Lung cancer is the most common cancer in the world today, it represented 12.3% of all new cancer cases. In men the highest incidence is observed in Europe (especially Eastern Europe) and North America. In women, incidence is highest in North America and Europe Northwest. In Europe, every year, approximately 400,000 new cases diagnosed. This represents approximately 25% of all new cases of lung cancer in men and 6% of all new cases in women.

There are differences in the frequency of lung cancer among various regions and populations of Europe. In men the cumulative incidence and risk is highest in Eastern Europe. In women the highest incidence is found in Northern Europe, almost 2 times higher than in Eastern and South Eastern Europe. In men, the mortality rate declines in North West European countries (UK, Finland) or low but stable (Sweden, Norway). At the same time in several countries in Central and Eastern Europe has seen an increase in mortality rates (Hungary, Romania).

Lung cancer is the most common cancer to 14% of all cancers. Determine 28% of all cancer deaths.

In women, lung cancer is the leading cause of death by 25% and breast cancer is second with 16%.

In Romania incidence in 1995 it was 51.6 per 100,000 inhabitants and was responsible for 15% of all cancer deaths. In Romania the estimated incidence for 2000 was 40.19 to 100,000 inhabitants and the mortality of 36.09 to 100,000 inhabitants.

 

Risk Factors

 

1. Smoking is the cause of 85% -90% of lung cancers. The risk is 30 times higher in smokers as nonsmokers. The risk decreases after smoking cessation, but this becomes significant after 5 years of stopping smoking. Smoking is the leading cause of lung cancer known. There is a clear dose-response relationship between lung cancer risk and number of cigarettes smoked / day, inhalations degree and the age at which began to smoke. A lifetime smoker has a risk of lung cancer by 20-30 times that of a nonsmoker. Smoking increases the risk of lung cancer in all histological forms, although the relative risk is higher for squamous cell carcinoma and small cell carcinoma than for adenocarcinoma. Adenocarcinoma was always more common in women than in men, both in smokers as well as nonsmokers. Proof that the risk of lung cancer is higher in women than in men at similar levels of exposure to smoking was diminished by recent studies in Europe, which concluded that the risk is similar in the two sexes.

 

Men Women

Small cell adenocarcinoma squamous + + small cell adenocarcinoma Squamous

1.0 1.0 1.0 1.0 Non-Smoker

Ex-smoker 6.2 3.5 3.8 1.1

Active smokers 57.9 18.2 4.1 8

 

The relative risk of lung cancer for cigarette smokers by gender and histologic type (European multicentre study)

1. Passive exposure to cigarette smoke is also a known factor for lung cancer. It is estimated that passive exposure to cigarette smoke increases the risk by 15-20%. It seems that passive exposure to cigarette smoke increases the risk of squamous cell carcinoma and adenocarcinoma less and small cell carcinoma.

2. Exposure to asbestos increases the risk of asbestosis lung cancer and acts synergistically with smoking. Also a risk factor for mesothelioma.

3. Exposure to radioactive dust and radon in uranium mines.

4. China is involved air pollution inside the house through food processing.

5. ENT cancers and esophageal cancer is associated with an increased risk of lung cancer due to the effect of “field cancerization” smoking product.

The other factors known to increase the risk of lung cancer are occupational exposure to asbestos, certain metals (nickel, arsenic, cadmium), radon and ionizing radiation. Yet their contribution to the number of cases occurring in the population is small. Diet rich in vegetables and fruits (especially green vegetables and carrots) may provide modest protection.

 

Lung Cancer Prevention

 

Primary prevention

Smoking cessation is the best way to reduce lung cancer risk. There are many epidemiological studies confirm this phenomenon. The risk of lung cancer decreases with time elapsed after stopping smoking.

It is also easy to prove, from a public health standpoint, that it has immediate impact on lung cancer deaths – convincing adults get smokers to quit smoking rather than by trying to convince young people not to start smoking.

