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Small cell lung cancer

1. GENERAL INFORMATION

1.1 Incidence and mortality

Lung cancer is the most common cause of death from cancer in industrialised countries. In Europe, there were an estimated 300,000 new cases in men and 30,000 new cases in women in 2002 (Ferlay 2004). Small cell lung carcinoma is about 18% of all lung cancer (Curado 2007). In the European male populations small cell carcinoma annual incidence rates (age-standardized) varied from slightly more than 15 (the Netherlandand, Slovenia, Estonia, South of Spain, Croatia, Germany) to less than 2 (Ragusa and Latvia); in women rates varied from a little bit more than 5 and less than 1 in women (Parkin 2002). Trend in lung cancer incidence and mortality are reflection of population-level changes in smoking behaviour. The UK was the first to show the incidence and mortality falling since 1970-74, followed by Finland, Australia, The Netherlands, New Zeeland, the USA, Singapore and more recently, Denmark, Germany, Italy and Sweden ( Bray 2003). Actually for the Italian men, lung cancer mortality and incidence rates reached their maximum values during the late 1980s and steeply decreased thereafter. For women, both indicators appear to be increasing (Inghelmann 2007). There are clear differences in time trends by histological type. In part, it may be due to an ever-increasing proportion of ex-smokers in the population, since the decline in risk of lung cancer on smoking cessation is faster for squamous cel tumours than for small cell carcinoma and adenocarcinoma (Jedrychowski 1992). In Italy, a total of 33,500 incident cases, 72,000 prevalent cases and 28,000 deaths are estimated in Italy in 2005. The lung cancer incidence is expected to decrease to a level in 2010 similar to the one in 1970 (the lowest rate observed in the Italian study). It has been estimated that the preventive effect of the reduction of smoking among men amounted about 55,000 lung cancer cases prevented between 1988 and 2005 ( Inghelmann 2007).

1.2 Survival

Survival for lung cancer patients remain poor, with five-year relative survival of 11% in European patients during 2000-02 (Verdecchia 2007). Relative survival for lung cancer was strongly dependent on age at diagnosis, being much greater in young than in old patients. In the young age group (15-44 years) five-year survival was 23% but only 7% in those of 75 years and above. The age-standardised five-year relative survival for lung cancer varied more than two-fold across Europe. Five-year survival was particularly high in Austria, Belgium, Germany, Iceland and Switzerland (>14%); and low in the Czech Republic, Denmark, England, Scotland, and Malta. 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 (Janssen-Heijnen 1998 ). An analysis of survival in Denmark, Finland, and Norway suggested that lower survival in Denmark was due to unfavourable stage distribution ( Storm 1999). Greater than 50% of patients are diagnosed at a advanced stage, for which the 5-year survival is only 3%, but patients with localized stage at diagnosed had 5-year survival of 49% (Jemal 2004). Overall there was modest tendency for lung cancer survival to improve with time: in Europe 5-year survival increased for all European regions except central Europe, which showed the highest survival 13•4%. In eastern Europe, lung-cancer survival increased until 1999, reaching 9•8% and then slightly decreased (Verdecchia 2007).

1.3 Etiologic and risk factors

There is overwhelming evidence that tobacco smoking is the major cause of lung cancer. Cigarette smoking is responsible of 85-90% of new cases of lung cancer ( IARC 1986). The risk depends on the number of cigarettes smoked per day, duration, age at onset, time since quitting, type of inhalation, tar and nicotine content, presence of 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 20-30% ( IARC 2006). Tobacco smoking increases the risk of all major histological types of lung cancer, but appears to be the strongest for squamous cell carcinoma, followed by small cell carcinoma and adenocarcinoma. Carcinogens that are causes of lung cancer include aluminium; arsenic; asbestos; chloromethyl methyl ether and/or bischloromethyl ether; coal-tar fumes; pollutants from iron and steel founding; untreated mineral oils; mustard gas; soot; talc containing asbestiform tremolite; and vinyl chloride (IARC 1986). Occupational exposure have been associated with increased risk of lung cancer more than of many other tumour type ( Stewart 2003). The risk is also increased in a variety of occupations involving exposure to asbestos of various type. The risk is increased multiplicatively amongst persons who both smoke and are exposed to asbestos. Such phenomenon has been recorded in relation to other occupational lung cancers (Stewart 2003 ). Occupational exposure to carcinogens such as asbestos, crystalline silica, radon, polycyclic aromatic hydrocarbons, chromium, nickel compounds have been recognised to be a risk factor (Boffetta 2002). Atomic bomb survivors and patients treated with radiotherapy are at 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 deay products have found to be at an increased risk of lung cancer (Samet 1989). Lung cancer incidence rates are higher in cities than in rural setting ( Dockery 1993; Pope 2002). Urban air pollution is a risk factor for lung cancer and the excess risk may be in order of 50% (Stewart 2003). Recently, the World Cancer Research Fund and the American Institute for Cancer Research (WCRF&AICR 2007) in their extensive report on the scientific literature on diet, physical activity and prevention of cancer, have made important conclusions, for lung cancers. The panel of experts after the revision of 561 publications concluded as follows: Arsenic in drinking water and pharmacological doses of beta-carotene (smokers only) are causes of lung cancer Fruits and foods containing carotenoids probably protect against this cancer. There is limited evidence suggesting that non-starchy vegetables, selenium and foods containing it, foods containing quercetin protect against lung cancer. There is also limited evidence suggesting that red meat, processed meat, total fat, butter, pharmacological doses of retinol (smokers only). The relationship between activity, BMI, and lung cancer makes the evidence difficult to interpret. There is limited evidence suggesting that physical activity protects against lung cancer.

1.4 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 because of the low sensitivity of these tests (Brett 1968; Marcus 2000; Kubik 1990; Melamed 1987; Tockman 1986). Sensitivity can be variable dependent on histological type (greater for small cell and squamous cell carcinomas), tumour size and location. The results of the Early Lung Cancer Action Project (Henschke 1999) showed that spiral CT can identify very small lung cancers in high-risk people, with resectability rate of 96% and a proportion of stage I tumours greater than 80%. The demostration 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 (aged 50 years or older who had smoked for 20 pack-years or more) volunteers. This study confirmed the promising results for accuracy and sensitivity of low-dose spiral CT with 95% resectability in screening-detected lung cancers, and 77% of stage I disease. The major concern of spiral CT is the high frequency of false-positive findings for benign nodules. Most of these lesions are very small and may not require immediate investigastion (PET scan and/or fine-needle aspiration biopsy). Adenocarcinoma was overappresented in these studies, which may suggest that CT can detect peripheral lesions and miss some central lesions, probably squamous tumours. Randomised trials are on going to measure the efficacy of low-dose spiral CT for reducing lung cancer mortality. However, the renewed enthusiasm for lung cancer screening restrained by the Bach et al. paper ( Bach 2007). The results from the longitudinal analysis of 3246 asymptomatic current or former smokers screened for lung cancer showed any decrease of risk of advanced lung cancer or death from lung cancer. By contrast, screening for lung cancer with low-dose CT increased the rate of lung cancer diagnosis and treatment. Until more conclusive data are available, asymptomatic individuals should not be screened outside of clinical reearch studies that have reasonable likehood of further clarifying the potential benefits and risks.

 

2. PATHOLOGY AND BIOLOGY

2.1 Biological data

2.1.1 Neuroendocrine phenotype

SCLC is a form of lung cancer that displays a neuroendocrine phenotype ((H: ‘type’ – ‘phenotype’)). Neuroendocrine tumours of the lung are a distinct subset of lung tumours showing characteristic morphological, ultrastructural, immunohistological and molecular characteristics. SCLC is a distinct histologic type accounting for 15-25% of all lung malignancies, while typical and atypical carcinoid and LCNEC (large cell neuroendocrine carcinoma) comprise only 2-3%. A preinvasive lesion has not been identified. When performing histologic examination, SCLC is characterised by the presence of neurosecretory granules in the cytoplasm. These granules contain peptide hormones such as antidiuretic hormone (ADH or vasopressin), gastrin releasing peptide, or neuromedin. Neural cell adhesion molecules are found on the surface of SCLC cells. Other forms of lung cancer display different, characteristic antigens on the cell surface.

2.1.2 Chromosomal abnormality

p53 and Rb tumour suppressor genes are frequently (50-80%) mutated in small cell carcinoma. Rb tumour suppressor gene expression is frequently absent and this correlates with loss of heterozygocity at the 13p14 chromosomal locus. By contrast, p16INK4 is always present in Rb negative tumours; 90% of tumours express bcl2 with a low frequency of expression of bax. Ras mutations are not typical for any subtype of neuroendocrine lung tumours. More recently, the expression of the tyrosine-kinase receptor c-kit, also known as CD117, was found in about 40% of small cell tumour samples (Micke 2003). C-kit and its ligand stem cell factor are also coexpressed in many SCLC cell lines, leading to the hypothesis that this coexpression constitutes an autocrine growth loop.

