogenic carcinoma. Cancer 1948; 2: 634-656

Kawai T, Hiroi S, Torikata C. Expression in lung carcinomas of platelet-derived growth factor and its receptors. Lab Invest 1997; 77: 431-436 [Medline]

Keller SM, Adak S, Wagner H, Herskovic A, Brooks BJ, Perry MC, et al. Prospective randomized trial of postoperative adjuvant therapy in patients with completely resected stages II and IIIa non-small cell lung cancer: an intergroup trial (E3590). Proc ASCO 1999; 18: 465a

Keller SM. Adjuvant therapy of resected non-small-cell lung cancer. Curr Opin Oncol 2000; 12: 149-155 [Medline]

Kelly K, Bunn PA, Livingston RB, Gandara DR. A randomized phase III trial of paclitaxel plus carboplatin (PC) versus vinorelbine plus cisplatin (VC) in untreated advanced non-small cell lung cancer (NSCLC): a Southwest Oncology Group (SWOG) trial. Proc ASCO 1999; 18: 461a

Kernstine KH, Stanford W, Mullan BF, Rossi NP, Thompson BH, Bushnell DL, et al. PET, CT, and MRI with Combidex for mediastinal staging in non-small cell lung carcinoma. Ann Thorac Surg 1999; 68: 1022-1028 [Medline]

Khuder SA, Mutgi AB. Effect of smoking cessation on major histologic types of lung cancer. Chest 2001; 120: 1577-1583 [Medline]

Kim DY, Lee KW, Yun T, Kim DW, Kim TY, Heo DS, et al. Efficacy of platinum-based chemotherapy after cranial radiation in patients with brain metastasis from non-small cell lung cancer. Oncol Rep 2005; 14: 207-211 [Medline]

Kirby TJ, Mack MJ, Landreneau RJ, Rice TW. Lobectomy–video-assisted thoracic surgery versus muscle-sparing thoracotomy. A randomized trial. J Thorac Cardiovasc Surg 1995; 109: 997-1001 [Medline]

Kiricuta IC, Mueller G, Stiess J, Bohndorf W. The lymphatic pathways of non-small cell lung cancer and their implication in curative irradiation treatment. Lung Cancer 1994; 11: 71-82 [Medline]

Klastersky J, Sculier JP, Ravez P, Libert P, Michel J, Vandermoten G, et al. A randomized study comparing a high and a standard dose of cisplatin in combination with etoposide in the treatment of advanced non-small-cell lung carcinoma. J Clin Oncol 1986; 4: 1780-1786 [Medline]

Konaka C, Ikeda N, Hiyoshi T, Tsuji K, Hirano T, Kawate N, et al. Peripheral non-small cell lung cancers 2.0 cm or less in diameter: proposed criteria for limited pulmonary resection based upon clinicopathological presentation. Lung Cancer 1998; 21: 185-191 [Medline]

Korst RJ, Ginsberg RJ, Ailawadi M, Bains MS, Downey RJ, Jr., Rusch VW, et al. Lobectomy improves ventilatory function in selected patients with severe COPD. Ann Thorac Surg 1998; 66: 898-902 [Medline]

Korst RJ, Ginsberg RJ, Ailawadi M, Bains MS, Downey RJJ, Rusch VW, et al. Lobectomy improves ventilatory function in selected patients with severe COPD. Ann Thorac Surg 1998; 66: 898-902 [Medline]

Kosmas C, Tsavaris N, Panopoulos C, Vadiaka M, Stavroyianni N, Kourelis T, et al. Gemcitabine and vinorelbine as second-line therapy in non-small-cell lung cancer after prior treatment with taxane+platinum-based regimens. Eur J Cancer 2001b; 37: 972-978 [Medline]

Kosmas C, Tsavaris N, Vadiaka M, Stavroyianni N, Koutras A, Malamos N, et al. Gemcitabine and docetaxel as second-line chemotherapy for patients with nonsmall cell lung carcinoma who fail prior paclitaxel plus platinum-based regimens. Cancer 2001a; 92: 2902-2910 [Medline]

Kosmidis P, Mylonakis N, Skarlos DV, Samantas E, Beer M, Theocharis D, et al. A comparative study of cisplatin and vinblastine versus ifosfamide, cisplatin and vinblastine in non-operable non-small-cell lung cancer. A study of the Hellenic Co-operative Oncology Group for Lung Cancer Trials. Ann Oncol 1994; 5: 159-162 [Medline]

Kris MG, Natale RB, Herbst RS, Lynch TJ, Jr., Prager D, Belani CP, et al. Efficacy of gefitinib, an inhibitor of the epidermal growth factor receptor tyrosine kinase, in symptomatic patients with non-small cell lung cancer: a randomized trial. JAMA 2003; 290: 2149-2158 [Medline]

Krol AD, Aussems P, Noordijk EM, Hermans J, Leer JW. Local irradiation alone for peripheral stage I lung cancer: could we omit the elective regional nodal irradiation? Int J Radiat Oncol Biol Phys 1996; 34: 297-302 [Medline]

Kubik A, Parkin DM, Khlat M, Erban J, Polak J, Adamec M. Lack of benefit from semi-annual screening for cancer of the lung: follow-up report of a randomized controlled trial on a population of high-risk males in Czechoslovakia. Int J Cancer 1990; 45: 26-33 [Medline]

Kubik A, Polak J. Lung cancer detection. Results of a randomized prospective study in Czechoslovakia. Cancer 1986; 57: 2427-2437 [Medline]

Kunitoh H, Kato H, Tsuboi M, Shibata T, Asamura H, Ichonose Y, et al. Phase II trial of preoperative chemoradiotherapy followed by surgical resection in patients with superior sulcus non-small-cell lung cancers: report of Japan Clinical Oncology Group trial 9806. J Clin Oncol 2008; 26: 644-649 [Medline]

Kurie JM, Lee JS, Khuri FR, Morice RC, Walsh GL, Broxson A, et al. 4-hydroxyphenylretinamide (4-HPR) in the reversal of bronchial metaplasia and dysplasia in smokers. Proc ASCO 1999; 18: 473a

Kutlu CA, Pastorino U, Maisey M, Goldstraw P. Selective use of PET scan in the preoperative staging of NSCLC. Lung Cancer 1998; 21: 177-184 [Medline]

Lally BE, Detterbeck FC, Geiger AM, Thomas CR, Jr., Machtay M, Miller AA, et al. The risk of death from heart disease in patients with nonsmall cell lung cancer who receive postoperative radiotherapy: analysis of the Surveillance, Epidemiology, and End Results database. Cancer 2007; 110: 911-917 [Medline]

Lally BE, Zelterman D, Colasanto JM, Haffty BG, Detterbeck FC, Wilson LD. Postoperative radiotherapy for stage II or III non-small-cell lung cancer using the surveillance, epidemiology, and end results database. J Clin Oncol 2006; 24: 2998-3006 [Medline]

Landreneau RJ, Hazelrigg SR, Mack MJ, Dowling RD, Burke D, Gavlick J, et al. Postoperative pain-related morbidity: video-assisted thoracic surgery versus thoracotomy. Ann Thorac Surg 1993; 56: 1285-1289 [Medline]