 

Time from

The relative risk of smoking interruption

 

Men Women

Smokers 1.00 1.00

2-9 years 0.66 0.41

0-19 years 0.27 0.19

20-29 0.17 0.08

> 30 years 0.08 0.13

Non-smoking 0.04 0.11

 

The effect of stopping smoking (gender)

 

Although individuals can be persuaded to stop smoking and breast teenagers do not start to smoke, it is very difficult in the absence of social pressures that make smoking unattractive and a network smoking laws that make it expensive and difficult. There opposing pressures from various interest groups (ministry of agriculture, finance, tobacco growers and tobacco industry).

 

Early detection (screening)

Screen out means tests or exams on the use of asymptomatic individuals to identify disease at an early stage (before it becomes clinically apparent). It is essential if screening has to have a certain value, it has lead to an improvement in prognosis (low risk of death or complications of treatment). Regarding lung cancer, the main approach has so far been using Rx. lung screening method. Although it can cause asymptomatic cancers detected (for duration of survival is higher than usual), there is no demonstrable improvement in terms of reducing the number of deaths from lung cancer. Screening has recently renewed interest as low dose spiral CT can detect small asymptomatic lesions more efficiently than conventional X rays. Although the apparent cure rates for such injuries are very good, the same concerns apply in terms of efficiency, and to be demonstrated in trials conducted well before the technique is proposed for widespread application.

 

Histological Types

I. preinvasive

1. squamous dysplasia / carcinoma in situ

2. atypical adenomatous hyperplasia

3. Hyperplasia diffuse idiopathic pulmonary neuroendocrine ceulelor

II. Invasive lesions

1. squamous cell carcinoma 25% -30% (variants: papillary, clear cell, small cell bazaloid). Volume doubling time is 100 days. Frequently are centrally located, the central necrosis (cavitary lesion) and disseminates regional lymph nodes. The histological type most resectable and prognosis is most bun.Se characterized histologically by the presence of keratin pearls. It is associated most frequently with hypercalcemia.

2. Adenocarcinoma is 25-40%.

Histologically form glands and produce mucin. Volume doubling time is 187 days. Appear from Goblet cell. It is more common in women and is located peripherally. It is the most common subtype in people who do not smoke.

Classification of adenocarcinoma:

– In situ Adenocarcinoma (AIS, formerly called adenocarcinoma bronschiolo-alveollary): nodule≤ 3cm, mucinous, nonmucinos, or mixed nonmucinos / mucinous.

– Minimally invasive Adenocarcinoma (MIA): node ≤ 3 cm, with invasion ≤ 5 mm mucinous, nonmucinos, or mixed nonmucinos / mucinous.

-Adenocarcinom Invasively invasion ≥ 5 mm, acinar, papillary or solid micropapilar with mucin.

– Invasive adenocarcinoma: mucinous adenocarcinoma, colloid, fetal and enteric. Precursor lesion for adenocarcinoma is atypical alveolar hyperplasia (AAH). The rate of progression to adenocarcinoma AAH is quite lower than 1% -5% for a period of years.

3. 10-15% large cell carcinoma. Has particularly peripheral location. Histologically contains large cells undifferentiated. Tumor doubling time is 100 days. It includes versions with giant cell and clear cell without clinical importance. A subset of these carcinomas has neuroendocrine features, respond better to chemotherapy and have a poor prognosis. It shows that a large mass on chest radiography peripheral. Histologically this is presented as strings of atypical cells with focal necrosis without signs of keratinization (typical for squamous cell carcinoma) or glands training (typically adenocarcinomas).

They tend to metastasize to lymph nodes and distant and appears as a peripheral lesion.

4. Small Cell Carcinoma represents 20-25% of lung cancer. It has two subtypes of cells: the “oat” and intermediate cells. Is has particularly a central location. Kulcitsky cell is the cell of origin. Volume doubling time is 33 days. The electron microscope is distinguished neurosecretory granules and neurofilament. It contains amino acids and enzymes that synthesize decarboxylates antidiuretic hormone secretion with a rare syndrome of inappropriate antidiuretic hormone. Two thirds of patients have metastatic disease at presentation. The fast pace of growth, marked tendency to metastasize, chemoresponsivity and the treatment is different from the other three subtypes grouped under the new small cell lung carcinoma.