2.2 Histological types

2.2.1 Pathological data

The WHO classification of lung and pleural tumours has been recently updated (Travis 1999). SCLC is characterized by small, round cells generally less than the diameter of 3 resting lymphocytes, with nuclei staining deep blue and a small ring of cytoplasm. They display a high rate of mitosis and frequent large zones of necrosis. Crush or traction artifact is often present in biopsy samples. Small cell carcinoma is usually adequately diagnosed by demonstrating neuroendocrine differentiation by light microscopy; immunohistochemistry is rarely required. Grading of small cell carcinoma is inappropriate since it is consistently a high-grade tumour. When squamous dysplasia and in situ carcinoma are seen in adjacent areas, the diagnosis of SCLC should be made with caution since these lesions are more frequently associated with squamous cell carcinomas.

2.2.2 Pathological variant type

A single variant of small cell carcinoma is recognized: combined small cell carcinoma and any other non-small-cell component. This latter component should be noted in the pathology diagnosis.

2.2.3 ICD-O codes

The morphology codes of the ICD-O (“International Classification of Diseases for Oncology”) are provided in brackets for each subtype of SCLC (ICD-O 1990).

small cell carcinoma, NOS (M-8041-3)
small cell – large cell carcinoma (M-8045-3)

2.3 Accuracy and reliability of pathological diagnosis

2.3.1 Accuracy and reliability of pathological diagnosis

Inaccurate diagnosis is unlikely where there is a typical clinical presentation supported by findings on bronchoscopy. The accuracy of cytological assessments is 70-80% and reproducability is around 90%. Isolated metastases must be distinguished from other small round cell tumours.

3. DIAGNOSIS

3.1 Signs and symptoms

The signs and symptoms of SCLC depend on the location of the primary tumour and site of the metastatic lesions. More than 80% of SCLC-patients report that symptoms have been present for 3 months or less, and very few are asymptomatic at the time of diagnosis. SCLC usually presents as large, rapidly growing lesions arising from the centrally located tracheobronchial airways and invading the mediastinum. Typically, patients present with cough (75% of patients) or dyspnea, wheezing, and chest pain (20-35% of patients). The submucosal nature of SCLC accounts for the relative infrequency of haemoptysis (about 15%) as compared to squamous carcinoma. Weight loss, fatigue and anorexia occur in up to one-third of patients. SCLC is the most common type of lung cancer associated with the signs and symptoms of mediastinal involvement, including superior vena cava syndrome, hoarseness or dysphagia. At the time of diagnosis, two-thirds of the patients with SCLC have one or more clinically detectable distant metastasis, located in bone (30%), liver (25%), bone marrow (20%) or the central nervous system (10%). Symptoms related to distant metastases may or may not be present.

Several paraneoplastic syndromes appear to be specifically associated with SCLC, such as the syndrome of inappropriate antidiuretic hormone secretion (11%), ectopic Cushing’s syndrome (2.4%) and the Eaton-Lambert or myasthenia-like syndrome.

3.2 Diagnostic strategy3.2.1 Diagnostic strategy

Physical examination and chest X-ray films are recommended on a type C basis for the diagnosis of SCLC. The chest X-ray usually shows a large, centrally located, non-cavitated mass associated with hilar and mediastinal adenopathies and signs of mediastinal invasion. For screening purposes, the sensitivity of chest X-ray ranges from 45 to 50%, sputum cytology from 25 to 30% and their combination from 60 to 67%. This differs from what would typically be expected in non-small cell lung cancer patients. Tumour markers, such as neuron-specific enolase, creatine kinase BB or neuroendocrinological markers, are not useful as diagnostic tools due to their low sensitivity and specificity. Tumour markers are elevated in 60-65% of cases at diagnosis and correlate to tumour bulk.

3.3 Pathological diagnosis

3.3.1 Cytological and histological specimens

Bronchial biopsy and bronchial washing during fiberoptic bronchoscopy are recommended on a type C basis. The sensitivity of this strategy in diagnosing endobronchial cancer is over 80%, but it may be lower for submucosal lesions such as small cell lung cancer. The addition of endobronchial needle aspiration (EBNA) to bronchial biopsy and bronchial washing may increase the sensitivity of fiberoptic bronchoscopy, especially for patients with submucosal abnormalities (in one study this increase was from 68% to 89%) (Govert 1999). To avoid unnecessary opening of the pleural cavity, the use of video-assisted thoracoscopic evaluation is indicated. If a pathological diagnosis of a primary tumour is not forthcoming, then other major invasive diagnostic techniques are suitable for individual clinical use on a type R basis. These techniques include surgical biopsy of scalene or cervical nodes, cervical mediastinoscopy for patients with pretracheal and laterotracheal nodes or superior vena cava syndrome, or mediastinotomy for lesions located at the left hilum and associated with subaortic nodes or nodes of the anterior mediastinal chain. A fine-needle aspiration cytology may be helpful for peripherally located lesions. However, in a patient presenting with a solitary parenchymal nodule without mediastinal adenopathy, which is increasing in size over a short period of time, diagnostic and therapeutical surgery may be considered recommended on a type R basis.

4. STAGING

4.1 Stage classification

4.1.1 Conventional two-stage system

SCLC is traditionally staged as limited or extensive disease, according to the Veterans Administration Lung Group system. The definition of limited disease is based on the feasibility of encompassing all the detectable tumour within a ‘tolerable’ radiotherapy port. However, an exact definition of what constitutes a tolerable radiotherapy port is lacking. The prognosis and the choice of therapeutical modalities for treating SCLC patients depends on the extent of the disease.

4.1.2 Limited disease

The definition of limited disease includes patients with disease restricted to one hemithorax with regional lymph node metastasis (including ipsilateral and contralateral hilar, mediastinal and supraclavicular nodes) and without malignant pleural effusions. Left laryngeal nerve involvement and superior vena cava obstruction are considered as limited disease. Recently, patients with contralateral mediastinal and/or supraclavicular metastasis and/or ipsilateral malignant pleural effusion have been included in this group since their prognosis is better than that of patients with distant metastases.

4.1.3 Extensive disease

Extensive disease represents any tumour beyond the boundaries defined above (4.1.2.).

4.1.4 Other classifications

The TNM classification can be more useful than the conventional classification system only in very limited disease when a possible indication for primary surgery can be considered.

4.1.5 TNM classification (UICC 2002)
TNM Classification
TX: Primary tumour can not 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 tumour
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 that directly invades any of the following: chest wall (including superior sulcus tumours), diaphragm, mediastinal pleura, or parietal pericardium or tumour in the main bronchus less than 2 cm distal to the carina, but without involvement of the carina, or associated atelectasis or obstructive pneumonitis of the entire lung
T4: Tumour of any size that invades any of the following: mediastinum, heart, great vessels, trachea, esophagus, vertebral body, carina; or separate tumour nodules in the same lobe; or tumour with a 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. Such patients may be further evaluated by videothoroscopy (VATS). 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 Nodes (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 Distant metastasis 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).

 

4.1.6 Stage grouping (UICC 2002)
Stage Grouping
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

 

4.2 Staging and restaging procedures

4.2.1 Aim of staging

The staging procedures for SCLC are aimed at evaluating the extent of local and distant spread of disease and at defining the treatment strategy. Detailed staging procedures are of value in identifying patients with a good prognosis who are amenable to locoregional treatment.

4.2.2 Staging procedure

The recommended staging procedures on a type R basis include:

  • CT scan of thorax and upper abdomen
  • Radionuclide bone scan
  • CT or MRI of the brainContrast-enhanced CT of the chest and upper abdomen is suitable for individual clinical use on a type R basison a type R basis in patients, who have not been already proven to have netastatic disease by clinical examination or other imaging techniques. CT examination is useful in detecting patients with no nodal involvement or with N1 nodal involvement who may benefit from a surgical approach. In addition, contrast-enhanced CT is useful in identifying true limited disease cases that are candidate for thoracic irradiation combined with chemotherapy (Patz 1999). Mediastinoscopy and/or mediastinotomy are useful to rule out occult mediastinal nodal metastases if the chest CT is not definitive (nodal involvement is considered malignant if it is >1-1,5 cm) particularly if a surgical approach has been planned in the light of a pathological diagnosis. Bone marrow examination is not routinely indicated since only 1.7% of cases have extensive disease based on marrow involvement alone. Patients with bone marrow involvement have only a slightly worse prognosis compared with other extensive disease patients, and there is no effect on the tolerance of chemotherapy ( Campling 1986). Therefore, bone marrow examination is suitable for individual clinical use in selected patients with a suspicion of bone marrow involvement, e.g. patients with thrombocytopenia. Radionuclide bone scan is suitable for individual clinical use on a type R basis in patients with clinical signs and symproms of bone metastases. Given the high frequency of brain metastases in SCLC, even in asymptomatic patients, and considering the implication for prophylactic brain irradiation, contrast-enhanced CT or MRI of the brain is suitable for individual clinical use in patients with limited disease on a type R basis. [18F]Fluorodeoxy-D-glucose positron emission tomography (FDG-PET) is suitable for individual clinical use on a type 3 level of evidence in patients with presumed limited-stage disease. Stage migration by FDG-PET can lead to a significant change in treatment strategy in these patients. Sensitivity of FDG-PET is superior to that of CT in the detection of extrathoracic lymph node involvement and distant metastases except to the brain ( Brink 2004).
4.2.3 Restaging procedure

Routine restaging in patients who have responded to medical treatment is probably of little value. It may be useful to define a patient’s prognosis and to determine those patients who might be candidates for prophylactic cranial irradiation. Tumour markers, such as neuron-specific enolase, creatine kinase BB or other neuroendocrine markers, are elevated in 60-65% of cases at diagnosis, correlate with tumour bulk and may be usefully employed to monitor treatment outcome. Although rising levels of biomarkers may anticipate clinical evidence of tumour relapse by several weeks or months, changes in tumour markers are seldom used to guide therapy. Any diagnostic procedures aimed at anticipating relapse are of marginal value since the effect of salvage treatments is very modest and not curative.