Landreneau RJ, Sugarbaker DJ, Mack MJ, Hazelrigg SR, Luketich JD, Fetterman L, et al. Wedge resection versus lobectomy for stage I (T1 N0 M0) non-small-cell lung cancer. J Thorac Cardiovasc Surg 1997; 113: 691-698 [Medline]

Langer CJ, Manola J, Bernardo P, Kugler JW, Bonomi P, Cella D, et al. Cisplatin-based therapy for elderly patients with advanced non-small-cell lung cancer: implications of Eastern Cooperative Oncology Group 5592, a randomized trial. J Natl Cancer Inst 2002; 94: 173-181 [Medline]

Lanzotti VJ, Thomas DR, Boyle LE, Smith TL, Gehan EA, Samuels ML. Survival with inoperable lung cancer: an integration of prognostic variables based on simple clinical criteria. Cancer 1977; 39: 303-313 [Medline]

LCSG. The benefit of adjuvant treatment for resected locally advanced non-small-cell lung cancer. The Lung Cancer Study Group. J Clin Oncol 1988; 6: 9-17 [Medline]

LCSG. The Lung Cancer Study Group. Effects of postoperative mediastinal radiation on completely resected stage II and stage III epidermoid cancer of the lung. N Engl J Med 1986; 315: 1377-1381 [Medline]

Le Chevalier T, Arriagada R, Quoix E, Ruffie P, Martin M, Tarayre M, 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: 417-423 [Medline]

Le Chevalier T, Arriagada R, Tarayre M, Lacombe-Terrier MJ, Laplanche A, Quoix E, et al. Significant effect of adjuvant chemotherapy on survival in locally advanced non-small-cell lung carcinoma. J Natl Cancer Inst 1992; 84: 58 [Medline]

Le Chevalier T, Scagliotti G, Natale R, Danson S, Rosell R, Stahel R, et al. Efficacy of gemcitabine plus platinum chemotherapy compared with other platinum containing regimens in advanced non-small-cell lung cancer: a meta-analysis of survival outcomes. Lung Cancer 2005; 47: 69-80 [Medline]

Leighl NB, Shepherd FA, Kwong R, Burkes RL, Feld R, Goodwin PJ. Economic analysis of the TAX 317 trial: docetaxel versus best supportive care as second-line therapy of advanced non-small-cell lung cancer. J Clin Oncol 2002; 20: 1344-1352 [Medline]

Lester JF, Macbeth FR, Coles B. Prophylactic cranial irradiation for preventing brain metastases in patients undergoing radical treatment for non-small-cell lung cancer: A cochrane review. Int J Radiat Oncol Biol Phys. 2005; 63: 690-4 [Medline]

Leu KM, Kim KM, Larson M, Larson M, Schiller JH. Phase I/II trial of docetaxel and vinorelbine in patients with non-small cell lung cancer previously treated with platinum-based chemotherapy. Lung Cancer 2001; 34: 105-113 [Medline]

Libby DM, Smith JP, Altorki NK, Pasmantier MW, Yankelevitz D, Henschke CI. Managing the small pulmonary nodule discovered by CT. Chest 2004; 125: 1522-1529 [Medline]

Lilenbaum RC, Schwartz MA, Seigel L, Belette F, Blaustein A, Wittlin FN, et al. Phase II trial of weekly docetaxel in second-line therapy for nonsmall cell lung carcinoma. Cancer 2001; 92: 2158-2163 [Medline]

Lippman SM, Lee JJ, Karp DD, Vokes EE, Benner SE, Goodman GE, et al. Randomized phase III intergroup trial of isotretinoin to prevent second primary tumors in stage I non-small-cell lung cancer. J Natl Cancer Inst 2001b; 93: 605-618 [Medline]

Lippman SM, Spitz MR. Lung cancer chemoprevention: an integrated approach. J Clin Oncol 2001a; 19: 74S-82S [Medline]

Liptay MJ. Solitary pulmonary nodule: treatment options. Chest 1999; 116: 517S-518S [Medline]

Lloyd C, Silvestri GA. Mediastinal staging of non-small-cell lung cancer. Cancer Control 2001; 8: 311-317 [Medline]

Lynch TJ, Bell DW, Sordella R, Gurubhagavatula S, Okimoto RA, Brannigan BW, et al. Activating mutations in the epidermal growth factor receptor underlying responsiveness of non-small-cell lung cancer to gefitinib. N Engl J Med 2004; 350: 2129-2139 [Medline]

Mac Manus MP, Wada M, Matthews JP, Ball DL. Characteristics of 49 patients who survived for 5 years following radical radiation therapy for non-small cell lung cancer: the potential for cure. Int J Radiat Oncol Biol Phys 2000; 46: 63-69 [Medline]

Machtay M, Lee JH, Shrager JB, Kaiser LR, Glatstein E. Risk of death from intercurrent disease is not excessively increased by modern postoperative radiotherapy for high-risk resected non-small-cell lung carcinoma. J Clin Oncol 2001; 19: 3912-3917 [Medline]

MacManus MP, Hicks RJ, Matthews JP, Hogg A, McKenzie AF, Wirth A, et al. High rate of detection of unsuspected distant metastases by pet in apparent stage III non-small-cell lung cancer: implications for radical radiation therapy. Int J Radiat Oncol Biol Phys 2001; 50: 287-293 [Medline]

Manegold C, von Pawel J, Zatloukal P, Ramlau R, Gorbounova V, Hirsch V, et al. Randomised, double-blind multicentre phase III study of bevacizumab in combination with cisplatin and gemcitabine in chemotherapy-naïve patients with advanced or recurrent non-squamous non-small cell lung cancer (NSCLC): BO17704. ASCO Annual Meeting Proceedings 2007; 25, No. 18S: LBA7514

Marcus PM, Bergstralh EJ, Fagerstrom RM, Williams DE, Fontana R, Taylor WF, et al. Lung cancer mortality in the Mayo Lung Project: impact of extended follow-up. J Natl Cancer Inst 2000; 92: 1308-1316 [Medline]

Marino P, Pampallona S, Preatoni A, Cantoni A, Invernizzi F. Chemotherapy vs supportive care in advanced non-small-cell lung cancer. Results of a meta-analysis of the literature. Chest 1994; 106: 861-865 [Medline]

Marino P, Preatoni A, Cantoni A. Randomized trials of radiotherapy alone versus combined chemotherapy and radiotherapy in stages IIIa and IIIb nonsmall cell lung cancer. A meta-analysis. Cancer 1995; 76: 593-601 [Medline]

Marom EM, McAdams HP, Erasmus JJ, Goodman PC, Culhane DK, Coleman RE, et al. Staging non-small cell lung cancer with whole-body PET. Radiology 1999; 212: 803-809 [Medline]

Martini N, Bains MS, Burt ME, Zakowski MF, McCormack P, Rusch VW, et al. Incidence of local recurrence and second primary tumors in resected stage I lung cancer. J Thorac Cardiovasc Surg 1995; 109: 120-129 [Medline]

Martini N, Kris MG, Flehinger BJ, Gralla RJ, Bains MS, Burt ME, et al. Preoperative chemotherapy for stage IIIa (N2) lung cancer: the Sloan-Kettering experience with 136 patients. Ann Thorac Surg 1993; 55: 1365-1373 [Medline]