5. Carcinoid tumors represent <1% of lung tumors. They form from Kulchitsky cells, same as small cell carcinoma. They are centrally located. They evolution indolence and rarely metastasize.

Histopathological data for lung cancer were reviewed on a sample of 4928 patients studied between 1964 and 1985. Analysis of these data indicates that lung cancer is increasing in our region. Squamous cell carcinoma remains the most common histologic type of adenocarcinoma in men followed. Small cell carcinoma is the second most common in women after adenocarcinoma. Small cell carcinoma has increased in recent years and become the most common type in women after adenocarcinoma histology.

The generic term non-small cell carcinoma (NSCLC) should be avoided and when IHC is used with TTF-1 (adenocarcinoma) or p63 (squamous cell carcinoma) use terminology: NSCLC that favors adencarcinoma or squamous NSCLC who encourages her. EGFR activating mutations are frequently seen in nonmucinous adenocarcinomas (previously called bronchiolo-alveollary carcinoma) carcinoma and papillary adenocarcinomas. The bronchiolo-alveollary term is discouraged.

Immuno-histochemical staining

A panel suitable for coloring imunohistochice is recommended to exclude metastatic carcinoma of palamine. Immunoreactivity for TTF-1 is seen in aadenocarcinomul primary lung adenocarcinomas and most nonmucinoase (70-100%). Metastatic adenocarcinoma of the lung is always negative for TTF-1 except that metastatic thyroid tumors and is also thyroglobulin is positive. Immunoreactivity relatively sensitive and specific for mesothelioma includesWT-1, calretinine, D2-40, HMBE-1, and Cytocheratine 5/6 (which is negative in adenocarcinomas). In squamous cell carcinoma is positive on protein p63 IHC.

Napsine type II pneumocytes expressed in proximal and distal renal tubules and appears to be expressed in> 80% of lung adenocarcinomas and may be useful as an adjunct to TTF-1. TTF-1 and P63 are useful in differentiating between adenocarcinoma and squamous cell carcinoma diagnosis. P63 is positive squamous cell carcinoma and adenocarcinoma negative primary.

CD 56, chromogranin and synaptofizine are used to identify neuroendocrine tumors

Differentiation between malignant mesothelioma and lung adenocarcinoma is done by using a panel of markers: in adenocarcinoma immunoreactive antibodies include CEA, B72.3, Ber-EP4, MOC31, CD 15 and TTF-1 (negative in mesothelioma).

 

Molecular diagnosis of lung cancer

EGFR and KRAS

EGFR is found on the surface of normal epithelial cells and are often overexpressed in a variety of malignancies. This mutation activating (sensitizing) of EGFR is a critical biological determinant for selection of appropriate therapy in patients with lung cancer. There is a significant association between EGFR mutations in exon 19 deletion and exon 21 in particular, and exon 18, and sensitivity to tyrosine kinase inhibitors (TKI). Exon 20 mutation can predict resistance to TKI. Mutations in EGFR and KRAS are mutually exclusive.

KRAS mutations associated with resistance to TKI and KRAS gene sequencing can be useful for selected patient candidates for TKI. The prevalence of EGFR mutation in adenocarcinoma patients is 10% to 50% in Western and Asian patients with EGFR mutation great frequency in nonsmokers, women, and non-mucinous cancers. KRAS mutations are more common in the West, in smokers and in mucinous adenocarcinomas. Primary resistance to TKI therapy is associated with KRAS mutation. Resistance is associated with mutations won in subsidies of EGFR gene amplification alternative kinases, histologic transition from the SCLC and NSCLC epithelial to mesenchymal transition from.

Anaplastic lymphoma kinase (ALK) gene rearrangement is ALK fusion of different genes and partner. ALK fusions have been identified in a subset of patients with NSCLC who ALK inhibitors may be an effective therapeutic strategy. Crizotinib is approved by the FDA for patients with locally advanced or metastatic bola NSCLC ALK gene rearrangement that. In most cases ALK translocations and mutations of EGFR are mutually exclusive. Current standard methods for detecting ALK fluorescence in situ hybridization NSCLC is (FISH), although other methods are evaluated including polymerase chain reaction (PCR) and IHC.