5. PROGNOSIS

5.1 Natural history

5.1.1 Natural history

The natural history of SCLC differs from other types of lung cancer in that there is both early and extensive spread of the disease. The vast majority of patients (70-80% of cases) will have dissemination, occult or otherwise, at the time of presentation. Furthermore, SCLC has a rapid growth rate and a short doubling time (25-160 days). From the time of diagnosis the median survival in untreated patients is 3 months for limited disease and 1.5 months for extensive disease. SCLC usually arises in central bronchi, but they may also occur peripherally. They tend to grow rapidly, invade and spread both early and widely. Consquently, up to 70-80% of cases have spread beyond the thorax at the time of initial diagnosis. Invasion of adjacent structures is common. External compression or intraluminal invasion of the vascular wall of the superior vena cava (SCV) from direct invasion or from adjacent lymph nodes give rise to the SCV syndrome. Pleural effusions may be caused by direct extension of the cancer to the pleural surface, by thoracic duct involvement, or by obstruction of pulmonary lymphatics. Hoarseness or dysphagia may be secondary either to invasion of the left recurrent laryngeal nerve or to diaphragmatic paralysis due to phrenic nerve involvement. Lymph node metastases have been found in 85% of cases at autopsy and in 90% of patients with distant metastases. Lymphatic spread is similar to the behaviour of non-small cell lung cancer. The commonest sites of extrathoracic metastases are: bone, bone marrow, liver, and the CNS. Although other metastases, including those to the remaining lung tissue, opposite lung, pancreas, spleen, heart, thyroid, eye, ovary, kidneys, adrenals, soft tissue, and other internal organs, may be found. CNS metastases occur in approximately 20% of patients at diagnosis. The frequency of metastases rises during the course of the disease. Fifty per cent of patients have brain failure by 2 years follow-up, while there is an evidence of brain lesions in 80 % of cases at postmortem examination. Spinal, epidural or leptomeningeal space metastatic disease is observed more frequently in SCLC than in non small cell lung cancer.

5.2 Prognostic and predictive factors

5.2.1 Extent of disease

For SCLC, limited-stage disease is by far the most important favourable prognostic factor. Recently supraclavicular lymphadenopathy (SCLN) and benign pleural effusions have been included in the limited-stage category. In a study including more than 1000 patients, lymph node involvement was observed in 17% of patients and was strongly correlated with the presence of distant metastasis at baseline, explaining its overall prognostic value. In limited disease, survival tends to be slightly lower in the presence of supraclavicular lymphadenopathy (Urban 1998).

5.2.2 Other relevant prognostic factors

Numerous prognostic factors of both clinical and biological significance have been identified. A review of eleven multivariate statistical analyses (patient groups ranging in size from 411 to > 2500), published between 1980-1991 provided considerable information about which factors are of independent prognostic significance. The most relevant prognostic factors were: stage, performance status, presence of mediastinal involvement, supraclavicular nodes and/or pleural effusion (in patients with limited disease), presence of liver, bone, bone marrow and/or brain metastases. Advanced age (>70 years) is no longer considered a significant adverse prognostic factor at least in limited disease. Elevated levels of lactate dehydrogenase and alkaline phosphatase, decreased level of sodium, haemoglobin and albumin are associated with poor prognosis. According to the SWOG analysis, patients with limited disease, no pleural effusion and normal LDH have a 40% 2-year survival, while patients with extensive disease and high LDH have a 2% 2-year survival ( Albain 1990). The expression of the tyrosine-kinase receptor c-kit in small cell tumour samples was significantly associated with decreased survival in patients with advanced disease and poor response to chemotherapy in one study (Micke 2003). However, the c-kit prognostic value was not confirmed by other studies (Blackhall 2003; Boldrini 2004).

6. TREATMENT

6.1 Treatment of limited disease SCLC

Platinum-based chemotherapy combined with thoracic radiotherapy and prophylactic cranial irradiation is standard treatment on a type 1 level of evidence (Pignon 1992; Auperin 1999) for patients with limited disease SCLC and good performance status. Primary surgery can be considered as an alternative to thoracic radiotherapy in very selected patients with stage I or stage II disease on a type 3 level of evidence.

6.2 Treatment of limited disease SCLC, STAGE I

6.2.1 Treatment strategy

One percent of patients with small cell lung cancer will present with stage I disease. The endpoint of treatment for these patients is cure, which can be achieved in 60% of cases. Cure rate is related primarily to the extent of the tumour; it has been reported as 60% in stage T1N0 and 28% in stage T2N0 disease in retrospective studies which included patients having undergone primary surgery followed by chemotherapy ( Shields 1982).
Standard treatment includes chemotherapy (at least 4-6 cycles of combination chemotheray) on a type C basis as an adjuvant to surgery in operable patients or combined with thoracic irradiation in patients unsuitable for surgery.
In most clinical centres primary surgery followed by adjuvant chemotherapy is increasingly being used as the standard treatment strategy for operable patients, on a type C basis (Tsuchiya 2005; Deslauriers 1997; Shields 1982). A survival advantage over historical controls has been observed in several non-randomised-trials which included patients undergoing primary surgery (Osterlind 1986; Shepherd 1983; Shepherd 1991a). The incidence of surgical mortality or morbidity was similar to those reported for patients undergoing operations for other types of lung cancer. The 3-5 year-survival rates of stage I patients post-surgery range between 45 and 80% after resection and adjuvant chemotherapy. Local control at 5 years approaches 90%. Since the probability of achieving local control with surgery in stage I patients is high, postoperative radiotherapy is not recommended in operated patients on a type R basis ( Deslauriers 1997; Eberhardt 1999; Fujimori 1997).
Two small trials have evaluated chemotherapy followed by surgery for resectable selected stage IB/IIA. All patients were completely resected (R0). Vital residual disease (either SCLC or non-SCLC-histopathologies) was found in 50-75% of patients. No patient experienced local/locoregional failure. A median survival of over 60 months has been reported, with the 3-5 year survival rates ranging between 73% and 63% (Eberhardt 1999; Fujimori 1997).
When it may otherwise be difficult to obtain a pathological diagnosis, diagnostic and therapeutic surgery is recommended for peripherally located lesions on a type R basis. Extensive mediastinal node dissection is not recommended if N2-N3 nodal involvement is discovered (surgical stage III). In these patients, adjuvant chemotherapy (4-6 cycles of platinum-based combination chemotheray) is recommended on a type 3 level of evidence.
Although brain relapse is reported to be relatively rare (around 15%) in most recent surgical series (Tsuchiya 2005) prophylactic cranial irradiation is suitable for individual clinical use after adjuvant chemotherapy on a type R basis.