Martini N, Rusch VW, Bains MS, Kris MG, Downey RJ, Flehinger BJ, et al. Factors influencing ten-year survival in resected stages I to IIIa non-small cell lung cancer. J Thorac Cardiovasc Surg 1999; 117: 32-36 [Medline]

Martoni A, Di Fabio F, Guaraldi M, Piana E, Ramini R, Lelli G, et al. Prospective phase II study of single-agent gemcitabine in untreated elderly patients with stage IIIB/IV non-small-cell lung cancer. Am J Clin Oncol 2001; 24: 614-617 [Medline]

McCaughan BC, Martini N, Bains MS, McCormack PM. Chest wall invasion in carcinoma of the lung. Therapeutic and prognostic implications. J Thorac Cardiovasc Surg 1985; 89: 836-841 [Medline]

McFarlane MJ, Feinstein AR, Wells CK. Clinical features of lung cancers discovered as a postmortem ‘quot;surprise’quot;. Chest 1986; 90: 520-523 [Medline]

McKenna RJ, Jr., Houck W, Fuller CB. Video-assisted thoracic surgery lobectomy: experience with 1,100 cases. Ann Thorac Surg 2006; 81: 421-425 [Medline]

Melamed MR. Lung cancer screening results in the National Cancer Institute New York study. Cancer 2000; 89: 2356-2362 [Medline]

Mentzer SJ, Swanson SJ. Treatment of patients with lung cancer and severe emphysema. Chest 1999; 116: 477S-479S [Medline]

Micheli A, Mugno E, Krogh V, Quinn MJ, Coleman M, Hakulinen T, et al. Cancer prevalence in European registry areas. Ann Oncol 2002; 13:840 -65 2002 [Medline]

Milano MT, Constine LS, Okunieff P. Normal tissue tolerance dose metrics for radiation therapy of major organs. Semin Radiat Oncol 2007; 17: 131-140 [Medline]

Miller VA, Kris MG, Shah N, Patel J, Azzoli C, Gomez J, et al. Bronchioloalveolar pathologic subtype and smoking history predict sensitivity to gefitinib in advanced non-small-cell lung cancer. J Clin Oncol 2004; 22: 1103-1109 [Medline]

Mitsudomi T, Steinberg SM, Oie HK, Mulshine JL, Phelps R, Viallet J, et al. ras gene mutations in non-small cell lung cancers are associated with shortened survival irrespective of treatment intent. Cancer Res 1991; 51: 4999-5002 [Medline]

Mountain CF, Dresler CM. Regional lymph node classification for lung cancer staging. Chest 1997; 111: 1718-1723 [Medline]

Mountain CF. Revisions in the International System for Staging Lung Cancer. Chest 1997; 111: 1710-1717 [Medline]

MRC. Report to the Medical Research Council by its Lung Cancer Working Party. Inoperable non-small-cell lung cancer (NSCLC): a Medical Research Council randomised trial of palliative radiotherapy with two fractions or ten fractions. Br J Cancer 1991; 63: 265-270 [Medline]

Mulshine JL, Sullivan DC. Clinical practice. Lung cancer screening. N Engl J Med 2005; 352: 2714-2720 [Medline]

Nagai K, Tsuchiya R, Mori T, Tada H, Ichinose Y, Koike T, et al. A randomized trial comparing induction chemotherapy followed by surgery with surgery alone for patients with stage IIIA N2 non-small cell lung cancer (JCOG 9209). J Thorac Cardiovasc Surg 2003; 125: 254-260 [Medline]

Nakahara K, Ohno K, Mastumura A, Hirose H, Mastuda H, Nakano S, et al. Extended operation for lung cancer invading the aortic arch and superior vena cava. J Thorac Cardiovasc Surg 1989; 97: 428-433 [Medline]

Naruke T, Goya T, Tsuchiya R, Suemasu K. Prognosis and survival in resected lung carcinoma based on the new international staging system. J Thorac Cardiovasc Surg 1988; 96: 440-447 [Medline]

NCCN [Medline]

Nishio K, Nakamura T, Koh Y, Suzuki T, Fukumoto H, Saijo N. Drug resistance in lung cancer. Curr Opin Oncol 1999; 11: 109-115 [Medline]

Novello S, Kielhorn A, Stynes G, Selvaggi G, De Marinis F, Maestri A, et al. Cost-minimisation analysis comparing gemcitabine/cisplatin, paclitaxel/carboplatin and vinorelbine/cisplatin in the treatment of advanced non-small cell lung cancer in Italy. Lung Cancer 2005; 48: 379-387 [Medline]

NSCLC-CG. Chemotherapy in non-small cell lung cancer: a meta-analysis using updated data on individual patients from 52 randomised clinical trials. Non-small Cell Lung Cancer Collaborative Group. BMJ 1995; 311: 899-909 [Medline]

O’Connell JP, Kris MG, Gralla RJ, Groshen S, Trust A, Fiore JJ, et al. Frequency and prognostic importance of pretreatment clinical characteristics in patients with advanced non-small-cell lung cancer treated with combination chemotherapy. J Clin Oncol 1986; 4: 1604-1614 [Medline]

O’Doherty MJ, Marsden PK. Being equipped for clinical PET. Lancet 2000; 356: 1701-1703 [Medline]

Ohbuchi T, Morikawa T, Takeuchi E, Kato H. Lobectomy: video-assisted thoracic surgery versus posterolateral thoracotomy. Jpn J Thorac Cardiovasc Surg 1998; 46: 519-522 [Medline]

Ohta M, Tsuchiya R, Shimoyama M, Sawamura K, Mori T, Miyazawa N, et al. Adjuvant chemotherapy for completely resected stage III non-small-cell lung cancer. Results of a randomized prospective study. The Japan Clinical Oncology Group. J Thorac Cardiovasc Surg 1993; 106: 703-708 [Medline]

Okada M, Tsubota N, Yoshimura M, Miyamoto Y, Matsuoka H, Satake S, et al. Extended sleeve lobectomy for lung cancer: the avoidance of pneumonectomy. J Thorac Cardiovasc Surg 1999; 118: 710-713 [Medline]

Okada M, Tsubota N, Yoshimura M, Miyamoto Y. Proposal for reasonable mediastinal lymphadenectomy in bronchogenic carcinomas: role of subcarinal nodes in selective dissection. J Thorac Cardiovasc Surg 1998; 116: 949-953 [Medline]

Okawara G, Ung YC, Markman BR, Mackay JA, Evans WK. Postoperative radiotherapy in stage II or IIIA completely resected non-small cell lung cancer: a systematic review and practice guideline. Lung Cancer 2004; 44: 1-11 [Medline]

Omenn GS, Goodman GE, Thornquist MD, Balmes J, Cullen MR, Glass A, et al. Risk factors for lung cancer and for intervention effects in CARET, the Beta-Carotene and Retinol Efficacy Trial. J Natl Cancer Inst 1996; 88: 1550-1559 [Medline]

Ortholan C, Estivalet S, Barillot I, Costa A, Gerard JP. [Guide for external beam radiotherapy. Procedures 2007]. Cancer Radiother 2007; 11: 329-330 [Medline]

Paci E. Lung cancer screening: the methodological debate. Lung Cancer 2002; 38: S17-S21 [Medline]

