Small cell cancer (SCLC) has its origin in neuroendocrine cell precursors and is characterized by rapid growth, through both higher response rate to chemotherapy and radiotherapy and the development of treatment resistance in patients with metastatic disease. In Western countries the incidence of SCLC has fallen to 13%. All patients had a history of smoking. Further description of neuroendocrine tumors with high in 1990 which were previously included in SCLC contributed to decreasing the incidence of SCLC. Smoking cessation SCLC reduces not only the risk but also the risk of death of patients with SCLC located almost 50%. Only 1/3 of patients are diagnosed with localized disease where treatment is healing purposes. Due to natural aggressive evolution screening methods are unlikely to reduce mortality and smoking prevention remains the primary and most important intervention to reduce mortality.

Neuroendocrine tumors account for about 20% of lung tumors and most (14%) are small cell lung cancers (SCLC).

Screening

Currently available screening test is not efficient. Low dose spiral CT would decrease lung cancer mortality but only in case of NCSLC not in cases of SCLC.

Clinical

The disease typically present with symptoms of recent occurrence 8-12 weeks before requesting physician. SCLC is usually centrally located and can cause irritation or major airway obstruction. Common symptoms are cough, dipping, and hemoptysis. Squamous cell cancer is present and central location but he often shows central excavation. SCLC grow rapidly and metastasize to mediastinal lymph nodes and patients may present with high intrathoracic tumors and lymph node metastases primary tumor differentiation is impossible.

Pressure on mediastinal structures can cause various symptoms:

            -superior vena cava syndrome

            -recurrent laryngeal nerve compression – sore throat

            – hemidiaphragm paralysis due to compression of the phrenic nerve

            -disfagia due to esophageal compression

            -stridor due to compression of the upper airway

Neurologic manifestations may be due to brain metastases or spinal cord compression:

                         -dizziness

                        – visio impairment

                        -photophobia

                        -nausea, vomiting

                        -confusion

                          -location symptoms

                          -muscle weakness in the legs

Paraneoplastic syndromes

1. Inappropriate ADH secretion (15%)

2. Ectopic ACTH secretion (2-5%)

3. Lambert Eaton Myasthenic Syndrome 3. (3%)

4. Subacute cerebellar degeneration

5. Subacute sensory neuropathy

6. Limbic encephalopathy

Pathology

Pathological diagnosis is made according to the WHO classification, which uses morphology (small cell fusiform or round, little cytoplasm, high mitotic index, necrotic areas). Immunohistochemistry to confirm the diagnosis of SCLC is not mandatory (synaptofizine, cromgranine A, CD 56, TTF-1, MIB-1) but should be used in case of doubt.

It is a poorly differentiated tumor is classified as a high-grade neuroendocrine carcinoma. Up to 30% of autopsies performed on deceased patients with SCLC NSCLC highlights areas of differentiation. This is commonly seen in patients previously treated lung carcinogenesis suggesting that appears in a pluripotent stem cell capable of differentiation. Although 95% of small cell carcinomas may occur in the lung, they can occur in extrapulmonary locations as nasopharynx, GI tract, genitourinary tract.

Almost all SCLC are immunoreactive for keratin, epithelial membrane antigen and TTF-1. The SCLC is colored most positive for neuroendocrine differentiation markers: synaptofizine, neuron specific enolase, neural adhesion molecule. However, these markers can be used to differentiate SCLC from NSCLC because in 10% of cases there is at least one positivity marker for neuroendocrine differentiation in NSCLC.

The staging of small cell carcinoma aims to identify patients with limited disease who benefit from local treatment with radiotherapy plus chemotherapy and have a better prognosis that those with extensive disease have a poor prognosis and treated only with chemotherapy. Outside the state, there are important prognostic factors of performance status and weight loss in the last 3-6 months.

For staging is recommended:

• History, physical examination,

• Blood count, kidney and liver biochemical tests, LDH, liver function tests

• CXR,

• Cytological examination of pleural effusion, supraclavicular lymph’s. A patient is considered limited if disease pleural effusion is too low to perform imaging guided sampling or if:

1. pleural fluid cytology is negative for malignancy,

2. liquid is not bleeding and not exudate,

 3. medical -considers that the effusion is not due to cancer.

• Bronchoscopy,

• mediastinoscopy.

• signs of anemia in patients with bone marrow infiltration (erythroblastic in the periphery) are advised that puncture bone marrow or bone marrow biopsy, especially in patients with other metastases absent. Medullary invasion occurs in less than 5% of patients.

• C. T. lung and abdominal initially. If metastatic disease is not evident on CTor clinical data suggests invasion cranial bone or bone scintigraphy is recommended and cranial CT or MRI. Alternatively bone scans and C, two fluoro-2-deoxy D-glucose PET-CT may be performed. The PET-CT 9% -19% of patients are over-staged and 4% -8% are sub-stage. PET-CT data that impact the therapeutic decision and in particular where sub-staging must be confirmed pathologically. For most places metastatic PET-CT is superior to MRI or CT.