6.3 Treatment of limited disease SCLC, STAGE II

6.3.1 Treatment strategy

Less than 10% of cases of SCLC will be diagnosed with stage II disease. Extrathoracic metastases are the most common cause of treatment failure, even in patients who present with limited disease. The endpoint of treatment for this cohort of patients is long-term survival including cure, which can be achieved in 20%-30% of cases. The probability of cure is related to the extent of the primary tumour, being 30% in stage IIA-T1N1 and 10% in stage IIB-T2N1 (retrospective studies including primary surgery followed by chemotherapy) ( Shields 1982). In pathological stage II disease, 3-5-year survival rates range between 15-50%.
Standard treatment is chemotherapy and thoracic radiotherapy on a type 1 level of evidence (Pignon 1992). Surgery (before or after chemotherapy) is suitable for individual clinical use, or as a substitute for radiotherapy, in stage IIA-T1N1 operable patients, on a type 3 level of evidence, as long term survival has been reported (Tsuchiya 2005; Eberhardt 1999; Fujimori 1997; Shepherd 1989; Shields 1982).
One recent phase II trial assessed the role of primary surgery followed by 4 cycles of cisplatin and etoposide in patients with stage I-IIIA SCLC ( Tsuchiya 2005 ). Three-year survival in patients with stage II disease was 56% as opposed to 68% and 13% in patients with stage I and IIIA respectively. Two other small trials have prospectively evaluated chemotherapy followed by surgery for resectable selected stage IB/IIA. All patients were completely resected (R0). Vital residual disease (either SCLC or non-SCLC-histopathologies) was found in 50-75% of patients. No patient experienced local/locoregional failure. A median survival of over 60 months has been reported, with the 3-5 year survival rates ranging between 73% and 63% (Eberhardt 1999 ; Fujimori 1997). A randomised trial failed to demonstrate any significant advantage for surgery after induction chemotherapy in responsive patients over a chemo-radiation approach. In this study, however, there was a significant reduction (50%) of the number of patients undergoing randomisation after induction therapy and therefore any conclusion may be doubtful ( Lad 1994 ). Overall in the literature, there is some evidence of a reduction of locoregional relapses in patients undergoing surgical resection in comparison with those undergoing radiation therapy; the improved local control could contribute to better survival. It should be noted that both surgery and radiation therapy should be confined to fully ambulatory patients who have adequate pulmonary function. Studies have not addressed the role of postoperative radiation therapy, and it is therefore investigational.
When it may otherwise be difficult to obtain a pathological diagnosis, diagnostic and therapeutical surgery is recommended for peripherally located lesions on a type R basis, but extensive mediastinal node dissection is not recommended if N2-N3 nodal involvement is discovered (surgical stage III). In these patients, adjuvant chemotherapy (4-6 cycles of platinum-based combination chemotheray) is recommended on a type 3 level of evidence.
Prophylactic cranial irradiation for patients in complete remission (including those who have been submitted to radical surgery) is standard treatment on a type 1 level of evidence (Auperin 1999).

6.4 Treatment of limited SCLC, STAGE III

6.4.1 Treatment strategy

In patients with stage IIIA and IIIB disease, combination chemotherapy and thoracic radiotherapy is standard treatment on a type 1 level of evidence (Pignon 1992). An improvement in survival rates could not be demonstrated for surgery after induction chemotherapy in comparison with chemo-radiotherapy alone. Therefore surgery after induction chemotherapy is not recommended on a type 2 level of evidence for localised stage IIIa/IIIb SCLC ( Fujimori 1997; Lad 1994; Shields 1982). However, surgery has been shown to be feasible in stage IIB/IIIA disease following induction chemoradiotherapy. A 100% locoregional control following complete resection (R0) has been reported and the median survival of 68 months with a 5-year survival rate of 63% in R0 patients is encouraging. The median survival and 5-year survival rate for all eligible patients (46 patients with stages IB to IIIB) was 36 months and 46%. No significant differences in survival rates were observed between different TNM categories or between those with pathological complete response or persistent viable tumour (around 50% of R0 patients had vital residual disease, either SCLC or non-SCLC-histopathologies) (Eberhardt 1999). Surgery after induction chemoradiotherapy remains investigational for SCLC in stage IIB/IIIA disease. Prophylactic cranial irradiation in patients in complete remission (including those who have been submitted to radical surgery) is standard treatment on a type 1 level of evidence (Auperin 1999).

6.4.2 Treatment of elderly patients with limited SCLC

The management of elderly patients (aged > 70 years) with limited disease SCLC (LD SCLC) remains a controversial issue. Older age is often associated with increased toxicity of chemotherapy and radiotherapy, particularly severe myelosuppression. Age per se does not appear to be an independent prognostic factor in LD SCLC and therefore patients should not be treated from the outset with only palliative intent. Combination chemotherapy and chest radiotherapy can be regarded as the standard option on a type 1 level of evidence regardless of age. However, the benefit of adding thoracic irradiation to chemotherapy is most evident in patients younger than 65 years ( Pignon 1992 ). Therefore, thoracic radiotherapy could also be omitted in elderly patients with severe comorbidities or poor performance status or short life-expectancy. The early administration of thoracic RT combined with a platinum/etoposide regimen has been shown to improve local and distant control and survival; a platinum/etoposide based chemotherapy regimen with early concurrent thoracic radiotherapy is standard treatment for very selected elderly limited-stage SCLC on a type R basis (Goto 1999; Jeremic 1997; Murray 1993; Turrisi 1999; Schild 2005). Two cycles of carboplatin and oral etoposide combined with early concurrent accelerated hyperfractionated chest radiotherapy (45 Gy, 1.5 Gy twice daily starting on day 1) is either investigational or suitable for individual clinical use on a type 3 level of evidence ( Jeremic 1998). This combination was well tolerated and produced promising long term results (median survival 15 months; 2-year survival rate of 32%; 5-year survival rate of 13%) in 75 patients. Similar results have been obtained in elderly infirm or noncompliant patients treated with abbreviated chemotherapy (one cycle of CAV followed by one cycle of PE and thoracic irradiation, 20 to 30 Gy concurrent with PE) (Murray 1998). However, sequential chemoradiation, although less effective, can be considered as alternative option in elderly patients who are believed to carry an increased risk of toxicity with concurrent chemoradiation.

6.5 Treatment of extensive SCLC, STAGE IV

6.5.1 Treatment strategy

The cure rate for small cell lung cancer is low in patients with extensive disease with <5 % surviving 5 years. The treatment must be considered palliative for the majority of individuals. Combination chemotherapy improves median survival and is also able to improve intrathoracic symptoms in 50% of patients with pleural effusion, in 80% of patients with superior vena cava syndrome and in 70% of patients with lung atelectasis. A combination chemotherapy is therefore standard treatment on a type C basis (Murray 1997).
In patients with extensive disease, the addition of chest radiotherapy to chemotherapy is suitable for individual clinical use on a type R basis. Radiotherapy plus chemotherapy reduces progression in the chest without altering overall response rates, disease free survival, or overall survival.

6.5.2 Treatment of elderly patients with extensive SCLC

Age is not an independent prognostic factor in ED SCLC and therefore elderly patients should not be treated from the outset with only palliative intent. Administering full dose chemotherapy to elderly patients may be difficult because this population has reduced haematological, hepatic, and renal functions. Even in elderly patients, chemotherapy is standard treatment, on a type C basis in the absence of clinical reasons which suggest a more conservative approach. Single agent oral etoposide cannot be recommended any longer since in a randomised trial ( MRCLCWP 1996a; Souhami 1997) it was more toxic and slightly worse in terms of survival than the standard combination regimen. Therefore, standard combination chemotherapy with 4-6 cycles of PE or CE is standard treatment on a type R basis. A combination of carboplatin and oral etoposide is suitable for individual clinical use on a type 3 level of evidence. The response rates reported were 70-80% and the median survivals were 8-10 months for good-risk elderly patients ( Evans 1995; Matsui 1998; Okamoto 1998), while poor results have been reported with a similar regimen in poor-risk patients (Samantas 1999). Reduction of the starting dose of chemotherapy is suitable for individual clinical use on a type 3 level of evidence (Radford 1992; Stephens 1994) in patients at high risk of treatment-related complications. On a type 2 level of evidence, a full-dose cisplatin/etoposide regimen plus prophylactic lenogastrim shows a better therapeutic outcome with an acceptable toxicity profile when compared with attenuated doses of the same regimen ( Ardizzoni 2005).

6.5.3 Treatment of brain metastases

For decades, brain metastases have been treated with whole brain radiotherapy alone, giving a response rate of 50% (with stabilization or improvement of neurological functions) and a median survival of 5 months. Conventional irradiation of brain metastases consists of a total dose of 30 Gy, by giving 3 Gy per fraction and five fractions per week. Other fractionation schedules, such as a total of 20 Gy by giving 4 Gy per fraction, 5 fractions per week, led to the same results ( Postmus 1998). Brain metastases respond to chemotherapy in a similar manner as other metastases from small cell lung cancer; the probability of a response to chemotherapy is dependent on whether the primary tumour is sensitive or resistant, based on currently used criteria. Often a response may be achieved with the first cycle of chemotherapy, with rapid improvement of neurological symptoms ( Postmus 1997).
Clinically manifest brain metastases are present in about 10% of patients at the time of diagnosis. In patients with synchronous CNS metastases, standard treatment is chemotherapy and whole brain irradiation on a type C basis (Postmus 1997).
Since in some clinical practices, radiation therapy may not be available immediately, initial chemotherapy followed by brain irradiation is acceptable. Palliative whole brain radiation therapy may also be appropriate for patients who are not responding to chemotherapy, depending on their performance status. A radiosurgical approach followed by adjuvant whole brain irradiation is suitable for individual clinical use on a type 3 level of evidence ( Sawaya 1994) in highly selected patients. Local control (80%) seems to be superior to that achieved by whole brain radiotherapy alone (60%). It should be noted that the few patients (1-5%) who present with the brain as the single site of metastasis at initial diagnosis may have a good outcome, with survival rates similar to that seen in limited-stage disease (2-year survival rate around 20% in retrospective series) ( Kochhar 1997).
In patients with brain metastases as the sole site of relapse and who have a good performance status, higher total doses of cranial irradiation may be given. Regimens such as 30 Gy whole brain irradiation with 3 Gy per fraction five fractions per week and a boost, for up to three metastases, of 9-15 Gy with 3 Gy per fraction are appropriate. A combination of chemo-radiotherapy is suitable for individual clinical use on a type 3 level of evidence. A study comparing teniposide with teniposide and whole brain radiotherapy showed a much higher response rate (51% vs 22%) and a more frequent improvement of the neurological functions in the combined modality arm, but was without any survival benefit ( Postmus 1997). Brain relapses after prophylactic or therapeutic brain irradiation can be reirradiated – depending on the elapsed time interval and the performance status of the patient – to a total dose of 20-30 Gy given with 2 or 3 Gy per fraction and may be suitable for individual clinical use on a type R basis.