Paez JG, Janne PA, Lee JC, Tracy S, Greulich H, Gabriel S, et al. EGFR mutations in lung cancer: correlation with clinical response to gefitinib therapy. Science 2004; 304: 1497-1500 [Medline]

Palazzi M, Cataldo I, Gramaglia A, De Toma D, Milani F, Ravasi G. Preoperative concomitant cisplatin/VP16 and radiotherapy in stage III non-small cell lung cancer. Int J Radiat Oncol Biol Phys 1993; 27: 621-625 [Medline]

Parkin DM, Bray FI, Devesa SS. Cancer burden in the year 2000. The global picture. Eur J Cancer 2001; 37 Suppl 8:S4-66 [Medline]

Pastorino U, Bellomi M, Landoni C, De Fiori E, Arnaldi P, Picchio M, et al. Early lung-cancer detection with spiral CT and positron emission tomography in heavy smokers: 2-year results. Lancet 2003; 362: 593-597 [Medline]

Patchell RA, Tibbs PA, Walsh JW, Dempsey RJ, Maruyama Y, Kryscio RJ, et al. A randomized trial of surgery in the treatment of single metastases to the brain. N Engl J Med 1990; 322: 494-500 [Medline]

Patterson GA, Ilves R, Ginsberg RJ, Cooper JD, Todd TR, Pearson FG. The value of adjuvant radiotherapy in pulmonary and chest wall resection for bronchogenic carcinoma. Ann Thorac Surg 1982; 34: 692-697 [Medline]

Patz EF, Jr., Connolly J, Herndon J. Prognostic value of thoracic FDG PET imaging after treatment for non-small cell lung cancer. AJR Am J Roentgenol 2000b; 174: 769-774 [Medline]

Patz EFJ. Imaging bronchogenic carcinoma. Chest 2000a; 117: 90S-95S [Medline]

Payne DG. Is preoperative or postoperative radiation therapy indicated in non-small cell cancer of the lung? Lung Cancer 1994; 10 Suppl 1:S205-212 [Medline]

Pearson FG. Non-small cell lung cancer: role of surgery for stages I-III. Chest 1999; 116: 500S-503S [Medline]

Perez CA, Pajak TF, Rubin P, Simpson JR, Mohiuddin M, Brady LW, et al. Long-term observations of the patterns of failure in patients with unresectable non-oat cell carcinoma of the lung treated with definitive radiotherapy. Report by the Radiation Therapy Oncology Group. Cancer 1987; 59: 1874-1881 [Medline]

Perez CA, Stanley K, Rubin P, Kramer S, Brady L, Perez-Tamayo R, et al. A prospective randomized study of various irradiation doses and fractionation schedules in the treatment of inoperable non-oat-cell carcinoma of the lung. Preliminary report by the Radiation Therapy Oncology Group. Cancer 1980; 45: 2744-2753 [Medline]

Peto R, Darby S, Deo H, Silcocks P, Whitley E, Doll R. Smoking, smoking cessation, and lung cancer in the UK since 1950: combination of national statistics with two case-control studies. BMJ 2000; 321: 323-329 [Medline]

Phillips MH, Stelzer KJ, Griffin TW, Mayberg MR, Winn HR. Stereotactic radiosurgery: a review and comparison of methods. J Clin Oncol 1994; 12: 1085-1099 [Medline]

Piehler JM, Pairolero PC, Weiland LH, Offord KP, Payne WS, Bernatz PE. Bronchogenic carcinoma with chest wall invasion: factors affecting survival following en bloc resection. Ann Thorac Surg 1982; 34: 684-691 [Medline]

Pieterman RM, van Putten JW, Meuzelaar JJ, Mooyaart EL, Vaalburg W, Koeter GH, et al. Preoperative staging of non-small-cell lung cancer with positron-emission tomography. N Engl J Med 2000; 343: 254-261 [Medline]

Pignon JP, Tribodet H, Scagliotti GV, Douillard JY, Shepherd FA, Stephens RJ, et al. Lung Adjuvant Cisplatin Evaluation (LACE): A pooled analysis of five randomized clinical trials including 4,584 patients. ASCO Annual Meeting Proceedings 2006; 24, 18S: 7008

Pignon JP, Tribodet H, Scagliotti GV, Douillard JY, Shepherd FA, Stephens RJ, et al. Lung adjuvant cisplatin evaluation: a pooled analysis by the LACE Collaborative Group. J Clin Oncol 2008; 26: 3552-3559 [Medline]

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

Porte HL, Ernst OJ, Delebecq T, Metois D, Lemaitre LG, Wurtz AJ. Is computed tomography guided biopsy still necessary for the diagnosis of adrenal masses in patients with resectable non-small-cell lung cancer? Eur J Cardiothorac Surg 1999; 15: 597-601 [Medline]

Postmus PE, Smit EF. Chemotherapy for brain metastases of lung cancer: a review. Ann Oncol 1999; 10: 753-759 [Medline]

Pritchard RS, Anthony SP. Chemotherapy plus radiotherapy compared with radiotherapy alone in the treatment of locally advanced, unresectable, non-small-cell lung cancer. A meta-analysis. Ann Intern Med 1996; 125: 723-729 [Medline]

Pujol JL, Breton JL, Gervais R, Rebattu P, Depierre A, Morere JF, et al. Gemcitabine-docetaxel versus cisplatin-vinorelbine in advanced or metastatic non-small-cell lung cancer: a phase III study addressing the case for cisplatin. Ann Oncol 2005; 16: 602-610 [Medline]

Quekel LG, Kessels AG, Goei R, van Engelshoven JM. Miss rate of lung cancer on the chest radiograph in clinical practice. Chest 1999; 115: 720-724 [Medline]

Ramsey SD, Moinpour CM, Lovato LC, Crowley JJ, Grevstad P, Presant CA, et al. Economic analysis of vinorelbine plus cisplatin versus paclitaxel plus carboplatin for advanced non-small-cell lung cancer. J Natl Cancer Inst 2002; 94: 291-297 [Medline]

Ranson M, Davidson N, Nicolson M, Falk S, Carmichael J, Lopez P, et al. Randomized trial of paclitaxel plus supportive care versus supportive care for patients with advanced non-small-cell lung cancer. J Natl Cancer Inst 2000; 92: 1074-1080 [Medline]

Reilly JJJ. Evidence-based preoperative evaluation of candidates for thoracotomy. Chest 1999; 116: 474S-476S [Medline]

Rendina EA, De Giacomo T, Venuta F, Ciccone AM, Coloni GF. Lung conservation techniques: bronchial sleeve resection and reconstruction of the pulmonary artery. Semin Surg Oncol 2000; 18: 165-172 [Medline]

Ricci S, Antonuzzo A, Galli L, Tibaldi C, Bertuccelli M, Lopes PA, et al. Gemcitabine monotherapy in elderly patients with advanced non-small cell lung cancer: a multicenter phase II study. Lung Cancer 2000; 27: 75-80 [Medline]

Roach M, Gandara DR, Yuo HS, Swift PS, Kroll S, Shrieve DC, et al. Radiation pneumonitis following combined modality therapy for lung cancer: analysis of prognostic factors. J Clin Oncol 1995; 13: 2606-2612 [Medline]