 

 

The evaluation of a solitary pulmonary nodule: solitary pulmonary nodule characteristics are:

– Peripheral lung tumor mass <6 cm. in diameter

– The patient is asymptomatic

– Clinical exam is normal

– Blood count and liver tests are normal.

The risk of a pulmonary nodule is malignant to be high when:

– Age greater than 45 years (the risk is 30-50%):

– Older than 35 years, the risk is 15%

– Doubling time of the tumor: the 30-400 days, the risk is 30-50%. The doubling time of less than 30 days, greater than 40 days risk of 1%.

– The patient is a smoker.

 

Signs and symptoms:

-cough, dyspnea and hemoptysis,

-postobstructive secondary pneumonia,

– pleural effusion chest pain,

-Horner syndrome (miosis, ptosis, anhidrosis)

-disfonia ,

-decreases weight,

– brain, liver, bone metastasis.

 

Paraneoplastic syndromes:

1. The syndrome of inappropriate secretion of antidiuretic hormone

2. hypercoagulable state

3. ectopic ACTH syndrome

4. Eaton syndrome – Lambert (myasthenic syndrome)

5. gynecomastia

6. hypertrophic osteoatropathy

7. hypercalcaemia

 

Screening often after 20-30 years CXR and sputum cytology in patients smokers, chronic cough over 45 years did not result in a different mortality between the group and the control group studied, so that routine screening not recommended. Public education on smoking cessation is the only effective means of combating lung cancer.

 

For diagnosis are recommended:

• complete history and physical examination,

• sputum cytology,

• chest X-ray front and profile,

• bronchoscopy with transbronchial biopsy or cytology central lesions,

• transthoracic biopsy by needle for peripheral localized tumors,

• lung biopsy sight when other diagnostic procedures could not establish the diagnosis,

• thoracoscopy.

Sputum cytology – on three sputum exams are diagnoses in 50% of cases, 80% of centrally located tumors and 20% of tumors located peripherally.

Chest radiography radiographic highlights new lung lesions suspicious of cancer and peripheral lung lesions.

Bronchoscopy with transbronchial biopsy, cytology or cytology brewing bronchial lavage fluid diagnoses most patients.

Transthoracic needle biopsy is useful in the diagnosis when suspected lesion is located peripherally.

Thoracoscopy is useful in the diagnosis of peripheral nodule diagnosis or staging of a release or pleural effusion.

Lung Biopsy to diagnose invasive procedure view is useful in the diagnosis when other diagnostic methods could not establish the diagnosis.

In pulmonary nodules considered suspects biopsy may be performed by bronchoscopy, endobronchial ultrasound guided either by (EBUS) or navigational CT, Tru-cut biopsy

CT-guided biopsy or video-assisted thoracoscopy (VATS).

 

 

 

Differential diagnosis

1. Lung metastases from breast, kidney, pancreatic, colon, testis.

2. Malignant lymphoma localized mediastinal

3. Pulmonary benign tumors; neurofibromas, lipoma, adenoma

4. Pulmonary Tuberculosis

5. Lung abscess

6. Atypical pneumopathies

7. Silicosis

8. Histoplasmosis

9. Diseases of the chest wall

 

Natural Evolution

Dissemination

-through lymphatic way in the mediastinal and peritracheal nodes and through diaphragm in the para-aortic and para-renal lymph nodes

-through venous blood: brain metastases, liver, adrenal, bone, kidney, renal.

Complications

Tobias Pancoast Sindrom – apex tumors:invasion of the pleura, ribs.

Remote –metastases

– paraneoplastic syndromes

-superior vena cava syndrome: facial edema, cyanosis, venous hypertension, venous thoracic collateral circulation

– mediastinal syndrome

– bronchopulmonary overinfection

-pleuresia and neoplastic pericarditis

– paralysis of the phrenic nerve

For staging is recommended: history, complete clinical examination, blood counts, kidney and liver biochemical tests, chest X-ray, CT thorax and abdomen, mediastinoscopy, abdominal ultrasonography.