6.6 Treatment of relapsed/persistent/progressive SCLC

6.6.1 Treatment strategy

The prognosis of patients with relapse or persistent progressive SCLC is generally poor. The treatment approach needs to be tailored to each specific clinical situation. The cumulative objective response rate of second line chemotherapy is only 20% however, there is sufficient evidence to support that this translates in an improvement in quality of life and survival. In a study where patients were randomized at relapse to receive supportive care only or doxorubicin-based chemotherapy, median survival was 11 weeks for supportive care group versus 20 weeks for chemotherapy group ( Spiro 1989). In a recent study where relapsed SCLC patients were randomized to oral topotecan or best supportive care, a significantly faster rate of quality of life deterioration and worse survival (14 vs 26 weeks median survival) was observed in the control group ( O’Brien 2006).

6.6.2 Isolated lung relapse or persistent disease

Some patients with persistent or relapsing disease can be treated with radiotherapy if they have not already received it. Radiotherapy may be suitable for individual clinical use on a type R basis in patients with thoracic recurrences after chemotherapy. Total doses of 10 Gy in one fraction or 17 Gy as 2 weekly fractions of 8.5 Gy, delivered through ap-pa fields including the primary site and mediastinal nodes, are adequate for patients with poor a performance status (MRCLCWP 1992). Thirty Gy given as 10×3 Gy is also an accepted palliative schedule. In patients with tumour relapses to the lungs, as sole relapse site, salvage surgery may be suitable for individual clinical use on a type 3 level of evidence. In these highly selected patients a 5-year survival of approximately 20% can be achieved ( Shepherd 1991b ).

6.6.3 Early relapsed/progressive disease on chemotherapy (refractory relapse)

Tumours that progress on chemotherapy or relapse within 3 months after stopping first-line chemotherapy are considered resistant and seldom respond to second-line chemotherapy, either a multidrug regimen, single agent or new agents. Non-cross-resistant combination chemotherapy is suitable for individual clinical use on a type 3 level of evidence (Postmus 1993).
The efficacy and safety of topotecan in patients with recurrent SCLC has been demonstrated in several phase II-III studies. Among patients with refractory SCLC, the overall response rate of single agent topotecan was 2% to 7%, with 4% to 23% of patients achieving SD as a best response. Median overall survival for patients with refractory disease was 16 to 21 weeks (Perez-Soler 1996 ; Eckardt 1996 Brink; Ardizzoni 1997 ; Depierre 1997; von Pawel 1999; von Pawel 2001). In the subgroup analysis of the randomized trial comparing topotecan vs best supportive care, a survival advantage for chemotherapy treatment was seen also refractory patients. Therefore the use of topotecan in refractory SCLC is justified in selected cases on a type 2 level of evidence (Ardizzoni 2004; O’Brien 2006). The combination of cisplatin-topotecan shows activity in refractory SCLC patients (23.8% response rate), but 44-49% of patients show grade 3-4 thrombocytopenia and neutropenia (Ardizzoni 2003). Therefore, the combination of cisplatin and topotecan is still to be regarded as investigational.
Gemcitabine has only modest activity against refractory relapses (response rate 0-13%), but it presents a favourable toxicity profile and some degree of non-cross-resistance to most agents used against SCLC ( Van der Lee 2001 Brink; Masters 2003; Hainsworth 2003). Single-agent paclitaxel is active in patients refractory to cyclophosphamide, doxorubucin and etoposide (CDE), for an overall response rate of 29% (Smit 1998). The combination of paclitaxel and carboplatin yielded a high response rate (73%) in CDE-refractory patients (Groen 1999), while the same combination showed a response rate of 25% in patients refractory to PE or CAV front-line chemotherapy (Kakolyris 2001). The toxicity of paclitaxel plus carboplatin is mild, therefore its use is suitable for individual clinical use on a type 3 level of evidence (Groen 1999; Kakolyris 2001). The combination of ifosfamide, paclitaxel and carboplatin showed a response rate of 54% in patients who are resistant to CDE regimen (van Putten 2001). CPT-11 is active in 47% of patients with refractory or relapsed SCLC ( Masuda 1992). In the same setting, the combination of carboplatin and CPT-11 shows a response rate of 31 to 62% (Naka 2002; Hirose 2003), while CPT-11 combined with etoposide is active in 68% of patients (Masuda 1998). Grade 3-4 neutropenia occurs in about 50% of patients treated with these regimens (Naka 2002; Hirose 2003; Masuda 1998).

6.6.4 Relatively late relapse (sensitive relapse)

Tumours that relapse more than three months after first line chemotherapy may still be responsive to chemotherapy. Either retreatment with the same first-line chemotherapy or treatment with a different regimen are standard options on a type C basis. Several agents (oral or IV topotecan, irinotecan, taxanes, vinorelbine) have shown activity in sensitive relapsed tumours (response rate around 20%, range 15-37%, median survival 5 months) and therefore their use is suitable for individual clinical use on a type 3 level of evidence ( Ardizzoni 1997).
Topotecan 1.5 mg/mq/day x 5 days every 3 weeks has been compared with CAV in a phase III trial; most patients had already been treated with a PE regimen; similar activity and toxicity for both regimens were reported. However, the proportion of patients who experienced symptom improvement was greater in the topotecan group. There was no significant difference in median duration of response or survival among patients treated with topotecan compared with those treated with CAV (von Pawel 1999). A phase II comparator study found oral topotecan 2.3 mg/mq/day x 5 days every 3 weeks to be similar in activity to IV topotecan in patients with relapsed SCLC, sensitive to first-line chemotherapy, with less grade 4 neutropenia and greater convenience of administration (von Pawel 2001). These findings are confirmed by a phase III study in which oral topotecan demonstrates efficacy and tolerability similar to IV topotecan in chemosensitive SCLC, and offers patients a convenient alternative to intravenous therapy ( Eckardt 2007).
A recent randomized trial has finally proved an improvement in survival and quality of life with single agent oral topotecan versus best supportive care, even in the worst patient subgroup such as that with poor performance status (O’Brien 2006). Topotecan is, at the moment, the only chemotherapeutic agent registered for the treatment of relapsed SCLC, worldwide. Therefore, the use of single agent oral or IV topotecan is recommended on a type 2 level of evidence (von Pawel 1999; O’Brien 2006; Eckardt 2007). Whether combination chemotherapy could be superior to single agent in the setting of second line chemotherapy remains to be proven. A phase II trial has evaluated the combination of doxorubicin and paclitaxel in patients who relapsed after PE containing chemotherapy; a response rate of 52% has been observed in sensitive relapsed individuals (Sonpavde 2000). The combination of ifosfamide, paclitaxel and cisplatin has shown a response rate of 73% in patients who relapsed after carboplatin and etoposide ( Kosmas 2001). CPT-11 is active in 47% of patients with refractory or relapsed SCLC (Masuda 1992). In the same setting, the combination of carboplatin and CPT-11 shows a response rate of 31 to 62% (Naka 2002; Hirose 2003), while CPT-11 combined with etoposide is active in 68% of patients (Masuda 1998). Grade 3-4 neutropenia occurs in about 50% of patients treated with these regimens (Naka 2002; Hirose 2003; Masuda 1998).
Palliative radiotherapy may be suitable for individual clinical use on a type R basis in patients with thoracic recurrences after chemotherapy if thoracic radiotherapy was not given in the first-line treatment. Total doses of 10 Gy in one fraction or 17 Gy as 2 weekly fractions of 8.5 Gy, delivered through ap-pa fields including the primary site and mediastinal nodes, are adequate for patients with a poor performance status ( MRCLCWP 1992). Thirty Gy delivered as 10×3 Gy is also an accepted palliative schedule.