Roazzi P, Capocaccia R, Santaquilani M, Carrani E. Electronic availability of EUROCARE-3 data: a tool for further analysis. Ann Oncol 2003; 14 Suppl 5:v150-5. [Medline]

Rocha Lima CM, Herndon JE, Kosty M, Clamon G, Green MR. Therapy choices among older patients with lung carcinoma: an evaluation of two trials of the Cancer and Leukemia Group B. Cancer 2002; 94: 181-187 [Medline]

Rosell R, Abad-Esteve A, Moreno I, Barnadas A, Carles J, Fernandez C, et al. A randomized study of two vindesine plus cisplatin-containing regimens with the addition of mitomycin C or ifosfamide in patients with advanced non-small cell lung cancer. Cancer 1990; 65: 1692-1699 [Medline]

Rosell R, Gatzemeier U, Betticher DC, Keppler U, Macha HN, Pirker R, et al. Phase III randomised trial comparing paclitaxel/carboplatin with paclitaxel/cisplatin in patients with advanced non-small-cell lung cancer: a cooperative multinational trial. Ann Oncol 2002; 13: 1539-1549 [Medline]

Rosell R, Gomez-Codina J, Camps C, Javier SJ, Maestre J, Padilla J, et al. Preresectional chemotherapy in stage IIIA non-small-cell lung cancer: a 7-year assessment of a randomized controlled trial. Lung Cancer 1999; 26: 7-14 [Medline]

Rosell R, Li S, Skacel Z, Mate JL, Maestre J, Canela M, et al. Prognostic impact of mutated K-ras gene in surgically resected non-small cell lung cancer patients. Oncogene 1993; 8: 2407-2412 [Medline]

Rosenzweig KE, Sura S, Jackson A, Yorke E. Involved-field radiation therapy for inoperable non small-cell lung cancer. J Clin Oncol 2007; 25: 5557-5561 [Medline]

Roszkowski K, Pluzanska A, Krzakowski M, Smith AP, Saigi E, Aasebo U, et al. A multicenter, randomized, phase III study of docetaxel plus best supportive care versus best supportive care in chemotherapy-naive patients with metastatic or non-resectable localized non-small cell lung cancer (NSCLC). Lung Cancer 2000; 27: 145-157 [Medline]

Roth JA, Atkinson EN, Fossella F, Komaki R, Bernadette RM, Putnam JBJ, et al. Long-term follow-up of patients enrolled in a randomized trial comparing perioperative chemotherapy and surgery with surgery alone in resectable stage IIIA non-small-cell lung cancer. Lung Cancer 1998; 21: 1-6 [Medline]

Rowell NP, Williams CJ. Radical radiotherapy for stage I/II non-small cell lung cancer in patients not sufficiently fit for or declining surgery (medically inoperable): a systematic review. Thorax 2001; 56: 628-638 [Medline]

Rowell NP. Updated data for chart in NSCLC: a missed opportunity. Radiother Oncol 2000; 55: 85-87 [Medline]

Rozengurt E. Autocrine loops, signal transduction, and cell cycle abnormalities in the molecular biology of lung cancer. Curr Opin Oncol 1999; 11: 116-122 [Medline]

Ruckdeschel JC, Finkelstein DM, Ettinger DS, Creech RH, Mason BA, Joss RA, et al. A randomized trial of the four most active regimens for metastatic non-small-cell lung cancer. J Clin Oncol 1986; 4: 14-22 [Medline]

Rusch VW, Albain KS, Crowley JJ, Rice TW, Lonchyna V, McKenna RJ, et al. Neoadjuvant therapy: a novel and effective treatment for stage IIIb non-small cell lung cancer. Southwest Oncology Group. Ann Thorac Surg 1994; 58: 290-294 [Medline]

Rusch VW, Giroux DJ, Kraut MJ, Crowley J, Hazuka M, Winton T, et al. Induction chemoradiation and surgical resection for superior sulcus non-small-cell lung carcinomas: long-term results of Southwest Oncology Group Trial 9416 (Intergroup Trial 0160). J Clin Oncol 2007; %20;25: 313-318 [Medline]

Ryan GF, Ball DL, Smith JG. Treatment of brain metastases from primary lung cancer. Int J Radiat Oncol Biol Phys 1995; 31: 273-278 [Medline]

Salgia R, Skarin AT. Molecular abnormalities in lung cancer. J Clin Oncol 1998; 16: 1207-1217 [Medline]

Salminen E, Mac MM. FDG-PET imaging in the management of non-small-cell lung cancer. Ann Oncol 2002; 13: 357-360 [Medline]

Samet JM. Radon and lung cancer. J Natl Cancer Inst 1989; 81: 745-757 [Medline]

Sandler A, Gray R, Perry MC, Brahmer J, Schiller JH, Dowlati A, et al. Paclitaxel-carboplatin alone or with bevacizumab for non-small-cell lung cancer. N Engl J Med 2006; 355: 2542-2550 [Medline]

Sandler AB, Nemunaitis J, Denham C, von Pawel J, Cormier Y, Gatzemeier U, et al. Phase III trial of gemcitabine plus cisplatin versus cisplatin alone in patients with locally advanced or metastatic non-small-cell lung cancer. J Clin Oncol 2000; 18: 122-130 [Medline]

Saunders CA, Dussek JE, O’Doherty MJ, Maisey MN. Evaluation of fluorine-18-fluorodeoxyglucose whole body positron emission tomography imaging in the staging of lung cancer. Ann Thorac Surg 1999a; 67: 790-797 [Medline]

Saunders M, Dische S, Barrett A, Harvey A, Griffiths G, Palmar M. Continuous, hyperfractionated, accelerated radiotherapy (CHART) versus conventional radiotherapy in non-small cell lung cancer: mature data from the randomised multicentre trial. CHART Steering committee. Radiother Oncol 1999b; 52: 137-148 [Medline]

Sause W, Kolesar P, Taylor S, IV, Johnson D, Livingston R, Komaki R, et al. Final results of phase III trial in regionally advanced unresectable non-small cell lung cancer: Radiation Therapy Oncology Group, Eastern Cooperative Oncology Group, and Southwest Oncology Group. Chest 2000; 117: 358-364 [Medline]

Sause WT, Scott C, Taylor S, Johnson D, Livingston R, Komaki R, et al. Radiation Therapy Oncology Group (RTOG) 88-08 and Eastern Cooperative Oncology Group (ECOG) 4588: preliminary results of a phase III trial in regionally advanced, unresectable non-small-cell lung cancer. J Natl Cancer Inst 1995; 87: 198-205 [Medline]

Sawyer TE, Bonner JA, Gould PM, Foote RL, Deschamps C, Trastek VF, et al. Effectiveness of postoperative irradiation in stage IIIA non-small cell lung cancer according to regression tree analyses of recurrence risks. Ann Thorac Surg 1997; 64: 1402-1407 [Medline]

Scagliotti GV, De Marinis F, Rinaldi M, Crino L, Gridelli C, Ricci S, et al. Phase III randomized trial comparing three platinum-based doublets in advanced non-small-cell lung cancer. J Clin Oncol 2002; 20: 4285-4291 [Medline]