Bone scintigraphy is positive in up to 30% of patients without bone pain or elevated alkaline phosphatase.

In patients with solitary metastasis, pathologic confirmation should not delay treatment. In this case the size of solitary metastasis should be reevaluated after 2 treatments. As an alternative we recommend a secondary imaging method for example small lesion MRI in case of liver or bone.

If pleural effusion or pericardial metastasis is the only headquarters, malignant cells are not present and another plausible explanation exists outside of tumor invasion when treatment is carried out considering that is M0.

Because of its location central frequent biopsies can be obtained through bronchoscopy nine most. Other methods used are mediastinoscopy, endobronchial ultrasound (EBUS), endoscopic ultrasound, needle aspiration or transthoracic by thoracoscopy. A biopsy of a metastatic lesion location may be the preferred option if metastasis is easy and safe (skin, liver).

Before surgical resection patients who appear to have stage T1-2, N0 after the mediastinal PET-CT pathologic confirmation is necessary. Mediastinal staging is not necessary if the patient is not a candidate for surgical resection. Invasive mediastinal staging can be performed with conventional mediastinoscopy, EUS-FNA (transesophageal endoscopic ultrasound with fine needle aspiration), endobronchial ultrasound ptin guided aspiration transbronchyal (EBUS-TBNA) video-assisted thoracoscopy or (VATS).

In order to detect distant disease is recommended bone scan, bone scan, ultrasound or abdominal CT puncture bone biopsy osteomedullary, Cranial CT.

If a single positive test is no longer perform other procedures to identify disease at bay.

Due to the aggressive nature of SCLC staging should not delay the initiation of treatment more than 1 week.

Restaging after treatment is repeated before prophylactic cranial irradiation.

Staging VALSG (Veteran’s Administration Lung Study Group) classifies small cell carcinoma patients in two groups:

A limited disease (TNM stages I, II and III) 30-40%.

a) This group included patients with the disease are limited to a hemithoracs and which are suitable for the treatment of combined radiation therapy, chemotherapy.

At this stage include patients with limited disease to a lymph node metastases hemithoracs with hilarious ipsilateral mediastinal and supraclavicular and controlateral.

Exclude patients with limited disease T3-4 multiple pulmonary nodules or large tumor volume that does not fit in a tolerable radiation therapy plan.

The survival of these patients treated by radiotherapy and chemotherapy is 18% at 5 years, and median survival is 16 months.

 b) in this group there is a subset of patients with the disease “very” limited without mediastinal lymph extension. These patients benefit from surgical resection was complete and whether survival at 5 years was 50-60%.

B. extended illness include all patients with stage IV oriceT, any N, M1 a / b or T3-4 by multiple pulmonary nodules or large tumor volume that does not fit in a tolerable radiation therapy plan. It represents 60-70% of all patients.

Prognostic

Factors with poor prognosis are:

            Performance -Status 3-4

            Extensive -disease

            -LDH Increased (associated with greater tumor volume)

In limited Disease good prognostic factors are:

            -gender female

            -age <70 years

            Normal -LDH

            – Stage I disease

In extensive disease are good prognostic factors:

            – young age

            – good performance status

            -Normal -LDH

            -a single seat of metastasis

TREATMENT

Therapeutic indication

a) limited disease (clinical stage I)

In patients with C. T. lung and mediastinoscopy, the absence of mediastinal disease associated surgical treatment is recommended chemotherapy regimens 4-6.

b) limited disease (clinical stage II and IIII) without pleural effusion. In patients with limited disease without pleural effusion 4-6 chemotherapy regimens recommended type associated with concurrent radiotherapy EP. If after treatment the restaging not find any sign of disease prophylaxis is recommended cranial irradiation.

c) extensive disease (STD.IV)

It is recommended chemotherapy 4-6 courses. If disease progresses alternative chemotherapy is recommended. It can be used in palliative radiotherapy.

Therapeutic Methods

I line chemotherapy

Chemotherapy is the main therapeutic modality in small cell carcinoma. The response rate to various chemotherapeutic regimens is between 30-40% 80-86% complete responses in disease limited and 15-20% complete responses in extensive disease. Average survival for patients with limited disease was 12-14 months and 8 months for extensive disease.

Belt is repeated 3 weeks 4-6 cures both limited disease, as well as the extensive disease.

Frequently used as a cure is the EP (cisplatin plus etoposide) in patients using concomitant chemoradiotherapy that is not recommended use of myeloid growth factors. You can replace cisplatin with carboplatin without affecting results except that myelosuppression is marked with carboplatin.

The combination of carboplatin with irinotecan is recommended as an alternative to cure EP in extensive disease.

Alternating chemotherapy

3 cycles alternating with 3 courses EP CAV is an acceptable therapeutic strategy in limited disease but not superior to chemotherapy with one scheme in extensive disease.