6.7 Treatment of synchronous tumours

6.7.1 Treatment strategy

In extensive-stage SCLC, where 2-year survival is rare, synchronous tumours need to be treated if they are symptomatic. In limited-stage SCLC, treatment of the fast growing SCLC has priority over the treatment of synchronous tumours that occur with a high incidence, such as cancer of the breast, the colon and rectum, or the uterus in females and carcinomas of the prostate, colon and rectum or the bladder in males. If resectable, synchronous carcinomas should be resected after standard therapy for limited-stage SCLC. Non-resectable synchronous tumours may either require a palliative treatment programme, be treated by definitive radiotherapy alone, or be treated by combined radiotherapy and resection. Such treatment should be given after attaining complete remission of the lung cancer by the standard therapy for limited-stage SCLC, if the individual patient is able to tolerate it.

6.8 Chemotherapy for limited disease SCLC

A combination chemotherapy regimen for 4-6 cycles is standard option on a type C basis for localized stage II or III SCLC (Giaccone 1993; MRCLCWP 1989; Spiro 1989). SCLC is sensitive to alkylating agents such as cyclophosphamide and ifosfamide, platinum compounds (cisplatin and carboplatin), epipodophyllotoxins (etoposide and teniposide), anthracyclines such as doxorubicin and epirubicin, vinca alkaloids and methotrexate. Combination chemotherapy is superior to single-agent treatment. Drug combinations include 2 or 3 among the most active agents. Each of these regimens will produce complete response in 50-70% of patients with limited disease and overall responses in approximately 80-90%.

Combination standard options are:
PE: Cisplatin (75-100 mg/m2 day 1 or 25-30 mg/m2 days 1-3) + etoposide (100-120 mg/m2 day 1-3) q 3 weeks
CE: Carboplatin (AUC 5-6 day 1) + etoposide (100-120 mg/m2 day 1-3) q 3 weeks
ICE: Ifosfamide (5000 mg/m2 day 1) + carboplatin (300-400 mg/m2 day 1) + etoposide (100-120 mg/m2 days 1-3) + mesna (5000 mg/m2 day 1 and 3000 mg/m2 day 2)

None of these regimen has been demonstrated to be superior to the others in terms of survival. The 2-drug combination including cisplatin (or carboplatin) and etoposide is widely accepted as standard option thanks to its modest toxicity, particularly when combined with radiotherapy. A meta-analysis of randomized clinical trials comparing regimens which did or did not include cisplatin and etoposide has shown a survival benefit for PE regimen over other combinations (Paesmans 1999). Another meta-analysis icluding all chemotherapy studies comparing pltinum-based vs platinum-free chemotherapy demonstrated a superiority of chemotherapy regimens including platinum (Pujol 2000 ). A number of drugs, including taxanes, topoisomerase I inhibitors, gemcitabine and vinorelbine have shown activity in small cell lung cancer and they have been included in recent combinations. In patients with SCLC stages I-IV, the combination of paclitaxel, etoposide, and carboplatin shows improved overall and progression-free survival and less frequent hematologic toxicities than standard therapy with carboplatin, etoposide, and vincristine. This new combination is suitable for individual clinical use on a type 2 level of evidence ( Reck 2003). Several randomised trials addressed the question of the role of alternating chemotherapy (Evans 1987; Fukuoka 1991; Giaccone 1993; Wolf 1991). These studies, randomising CAV (cyclophosphamide + doxorubicin + vincristine) regimen against alternating CAV/PE regimen, provided mixed results. In one trial some benefit of the alternating regimen was observed in limited disease (2-year survival of 15% vs 20% for the alternating regimen) so that CAV/PE regimen for these patients may be considered suitable for individual clinical use on a type 2 level of evidence ( Fukuoka 1991). A general observation was that between the two regimens there is a certain degree of cross-resistance which is higher with the sequence PE followed by CAV than the inverse sequence (CAV followed by PE). A quality of life assessment of patients receiving weekly chemotherapy compared to that of patients receiving a 3-week-interval treatment demonstrated an advantage of the 3-week-interval option ( Gower 1995). This study demonstrated that quality of life may be critical for the individual choice of chemotherapy. Intensification of chemotherapy using weekly regimens does not improve outcome and should still be considered investigational. Maintenance chemotherapy with CAV (after induction PE combined with radiotherapy) is not associated with increased survival but with significant toxicity and therefore is not recommended (Beith 1996). The value of dose escalation with or without haemopoietic growth factors remains controversial. Most randomised trials have not shown a survival benefit for doses above the conventional therapeutic range ( Ihde 1994; Klasa 1991), even if in three recent randomized trials a greater dose-intensity was associated with survival improvement while maintaining acceptable toxicity in SCLC patients with a good performance status (Masutani 2000; Steward 1998 ; Thatcher 2000). In extensive stage (ES) or limited stage (LS) previously untreated SCLC patients, increasing dose intensity (DI) of cyclophosphamide, doxorubicin, and etoposide (CDE) by nearly 70%, by means of a combination of dose size and dose intensity increase with granulocyte colony-stimulating factor support, does not produce any significant survival benefit compared to conventional dose and schedule (Ardizzoni 2002). More recently, doubling the dose density of ifosfamide, carboplatin, and etoposide (ICE) chemotherapy with filgrastim and blood-progenitor-cell support in better-prognosis small-cell lung cancer (prognostic score of 0-1; 87% previously untreated LS patients), has led to shorter treatment duration and less neutropenic sepsis than did standard ICE without any improvement in overall survival ( Lorigan 2005). Therefore, for patients with either ES-SCLC or LS-SCLC, dose-dense/intense treatment is not recommended on a type 2 level of evidence outside of a clinical trial ( Ardizzoni 2002; Lorigan 2005). The use of very high dose chemotherapy with autologous bone marrow or peripheral stem cell reinfusion remains investigational both as initial induction treatment and as consolidation therapy after induction of complete response (Simon 2003). A recently presented randomized study from EBMT showed no advantage by using modern high-dose chemotherapy with periferimal hemopoietic stem cell support over standard dose chemotherapy (Smith 2006). The use of haemopoietic growth factors decreases the period of neutropenia and reduces the number of febrile episodes and the use of antibiotics. There are as yet no data to suggest that survival is improved. The duration of combination chemotherapy has been the subject of several trials ( Bleehen 1989; Giaccone 1993; Spiro 1989). There is no survival advantage in continuing chemotherapy beyond 4-6 cycles.

6.9 Chemotherapy for extensive disease, STAGE IV

Drug combinations for extensive disease SCLC include 2 or 3 of the most active agents. In extensive disease patients (ED/SCLC), the complete response rate is 15-20% and overall response is 70-80%; median survival is around 10 months. A combination regimen for 4-6 cycles is standard option on a type C basis. SCLC is sensitive to alkylating agents such as cyclophosphamide and ifosfamide, platinum compounds (cisplatin and carboplatin), epipodophyllotoxins (etoposide and teniposide), anthracyclines such as doxorubicin and epirubicin, vinca alkaloids and methotrexate. Combination chemotherapy is superior to single-agent treatment.

Combination standard options are:
PE:Cisplatin (75-100 mg/m2 day 1 or 25-30 mg/m2 days 1-3) + etoposide (100-120 mg/m2 day 1-3) q 3 weeks
CE: Carboplatin AUC 5-6 day 1300 mg/m2) + etoposide (100-120 mg/m2 day 1-3) q 3 weeks
ICE: Ifosfamide (5000 mg/m2 day 1) + carboplatin (300-400 mg/m2 day 1) + etoposide (100-120 mg/m2 day 1-3) + mesna (5000 mg/m2 day 1 and 3000 mg/m2 day 2)