Schaake-Koning C, van den Bogaert W, Dalesio O, Festen J, Hoogenhout J, van Houtte P, et al. Effects of concomitant cisplatin and radiotherapy on inoperable non-small-cell lung cancer. N Engl J Med 1992; 326: 524-530 [Medline]

Schiller JH, Adak S, Feins RH, Keller SM, Fry WA, Livingston RB, et al. Lack of prognostic significance of p53 and K-ras mutations in primary resected non-small-cell lung cancer on E4592: a Laboratory Ancillary Study on an Eastern Cooperative Oncology Group Prospective Randomized Trial of Postoperative Adjuvant Therapy. J Clin Oncol 2001; 19: 448-457 [Medline]

Schiller JH, Harrington D, Belani CP, Langer C, Sandler A, Krook J, et al. Comparison of four chemotherapy regimens for advanced non-small-cell lung cancer. N Engl J Med 2002; 346: 92-98 [Medline]

Schuette W. Treatment of brain metastases from lung cancer: chemotherapy. Lung Cancer 2004; 45 Suppl 2:S253-7 [Medline]

Sekido Y, Bader S, Latif F, Gnarra JR, Gazdar AF, Linehan WM, et al. Molecular analysis of the von Hippel-Lindau disease tumor suppressor gene in human lung cancer cell lines. Oncogene 1994; 9: 1599-1604 [Medline]

Selvaggi G, Scagliotti GV, Torri V, Novello S, Leonardo E, Cappia S, et al. HER-2/neu overexpression in patients with radically resected nonsmall cell lung carcinoma. Impact on long-term survival. Cancer 2002; 94: 2669-2674 [Medline]

Sen M, Demiral AS, Cetingoz R, Alanyali H, Akman F, Senturk D, et al. Prognostic factors in lung cancer with brain metastasis. Radiother Oncol 1998; 46: 33-38 [Medline]

Senan S, De RD, Giraud P, Mirimanoff R, Budach V. Literature-based recommendations for treatment planning and execution in high-dose radiotherapy for lung cancer. Radiother Oncol 2004; 71: 139-146 [Medline]

Senkus-Konefka E, Dziadziuszko R, Bednaruk-Mlynski E, Pliszka A, Kubrak J, Lewandowska A, et al. A prospective, randomised study to compare two palliative radiotherapy schedules for non-small-cell lung cancer (NSCLC). Br J Cancer 2005; 92: 1038-1045 [Medline]

Shepherd FA, Dancey J, Ramlau R, Mattson K, Gralla R, O’Rourke M, et al. Prospective randomized trial of docetaxel versus best supportive care in patients with non-small-cell lung cancer previously treated with platinum-based chemotherapy. J Clin Oncol 2000; 18: 2095-2103 [Medline]

Shepherd FA, Fossella FV, Lynch T, Armand JP, Rigas JR, Kris MG. Docetaxel (Taxotere) shows survival and quality-of-life benefits in the second-line treatment of non-small cell lung cancer: a review of two phase III trials. Semin Oncol 2001; 28: 4-9 [Medline]

Shridhar V, Siegfried J, Hunt J, del Mar A, Smith DI. Genetic instability of microsatellite sequences in many non-small cell lung carcinomas. Cancer Res 1994; 54: 2084-2087 [Medline]

Silini EM, Bosi F, Pellegata NS, Volpato G, Romano A, Nazari S, et al. K-ras gene mutations: an unfavorable prognostic marker in stage I lung adenocarcinoma. Virchows Arch 1994; 424: 367-373 [Medline]

Silvestri G, Pritchard R, Welch HG. Preferences for chemotherapy in patients with advanced non-small cell lung cancer: descriptive study based on scripted interviews. BMJ 1998; 317: 771-775 [Medline]

Silvestri GA, Littenberg B, Colice GL. The clinical evaluation for detecting metastatic lung cancer. A meta-analysis. Am J Respir Crit Care Med 1995; 152: 225-230 [Medline]

Sirzen F, Kjellen E, Sorenson S, Cavallin-Stahl E. A systematic overview of radiation therapy effects in non-small cell lung cancer. Acta Oncol 2003; 42: 493-515 [Medline]

Sklar MD. Increased resistance to cis-diamminedichloroplatinum(II) in NIH 3T3 cells transformed by ras oncogenes. Cancer Res 1988; 48: 793-797 [Medline]

Smith IE, O’Brien ME, Talbot DC, Nicolson MC, Mansi JL, Hickish TF, et al. Duration of chemotherapy in advanced non-small-cell lung cancer: a randomized trial of three versus six courses of mitomycin, vinblastine, and cisplatin. J Clin Oncol 2001; 19: 1336-1343 [Medline]

Socinski MA, Schell MJ, Peterman A, Bakri K, Yates S, Gitten R, et al. Phase III trial comparing a defined duration of therapy versus continuous therapy followed by second-line therapy in advanced-stage IIIB/IV non-small-cell lung cancer. J Clin Oncol 2002; 20: 1335-1343 [Medline]

Sone S, Takashima S, Li F, Yang Z, Honda T, Maruyama Y, et al. Mass screening for lung cancer with mobile spiral computed tomography scanner. Lancet 1998; 351: 1242-1245 [Medline]

Sorensen JB, Hirsch FR, Gazdar A, Olsen JE. Interobserver variability in histopathologic subtyping and grading of pulmonary adenocarcinoma. Cancer 1993; 71: 2971-2976 [Medline]

Sorensen JB, Stenbygaard LE, Dombernowsky P, Hansen HH. Paclitaxel, gemcitabine, and cisplatin in non-resectable non-small-cell lung cancer. Ann Oncol 1999; 10: 1043-1049 [Medline]

Soria JC, Brisgand D, Le Chevalier T. Do all patients with advanced non-small-cell lung cancer benefit from cisplatin-based combination therapy? Ann Oncol 2001; 12: 1667-1670 [Medline]

Souquet PJ, Chauvin F, Boissel JP, Cellerino R, Cormier Y, Ganz PA, et al. Polychemotherapy in advanced non small cell lung cancer: a meta-analysis. Lancet 1993; 342: 19-21 [Medline]

Spiridonidis CH, Laufman LR, Carman L, Moore T, Blair S, Jones J, et al. Second-line chemotherapy with weekly gemcitabine (GEM) and monthly docetaxel (DOC) in petients (Pts) with non-small cell lung cancer (NSCLC): a phase II study. Proc ASCO 2000; 19: 503a

Stamatis G, Eberhardt W, Stuben G, Bildat S, Dahler O, Hillejan L. Preoperative chemoradiotherapy and surgery for selected non-small cell lung cancer IIIB subgroups: long-term results. Ann Thorac Surg 1999; 68: 1144-1149 [Medline]

Stanley KE. Prognostic factors for survival in patients with inoperable lung cancer. J Natl Cancer Inst 1980; 65: 25-32 [Medline]

Stevenson H, Gazdar AF, Phelps R, Linnoila RI, Ihde DC, Ghosh B, et al. Tumor cell lines established in vitro: an independent prognostic factor for survival in non-small-cell lung cancer. Ann Intern Med 1990; 113: 764-770 [Medline]

Stewart BW, Kleihus P, Editors. World Cancer Report. Lyon: IARC Press. 2003;