The role of high-dose chemotherapy is controversial.

Currently not recommend the use of bevacizumab in SCLC.

In patients aged> 70 years myelosuppression, fatigue, lower organic reserves are more commonly found. Using the 4 cycles of carboplatin with etoposide seems to get favorable results because of carboplatin AUC dosing regardless of renal function decline with age ADATA. Elderly patients carboplatin AUC 5 is recommended.

II line chemotherapy

If the disease-free interval after Take-line chemotherapy is> 3 months then your chances of getting a response is 25%. Agencies are often used paclitaxel, docetaxel, topotecan, irinotecan, Navelbine, gemcitabine, ifosfamide, temozolomide and etoposide orally.

Topotecan alone is approved by the FDA in line IIa after disease progression on first line of chemotherapy. The duration of chemotherapy until smooth II is to obtain the best response plus another 2 courses of chemotherapy. The dose of 1.5 mg / m2 for 5 days is quite toxic so moderate dose reductions are recommended to alleviate the side effects of treatment.

Radiotherapy

It is used as topical treatment in limited disease. The optimal dose of 4500 cGy total is 3 weeks with a fractionation 150 cGy x 2 / day. It is recommended concurrent radiotherapy with chemotherapy in limited disease. It manages EP type 2 cycles performing during radiotherapy and two courses of chemotherapy after completing radiotherapy. Concurrent chemoradiation produces superior results compared to sequential chemoradiation.

By adding radiotherapy, survival at 2 years and 3 years was improved by 5%.

Prophylactic cranial irradiation is used in patients with limited disease who achieved complete or partial remission after treatment combined radiochemotherapy. Prophylactic cranial irradiation appears to prevent the occurrence of brain metastases and produce an increase in survival at 5 years by 5.4%. Similar effects were observed in patients with extensive disease.

The dose used is 25-30 Gy in fractions of 2-2.5 Gy / day.

Palliative radiotherapy is useful in relieving symptoms in patients with brain metastases, bone, mediastinal compression syndrome, spinal cord compression. The doses used are 30 Gy in 10 fractions.

Schemes used chemotherapy

Small cell lung cancer

Disease limit (maximum 4-6 cycles)

1) Cisplatin 80 mg / m2 i.v. day 1

    Etoposide 100 mg / m2 i.v. Days 1-3

    Repeat in 21 days.

————————————————– ———————-

2) Cisplatin 60 mg / m2 i.v. day 1

    Etoposide 120 mg / m2 i.v. Days 1-3

    Repeat in 21 days.

……………………………………………………

3) Carboplatin AUC 5-6 i.v. day 1

    Etoposide 100 mg / m2 i.v. Days 1-3

    Repeat in 21 days.

————————————————– ————————–

During chemotherapy + radiotherapy cisplatin plus etoposide is the recommended scheme.

The use of growth factors is not recommended during concomitant chemoradiotherapy.

Disease expansion (maximum 4-6 cycles)

————————————————– ————————–

1) Cisplatin 75-80 mg / m2 i.v. day 1

     Etoposide 80-100mg / m2 i.v. Days 1-3

     Repeat in 21 days.

————————————————– ————————–

2) Cisplatin 25 mg / m2 i.v. 1,2,3 days

     Etoposide 100 mg / m2 i.v. Days 1-3

     Repeat in 21 days.

————————————————– ————————–

5) 5-6 Carboplatin AUC i.v. day 1

     Etoposide 80-100mg / m2 i.v. Days 1-3

     Repeat in 21 days.

 ————————————————– ————————

6) Cisplatin 60 mg / m2 i.v. day 1

     Irinotecan 60 mg / m2 i.v. days 1, 8, 15

     Repeat in 21 days.

————————————————– ————————–

Cisplatin 30 mg / m2 i.v. Days 1 and 8

     Irinotecan 65mg / m2 i.v. days 1, 8

     Repeat in 21 days.

……………………………………………………………………

7) 5 Carboplatin AUC i.v. day 1

     Irinotecan 50 mg / m2 i.v. days 1, 8, 15

     Repeat in 21 days.

————————————————– —————————-

Second line

          Topotecan 1.5 to 1.2 mg / m2 x 5 days

           Repeat in 21 days

————————————————– —————————–

Surgery is recommended in patients with limited disease without affecting mediastinal proven by CT lung and mediastinoscopy and supraclavicular lymph without. Lobectomy or pneumonectomy is recommended.

5-10% of all patients had clinical stage I and were suitable for surgery. Survival at 5 years was 40%.

Patient survival at 5 years is 10-20% in patients with limited disease, and 3-5% in patients with extensive disease.

Surveillance

PET-CT or MRI head a routine follow-up is recommended. If there is a new pulmonary nodule should be investigated as a new localization of pulmonary cancer as secondary primary tumors are common in patients who are cured of SCLC. Smoking cessation should be encouraged in all patients with SCLC as secondary primary tumors rarely occur in patients who discontinue smoking.