No regimen has been demonstrated to be superior to the others in terms of survival outcomes. The 2-drug combination including cisplatin (carboplatin) and etoposide is widely accepted as a standard option on a type R basis due to its reduced toxicity. A recent meta-analysis of randomized clinical trials comparing regimens which did or did not include cisplatin and etoposide has shown a survival benefit for the PE regimen over other combinations (Paesmans 1999). Another meta-analysis icluding all chemotherapy studies comparing pltinum-based vs platinum-free chemotherapy demonstrated a superiority of chemotherapy regimens includin platinum (Pujol 2000). A number of new drugs, including taxanes, topoisomerase I inhibitors, gemcitabine and vinorelbine have shown activity in small cell lung cancer and they have been included in recent combinations. In view of the activity, low toxicity, and ease of administration, a combination of carboplatin and vinorelbine is suitable for individual clinical use on a type 3 level of evidence in ED/SCLC ( Gridelli 1998). A number of combinations (in particular Irinotecan plus cisplatin or paclitaxel, carboplatin and extended-schedule oral etoposide) seem to be active regimens in ED/SCLC, where an overall response rate of over 80%, a complete response rate of over 20% and a median survival of 10-13 months have been reported (Hainsworth 1998; Kudoh 1998; Sandler 2003). The combination of ifosfamide with cisplatin and etoposide (VIP) may marginally improve time to progression (median time to progression from 6 to 6.8 months) and overall survival (2-year survival from 5% to 13%) as compared with a PE regimen. This combination is suitable for individual clinical use on a type 2 level of evidence (Loehrer 1995). Prolonged oral etoposide, combined with cisplatin and ifosfamide, is suitable for individual clinical use on a type 3 level of evidence (Glisson 1998). In a recent randomized trial, a statistically significant difference in survival was found between patients with extensive-stage (ES) small-cell lung cancer assigned to receive irinotecan and cisplatin (IP) and those assigned to receive etoposide and cisplatin (EP): median survival 12.8 months vs 9.4 months; P = 0.002 ( Noda 2002). A multicenter randomized trial was designed to confirm these results in patients with ES-SCLC using a modified weekly regimen of IP vs EP to improve tolerability and dose intensity. There were no significant differences in response rate and overall survival between the two arms. Patients receiving weekly-IP had less myelosuppresion, but more diarrhoea than EP (Hanna 2005). In patients with SCLC stages I-IV, the combination of paclitaxel, etoposide, and carboplatin shows improved overall and progression-free survival and less frequent hematologic toxicities than standard therapy with carboplatin, etoposide, and vincristine (Reck 2003). A recent randomized phase III study comparing oral topotecan plus cisplatin (TC) vs PE in patients with ED-SCLC has shown comparable efficacy and tolerability of the two regimens (Eckardt 2007). These new combinations are suitable for individual clinical use on a type 2 level of evidence as an alternative to platin-etoposide regimen ( Noda 2002; Hanna 2005; Reck 2003; Eckardt 2005). The addition of paclitaxel to EP does not improve the time to progression and overall survival in patients with ES-SCLC compared with standard EP and is associated with unacceptable toxicity. This regimen is therefore not recommended on a type 2 level of evidence (Niell 2005). A quality of life assessment of patients receiving weekly chemotherapy compared with that of patients receiving a 3-week-interval treatment demonstrated an advantage of the 3-week-interval option (Gower 1995). This study demonstrated that quality of life may be critical for the individual choice of chemotherapy. Several randomised trials addressed the question of the role of alternating chemotherapy (Evans 1987; Fukuoka 1991; Giaccone 1993; Wolf 1991). Studies randomising patients to a CAV (cyclophosphamide + doxorubicin + vincristine) regimen versus an alternating CAV/PE regimen provided mixed results. A randomized trial of rapidly alternating CAV/PE versus sequential CAV/PE chemotherapy has shown no difference between the two regimens after long term follow-up ( Ueoka 1998). Intensification of chemotherapy using weekly regimens (such as CODE, cisplatin, vincristine, doxorubicin and etoposide, plus haemopoietic growth factors) does not improve outcome when compared with a CAV/PE regimen and therefore is not recommended (Furuse 1998). Maintenance chemotherapy with CAV (after induction PE combined with radiotherapy) is not associated with increased survival but shows significant toxicity and therefore is not recommended on a type 2 level of evidence (Beith 1996). Maintenance chemotherapy with oral etoposide after VIP seems well tolerated with a non-statistically significant trend toward improved survival in patients with ED-SCLC (Sandler 1999). The value of dose escalation with or without haemopoietic growth factors remains controversial. Randomised trials have not yet shown a survival benefit for doses above the conventional therapeutic range (Ihde 1994 ; Klasa 1991). In ES or limited stage (LS) previously untreated SCLC patients, increasing dose intensity (DI) of cyclophosphamide, doxorubicin, and etoposide (CDE) by nearly 70%, by means of a combination of dose size and dose intensity increase with granulocyte colony-stimulating factor support, does not produce any significant survival benefit compared to conventional dose and schedule (Ardizzoni 2002). More recently, doubling the dose density of ifosfamide, carboplatin, and etoposide (ICE) chemotherapy with filgrastim and blood-progenitor-cell support in better-prognosis small-cell lung cancer (prognostic score of 0-1; 87% previously untreated LS patients), has led to shorter treatment duration and less neutropenic sepsis than did standard ICE without any improvement in overall survival (Lorigan 2005). Therefore, for patients with either ES-SCLC or LS-SCLC, dose-dense/intense treatment is not recommended on a type 2 level of evidence outside of a clinical trial ( Ardizzoni 2002; Lorigan 2005). The use of haemopoietic growth factors decreases the period of neutropenia and reduces the number of febrile episodes and the use of antibiotics. There are as yet no data to suggest that survival is improved. Clinical guidelines for the use of growth factors have been recently updated (ASCO 2006). The duration of combination chemotherapy has been the subject of several trials (Bleehen 1989; Giaccone 1993; Spiro 1989). There is no survival advantage in continuing chemotherapy beyond 4-6 cycles. In patients with poor prognostic factors the early toxicity of chemotherapy may be life threatening. In a randomized trial, no survival benefit was obtained with a four-drug chemotherapy regimen compared with a less intensive two-drug combination in patients with extensive SCLC and poor prognosis ( MRCLCWP 1996b). Among biologic targeted therapies for SCLC, marimastat is the first matrix metalloproteinase inhibitor (MMPI) to be studied in randomized clinical trials in SCLC. Treatment with marimastat after induction therapy for SCLC does not result in improved survival and has a negative impact on quality of life. Its use is therefore not recommended on a type 2 level of evidence outside of a clinical trial (Shepherd 2002). A phase II study of Imatinib (STI571), c-kit tyrosine kinase inhibitor, in unselected SCLC patients was negative, but inconclusive since 80% of tumors did not express c-kit (Johnson 2003). More recently, STI571 has been shown to be inactive in spite of patients selection for c-kit-expressing SCLC (Dy 2005). The role of this drug in SCLC remains investigational. Phase I studies in small cell lung cancer patients demonstrate that oblimersen sodium (G3139; genasense bcl-2 antisense oligonucleotide) can be combined with paclitaxel or carboplatin and etoposide with an encouraging response rate ( Rudin 2002; Rudin 2002). Preliminary results of a randomized phase II study testing carboplatin and etoposide (CE) with or without G3139 in patients with ES-SCLC show that co-administration of G3139 with CE may be associated with increased toxicity (Rudin 2005). The role of this drug in SCLC remains controversial and is investigational. Novel vaccine utilizing dendritic cells (DC) genetically engineered to express wild-type p53 has demonstrated safety and substantial specific immune response in patients with ES SCLC, with an encouraging response rate (Gabrilovich 2005). In a phase III trial by the Federation National de Centres de Lutte contra le Cancer Group in France, 92 ED-SCLC patients with PS up to 2 and age < 70 years were randomized to placebo or thalidomide, starting after two cycles of induction chemotherapy treatment. Overall survival increased from 8.7 for placebo to 11.7 months for patients treated with thalidomide, respectively ( Pujol 2007). A large UK randomized trial has been recently completed and should be able to confirm or deny the role of thalidomide in SCLC.

6.10 Prophylactic cranial radiation therapy

Prophylactic cranial irradiation (PCI) is standard treatment on a type 1 level of evidence in patients who achieve complete remission after induction chemo-radiotherapy (Auperin 1999). A meta-analysis of seven trials that compared prophylactic cranial irradiation with no prophylactic cranial irradiation has been performed. The individual data on 987 patients with small cell lung cancer, 85% of whom had limited disease, who were in complete remission after chemotherapy plus thoracic radiotherapy were analysed. Prophylatic cranial irradiation improves both overall survival (with a 5.4% increase in the rate of survival at three years: 15.3% in the control group vs 20.7% in the treatment group) and disease-free survival. The benefit was similar after adjustment for the extent of disease, type of induction therapy, and performance status. Prophylatic cranial irradiation also reduced the cumulative incidence of brain metastasis at three years, from 58.6% in the control group to 33.3% in the treatment group. Because the examinations required to determine a complete remission differed in each trial (some trials only required a simple chest X-ray), prophylactic cranial irradiation is suitable for individual use on a type R basis in patients with a good partial response assessed using current diagnostic methods( Auperin 1999). It has been suggested in the past that cranial irradiation may increase neuropsychological syndromes, ataxic gait and brain abnormalities as indicated by CT scan (Pedersen 1988). Two recent randomized trials have failed to confirm significant neurotoxicity after PCI, while 25-59% of patients had abnormal neuropsychological assessment before PCI (Arriagada 1995; Arriagada 1997; Gregor 1997a). These preexisting impairments have been associated with paraneoplastic phenomena and patient characteristics (age, comorbidity, long-term tobacco use). The most frequent impairments are in terms of decreased verbal memory, frontal lobe dysfunction and fine motor coordination disturbances. Neurotoxicity of anticancer drugs, concurrent chemo-radiotherapy, and high individual radiation fractions are variables which may increase the probability of such impairments. Whether PCI leads to neuropsychological sequelae could not be addressed in the recent meta-analysis ( Auperin 1999). It is recommended that prophylactic cranial irradiation is administered after completion of chemotherapy (Gregor 1997a; Turrisi 1990) on a type C basis. Parallel opposed lateral portals are used. 1- 6 MeV photons are appropriate. Care has to be taken to ensure that the entire brain, including the basal frontal and temporal lobes, is irradiated and that the lenses of the eyes are spared. Total doses are limited by the risk of late normal tissue damage with consequent impairment of neuropsychological function. Most commonly 24-36 Gy are given with one 2-3 Gy fraction per day, 5 days per week for 2-3 weeks. Larger doses of radiation led to greater decreases in the risk of brain metastasis, according to a recent meta-analysis of four total doses (8 Gy, 24 to 25 Gy, 30 Gy, and 36 to 40 Gy). A trend toward a decrease in the risk of brain metastasis with earlier PCI administration has been also identified (Auperin 1999 ). Timing of PCT is another variable. In practice PCI should be introduced as early as possible after response to chemotherapy. The questions of optimal dose, scheduling and timing of treatment so as to further reduce the incidence of brain metastasis with minimal and acceptable toxicity need further studies.