Storm HH, Dickman PW, Engeland A, Haldorsen T, Hakulinen T. Do morphology and stage explain the inferior lung cancer survival in Denmark? Eur Respir J 1999; 13: 430-435 [Medline]

Strauss C, 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

Strauss GM, Herndon JE, Maddaus MA, Johnstone DW, Johnson EA, Watson DM, et al. Adjuvant chemotherapy in stage IB non-small cell lung cancer (NSCLC): Update of Cancer and Leukemia Group B (CALGB) protocol 9633. ASCO Annual Meeting Proceedings 2006; 24, 18S: 7007

Sugi K, Kaneda Y, Esato K. Video-assisted thoracoscopic lobectomy achieves a satisfactory long-term prognosis in patients with clinical stage IA lung cancer. World J Surg 2000; 24: 27-30 [Medline]

Sundstrom S, Bremnes R, Aasebo U, Aamdal S, Hatlevoll R, Brunsvig P, et al. Hypofractionated palliative radiotherapy (17 Gy per two fractions) in advanced non-small-cell lung carcinoma is comparable to standard fractionation for symptom control and survival: a national phase III trial. J Clin Oncol 2004; 22: 801-810 [Medline]

Suzuki K, Nagai K, Yoshida J, Nishimura M, Takahashi K, Nishiwaki Y. The prognosis of surgically resected N2 non-small cell lung cancer: the importance of clinical N status. J Thorac Cardiovasc Surg 1999; 118: 145-153 [Medline]

Swanson SJ, Herndon JE, D’Amico TA, Demmy TL, McKenna RJ, Jr., Green MR, et al. Video-assisted thoracic surgery lobectomy: report of CALGB 39802–a prospective, multi-institution feasibility study. J Clin Oncol 2007; 25: 4993-4997 [Medline]

Swensen SJ, Jett JR, Hartman TE, Midthun DE, Mandrekar SJ, Hillman SL, et al. CT screening for lung cancer: five-year prospective experience. Radiology 2005; 235: 259-265 [Medline]

Takeda K, Kudoh S, Nakagawa K, Takada M, Katakami N, Matsui K, et al. Randomized phase III study of docetaxel (D) versus vinorelbine (V) for elderly patients (pts) with advanced non-small cell lung cancer (NSCLC): Results of a West Japan Thoracic Oncology Group trial (WJTOG9904). ASCO Annual Meeting Proceedings 2005; 23, No. 16S: 7009

Tanaka K, Kubota K, Kodama T, Nagai K, Nishiwaki Y. Extrathoracic staging is not necessary for non-small-cell lung cancer with clinical stage T1-2 N0. Ann Thorac Surg 1999; 68: 1039-1042 [Medline]

ten Bokkel H, Bergman B, Chemaissani A, Dornoff W, Drings P, Kellokumpu-Lehtinen PL, et al. Single-agent gemcitabine: an active and better tolerated alternative to standard cisplatin-based chemotherapy in locally advanced or metastatic non-small cell lung cancer. Lung Cancer 1999; 26: 85-94 [Medline]

Thomas M, Rube C, Semik M, von Eiff M, Freitag L, Macha HN, et al. Impact of preoperative bimodality induction including twice-daily radiation on tumor regression and survival in stage III non-small-cell lung cancer. J Clin Oncol 1999; 17: 1185 [Medline]

Thongprasert S, Sanguanmitra P, Juthapan W, Clinch J. Relationship between quality of life and clinical outcomes in advanced non-small cell lung cancer: best supportive care (BSC) versus BSC plus chemotherapy. Lung Cancer 1999; 24: 17-24 [Medline]

Tockman MS. Survival and mortality from lung cancer in a screened population. Chest 1986; 89 Suppl: 324S-325S

Toloza EM, Harpole L, McCrory DC. Noninvasive staging of non-small cell lung cancer: a review of the current evidence. Chest 2003; 123: 137S-146S [Medline]

Travis WD, Brambilla E, Muller-Hermelink HK, Harris CC. Pathology and genetics of tumours of the lung, pleura, thymus and heart. World Health Organization Classification of Tumours. Lyon: IARC Press. 2004;

Trodella L, Granone P, Valente S, Valentini V, Balducci M, Mantini G, et al. Adjuvant radiotherapy in non-small cell lung cancer with pathological stage I: definitive results of a phase III randomized trial. Radiother Oncol 2002; 62: 11-19 [Medline]

Trovo MG, Minatel E, Franchin G, Boccieri MG, Nascimben O, Bolzicco G, et al. Radiotherapy versus radiotherapy enhanced by cisplatin in stage III non-small cell lung cancer. Int J Radiat Oncol Biol Phys 1992; 24: 11-15 [Medline]

Tsai CM, Chang KT, Perng RP, Mitsudomi T, Chen MH, Kadoyama C, et al. Correlation of intrinsic chemoresistance of non-small-cell lung cancer cell lines with HER-2/neu gene expression but not with ras gene mutations. J Natl Cancer Inst 1993; 85: 897-901 [Medline]

UICC. UICC (International Union Against Cancer). TNM classification of malignant tumours. Sobin LH, Wittekind Ch, editors. 6th ed. New York, Chichester, weinheim, Brisbane, Singapore, Toronto: Wiley-Liss. 2002;

van Meerbeeck JP, Kramer GW, Van Schil PE, Legrand C, Smit EF, Schramel F, et al. Randomized controlled trial of resection versus radiotherapy after induction chemotherapy in stage IIIA-N2 non-small-cell lung cancer. J Natl Cancer Inst 2007; 99: 442-450 [Medline]

van Putten JW, Baas P, Codrington H, Kwa HB, Muller M, Aaronson N, et al. Activity of single-agent gemcitabine as second-line treatment after previous chemotherapy or radiotherapy in advanced non-small-cell lung cancer. Lung Cancer 2001; 33: 289-298 [Medline]

Van Tinteren H, Hoekstra OS, Smit EF, van den Bergh JH, Schreurs AJ, Stallaert RA, et al. Effectiveness of positron emission tomography in the preoperative assessment of patients with suspected non-small-cell lung cancer: the PLUS multicentre randomised trial. Lancet 2002; 359: 1388-1393 [Medline]

Van Zandwijk N, Dalesio O, Pastorino U, De Vries N, Van Tinteren H. EUROSCAN, a randomized trial of vitamin A and N-acetylcysteine in patients with head and neck cancer or lung cancer. For the EUropean Organization for Research and Treatment of Cancer Head and Neck and Lung Cancer Cooperative Groups. J Natl Cancer Inst 2000b; 92: 977-986 [Medline]

Van Zandwijk N, Hirsch FR. Chemoprevention strategies for non-small cell lung cancer. Curr Opin Oncol 2002; 14: 185-190 [Medline]

Van Zandwijk N, Pastorino U, De Vries N, Van Tinteren H. Smoking Analysis of Euroscan, the Chemoprevention Study of the EORTC Head ‘amp; Neck and Lung Cancer Cooperative Groups in patients with cancer of the upper and lower airways. Lung Cancer 2000a; 29 suppl 1: 219

Vansteenkiste JF, Stroobants SG, De Leyn PR, Dupont PJ, Bogaert J, Maes A, et al. Lymph node staging in non-small-cell lung cancer with FDG-PET scan: a prospective study on 690 lymph node stations from 68 patients. J Clin Oncol 1998b; 16: 2142-2149 [Medline]

Vansteenkiste JF, Stroobants SG, De Leyn PR, Dupont PJ, Verbeken EK. Potential use of FDG-PET scan after induction chemotherapy in surgically staged IIIa-N2 non-small-cell lung cancer: a prospective pilot study. The Leuven Lung Cancer Group. Ann Oncol 1998a; 9: 1193-1198 [Medline]

Vansteenkiste JF, Stroobants SG, Dupont PJ, De Leyn PR, Verbeken EK, Deneffe GJ, et al. Prognostic importance of the standardized uptake value on (18)F-fluoro-2-deoxy-glucose-positron emission tomography scan in non-small-cell lung cancer: An analysis of 125 cases. Leuven Lung Cancer Group. J Clin Oncol 1999; 17: 3201-3206 [Medline]

Vansteenkiste JF, Vandebroek JE, Nackaerts KL, Weynants P, Valcke YJ, Verresen DA, et al. Clinical-benefit response in advanced non-small-cell lung cancer: A multicentre prospective randomised phase III study of single agent gemcitabine versus cisplatin-vindesine. Ann Oncol 2001; 12: 1221-1230 [Medline]

Vecht CJ, Haaxma-Reiche H, Noordijk EM, Padberg GW, Voormolen JH, Hoekstra FH, et al. Treatment of single brain metastasis: radiotherapy alone or combined with neurosurgery? Ann Neurol 1993; 33: 583-590 [Medline]

Vokes EE, Herndon JE, Kelley MJ, Watson DM, Cicchetti MG, Green MR. Induction chemotherapy followed by concomitant chemoradiotherapy (CT/XRT) versus CT/XRT alone for regionally advanced unresectable non-small cell lung cancer (NSCLC): Initial analysis of a randomized phase III trial. ASCO Annual Meeting Proceedings 2004; 22, No. 14S: 7005

Wada H, Hitomi S, Teramatsu T. Adjuvant chemotherapy after complete resection in non-small-cell lung cancer. West Japan Study Group for Lung Cancer Surgery. J Clin Oncol 1996; 14: 1048-1054 [Medline]

Wagner HJ. Postoperative adjuvant therapy for patients with resected non-small cell lung cancer: still controversial after all these years. Chest 2000; 117: 110S-118S

Walker WS. Video-assisted thoracic surgery (VATS) lobectomy: the Edinburgh experience. Semin Thorac Cardiovasc Surg 1998; 10: 291-299 [Medline]

Walsh GL, O’Connor M, Willis KM, Milas M, Wong RS, Nesbitt JC, et al. Is follow-up of lung cancer patients after resection medically indicated and cost-effective? Ann Thorac Surg 1995; 60: 1563-1570 [Medline]

Warram J. Preoperative irradiation of cancer of the lung: final report of a therapeutic trial. A collaborative study. Cancer 1975; 36: 914-925 [Medline]

Warren WH, Faber LP. Segmentectomy versus lobectomy in patients with stage I pulmonary carcinoma. Five-year survival and patterns of intrathoracic recurrence. J Thorac Cardiovasc Surg 1994; 107: 1087-1093 [Medline]

Washimi O, Nagatake M, Osada H, Ueda R, Koshikawa T, Seki T, et al. In vivo occurrence of p16 (MTS1) and p15 (MTS2) alterations preferentially in non-small cell lung cancers. Cancer Res 1995; 55: 514-517 [Medline]

WCRF’amp; AICR. World Cancer Research Fund and American Institute for Cancer Research. Food, Nutrition and Prevention of Cancer: a Global Perspective. American Institute of Cancer Research, Washington. 1997;

Weder W, Schmid RA, Bruchhaus H, Hillinger S, von Schulthess GK, Steinert HC. Detection of extrathoracic metastases by positron emission tomography in lung cancer. Ann Thorac Surg 1998; 66: 886-892 [Medline]

Williams J, Enger C, Wharam M, Tsai D, Brem H. Stereotactic radiosurgery for brain metastases: comparison of lung carcinoma vs. non-lung tumors. J Neurooncol 1998; 37: 79-85 [Medline]

Winton T, Livingston R, Johnson D, Rigas J, Johnston M, Butts C, et al. Vinorelbine plus cisplatin vs. observation in resected non-small-cell lung cancer. N Engl J Med 2005; 352: 2589-2597 [Medline]

Wozniak AJ, Crowley JJ, Balcerzak SP, Weiss GR, Spiridonidis CH, Baker LH, et al. Randomized trial comparing cisplatin with cisplatin plus vinorelbine in the treatment of advanced non-small-cell lung cancer: a Southwest Oncology Group study. J Clin Oncol 1998; 16: 2459-2465 [Medline]

Yano T, Yokoyama H, Inoue T, Asoh H, Tayama K, Ichinose Y. Surgical results and prognostic factors of pathologic N1 disease in non-small-cell carcinoma of the lung. Significance of N1 level: lobar or hilar nodes. J Thorac Cardiovasc Surg 1994; 107: 1398-1402 [Medline]

Yano T, Yokoyama H, Yoshino I, Tayama K, Asoh H, Hata K, et al. Results of a limited resection for compromised or poor-risk patients with clinical stage I non-small cell carcinoma of the lung. J Am Coll Surg 1995; 181: 33-37 [Medline]

Yokoi K, Kamiya N, Matsuguma H, Machida S, Hirose T, Mori K, et al. Detection of brain metastasis in potentially operable non-small cell lung cancer: a comparison of CT and MRI. Chest 1999; 115: 714-719 [Medline]

Younes RN, Gross JL, Deheinzelin D. Follow-up in lung cancer: how often and for what purpose? Chest 1999; 115: 1494-1499 [Medline]

Young H, Baum R, Cremerius U, Herholz K, Hoekstra O, Lammertsma AA, et al. Measurement of clinical and subclinical tumour response using [18F]-fluorodeoxyglucose and positron emission tomography: review and 1999 EORTC recommendations. European Organization for Research and Treatment of Cancer (EORTC) PET Study Group. Eur J Cancer 1999; 35: 1773-1782 [Medline]

Yuan S, Sun X, Li M, Yu J, Ren R, Yu Y, et al. A randomized study of involved-field irradiation versus elective nodal irradiation in combination with concurrent chemotherapy for inoperable stage III nonsmall cell lung cancer. Am J Clin Oncol 2007; 30: 239-244 [Medline]

Yun M, Kim W, Alnafisi N, Lacorte L, Jang S, Alavi A. 18F-FDG PET in characterizing adrenal lesions detected on CT or MRI. J Nucl Med 2001; 42: 1795-1799 [Medline]

Dr. Carlo Fallai (Author)
Fondazione IRCCS “Istituto Nazionale dei Tumori” – Milan, Italy
mail: carlo.fallai@istitutotumori.mi.it

Dr. Gemma Gatta (Consultant)
Istituto Nazionale Tumori – Milan, Italy
mail: gatta@istitutotumoti.mi.it

Dr. Silvia Spinazzé (Associate Editor)
START Programme
mail: SSPINAZZE@ausl.vda.it

Dr. Lucien Vanuytsel (Reviewer)
UH Gasthuisberg – Leuven, Belgium
mail: LVanuytsel@hhr.be