6.11 Thoracic radiation therapy of localized SCLC

Thoracic radiation added to chemotherapy improves local control and improves survival by 3-7% in patients with limited-stage SCLC (Pignon 1992; Warde 1992). The optimal total dose, volume, duration and timing have not been yet been proved conclusively. In the previously mentioned meta-analysis, no significant differences between sequential and non-sequential approaches (concurrent or alternating radiotherapy) could be observed. Individual randomized trials that addressed the importance of the timing of RT and the results are conflicting, with some studies showing a benefit of early radiation ( Jeremic 1997; Murray 1993; Murray 1997; Takada 2002), and others showing no difference between early, late or alternating radiotherapy (Gregor 1997b; Lebeau 1999; Work 1997; James 2003). The design of these trials differs significantly. Two meta-analyses using a different definition of early or late chest radiotherapy and of the type of radiotherapy came both to the conclusion that delivering thoracic radiation with 9 weeks or within 30 days after the start of chemotherapy improved the 5-year survival rate (Fried 2004; Pijls_Johannesma 2005) on a type 2 level of evidence. Chest radiation given hyperfractionated or in an overall treatment time of less than 30 days was alos associated with better 5-year survival. This beneficial effect only occurred when radiotherapy was administered concurrently with platinum and etoposide chemotherapy, and not when radiation was given together with anthracyclins. The latter was associated with higher toxicity and subsequent dose reductions. In one phase III trial, the five-year survival was significantly improved when thoracic radiotherapy was delivered from cycle one of cisplatin and etoposide chemotherapy in an accelerated way, i.e. giving 45 Gy in 30 fractions in 3 weeks (1.5 Gy BID) (26 % 5-year survival), compared to the same total dose but given in 5 weeks (16 % 5-year survival) ( Turrisi 1999). Although the incidence of acute grade 3 oesophagitis was significantly higher in the accelerated schedule (27 % vs. 11 %), this was reversible. The local failure rate was 52 % in the conventionally fractionated arm versus 36 % in the accelerated schedule. At present, four cycles of cisplatin and etoposide chemotherapy, from cycle one combined with accelerated chest radiotherapy to a dose of 45 Gy in 30 fractions in 3 weeks (1.5 Gy BID) can be recommended for patients in a good general condition on a type 2 level of evidence. In view of the still high mortality, local failure rates and toxicity, further research to optimise this treatment is still warranted. Another study has compared once-daily versus twice-daily thoracic radiotherapy (48-50 Gy) given with cycles 4 and 5 of PE chemotherapy (305 patients) (Bonner 1999). In both arms, however, the overall treatment time of the thoracic radiotherapy was the same, being approximately 5 weeks. As a consequence, the same biological radiation dose was administered in both arms of the study. It thus does not come as a surprise that no differences were observed between both arms, neither in the median survival, nort in the two year survival (21 months and 43%, respectively).

7. LATE SEQUELAE

7.1 Treatment late effects and sequelae

7.1.1 Treatment toxic deaths

The major toxicities of combination chemotherapy are due to side-effects of the specific agents used. Treatment-associated death rates from all causes are 0% to 4% in limited-stage and 2% to 8% in extensive stage SCLC patients.

7.1.2 Radiotherapy sequelae

Following radiation therapy, the most frequently reported sequelae noted were pneumonitis (approximately 10% grade 2 and 4.6% grade 3), pulmonary fibrosis (approximately 20% grade 2 and 8% grade 3 or greater), esophagitis (about 12% grade 2 and 3% grade 3) and esophageal stricture (about 1%). Thoracic spinal cord myelopathy was observed in four out of 1380 patients (0.3%). Radiation treatment fractionation (>2.67 Gy) is critical for the increased risk of radiation pneumonitis ( Roach 1995). Pulmonary impairment is moderate in long-term survivors, but is not strikingly worse than that expected in a heavy smokers population.

7.1.3 Prophylactic brain irradiation sequelae

Prophylactic brain irradiation may induce clinical and radiological signs of various types and degrees of brain injury, including neurological deficit, memory loss, and dementia. These sequelae were associated with concomitant administration of chemotherapy and doses of about 30 Gy in 10 fractions of 3 Gy. Symptoms appeared between a few months to several years after cranial irradiation. The most effective suggested management is to limit total radiation doses to 30 Gy with doses per fraction not greater than 2.0 Gy and to avoid concomitant chemoradiotherapy. Some degree of neurological impairment preexist to brain irradiation and they are probably disease-related so that prophylactic cranial irradiation seems not responsible for additional neurotoxicity. More recent studies are in favour of this observation ( Komaki 1995; Van Oosterhout 1996; Arriagada 1997).

7.2 Related and secondary tumours

7.2.1 Related tumours

Relative to the general population, the risk of all second cancers (non-small cell lung cancer in 50% of cases) among patients surviving for more than 2 years after therapy for SCLC is increased 3.5-fold. Second lung cancer risk was increased 13-fold among patients who received chest irradiation, while a 7-fold increase was observed in nonirradiated patients. The risk of a second primary lung cancer increases over time, with a cumulative incidence of 44% at 14 years. The highest risk was observed in those who continued to smoke after diagnosis, with evidence of an interaction between chest irradiation and continued smoking (relative risk = 21) or between treatment with alkylating agents and continued smoking (relative risk =19). Cigarette smoking cessation is associated with a reduction in risk for a second smoking-related lung cancer ( Richardson 1993; Glisson 1997; Tucker 1997).

7.2.2 Secondary tumours

Alkylating agents, such as nitrosoureas or procarbazine, especially when given protracted, and etoposide can increase the risk of therapy-related acute myeloblastic leukemias. The risk of an acute leukemia 2-3 years after therapy for SCLC ranged between 2-18% (Johnson 1986; Zulian 1993). Both radiation therapy and cytotoxic drugs have been implicated in second cancers (Tucker 1997).

8. FOLLOW-UP

8.1 General principles and objectives

8.1.1 General principles and objectives

The actual 5-year survival for limited-stage patients is higher than 5-10% (but can be as high as 60% in highly selected subgroups) and for extensive-stage is as low as 1-2%. About 70% of patients who are disease-free after 2 years do not relapse, and relapses 5 to 10 years after the beginning of initial therapy are rare. In 20% of patients a second primary will develop. After 3-4 years of disease-free survival the risk of a second primary exceeds the risk of late relapse. Overall, follow-up examinations have to consider recurrences (chest relapse is approximately 30%), treatment late effects, tobacco-related diseases as well as second primaries.

8.2 Suggested protocols

8.2.1 Suggested protocols

In patients with progressive disease, follow-up examinations are to be performed within a good palliative care program. In patients with no evidence of disease, routine chest X-ray is recommended on a type R basis every 3 months for the first 2 years in order to maximise the probability of an early detection of a chest relapse, which in highly selected cases may be successfully treated with surgery. The role of an annual chest examination in patients at high risk for second lung cancer has recently been reappraised leading to a meaningful benefit of diagnostic anticipation in terms of resectability, stage distribution and survival ( Strauss 1995). Being these patients at high risk of developing a second lung primary cancer, it seems to be reasonable to recommend a periodical chest X-ray examination for the lifelong period on a type R basis . Every other examination is dictated by patient complaints.

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Dr. Andrea Ardizzoni (Author)
University Hospita – Parma, Italy
mail: AArdizzoni@ao.pr.it

Prof. Dirk De Ruysscher (Author)
University Hospital – Maastricht, The Netherlands
mail: dirk.deruysscher@maastro.nl

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

Prof. Heine H. Hansen (Reviewer)
Rigshospitalet – Copenhagen, Denmark
mail: hansen.hh@rh.dk