C. T. thoracic and abdominal plays an important role in staging mediastinal lymph disease in identifying invasion, local invasion of chest wall tumor, vertebral bodies, mediastinal structures, small pleurisy or pleural nodules small metastases in the liver, kidney and adrenal.

Mediastinoscopy is useful in the evaluation of mediastinal lymph nodes, subcarinali, pre and paratracheal, so to category N. assessment performed in patients with central tumors and undifferentiated carcinoma. There is carried out in case of a normal chest radiograph well-differentiated tumors. It is the most accurate way to differentiate resectable N2 or N3 and N2 unresectable confirm malignancy in mediastinal lymph nodes. Patients with lymph node positive disease to mediastinoscopy have a worse prognosis that those with lymph node positive disease revealed by histological examination postoperatively. It is performed before surgery in patients who are considered resectable. Minimal N2 disease include patients with C. T. mediastinoscopy have normal lung but one station only microscopic lymph node invaded.

Clinical N2 disease (or advanced “bulky”) includes patients with mediastinal lymphadenopathy revealed preoperative chest radiography and CT evident at lung.

Specific biochemical markers: serum calcium, alkaline phosphatase, transaminases.

Bone scintigraphy and C. T. head recommended only when present signs and symptoms of illness.

Pulmonary CT with biopsy of lymph nodes greater than 1 cm in the lowest transverse diameter.

Pleural fluid cytology or pleural biopsy, cytology by puncture of lymph nodes, liver tumor nodule. Any tumor in the liver or adrenal detected by CT or ultrasound to be confirmed by needle biopsy before classify as metastasis. Marrow biopsy bone marrow examination is useful in small cell cancer, being positive in 24% of cases, but has no value in non-small cell carcinoma.

CT / MRI head reserved for patients with neurological signs or symptoms. If metastatic disease was detected in the chest, upper abdomen, other imaging tests are only necessary if you change the course of treatment.

If clinically suspected bone metastases then we recommend PET, CT and bone scintigraphy PET having the highest sensitivity. MRI bone can be useful to document a bone lesion located.

Fludeoxyglucose (FDG) -PET-CT has the highest sensitivity for mediastinal lymph nodes and distant metastasis evaluation.

Intraoperative staging consist of visual and tactile inspection of the lungs, diaphragm, pleura, ipsilateral mediastinal lymph nodes to be biopsied or removed. PET-CT data that impact the therapeutic decision and in particular where overstaging must be pathologically confirmed. For most offices metastatic PET-CT is superior to MRI or CT. However, in brain metastases PET-CT is inferior to MRI or CT.

 

 

TNM Staging for lung cancer

Primary Tumor (T)

Tx – primary tumor cannot be assessed, or tumor proven by the presence of malignant cells in sputum or bronchial lavage fluid but unviewed imaging or bronchoscopy.

T0 – no evidence of primary tumor

Tis- carcinoma in situ

T1 tumors ≤ 3 cm in greatest diameter, surrounded by lung or visceral pleura, without bronchoscopic evidence of invasion proximal to the lobar bronchus (exp. Not in the main bronchus) Note 1

T1a- tumor ≤ 2 cm in greatest diameter

T1b- tumor> 2 cm but ≤ 3 cm in greatest diameter

T2 – Tumor with any of the following size or extension:

• bigger than 3 cm in greatest diameter

• involves main bronchus,> 2 cm distal to the carina

• invades the visceral pleura

• associated with atelectasis or obstructive pneumonitis that extends to the region but does not involve the entire lung hilarious.

T2bis-tumor> 3 cm but ≤ 5 cm in greatest diameter

T2b-tumor> 5 cm but ≤ 7 cm in greatest diameter

T3 – Tumor> 7 cm directly invade one:

• chest wall (including superior sulci tumors), diaphragm, mediastinal pleura, parietal pericardium

Or tumor in the main bronchus • <2 cm distal to the carina, but without invasion of the Carina.

• pneumonia or atelectasis or obstructive lung nodules associated to all separated in the same lobe

T4 – tumor of any size that invades one:

• mediastinum, heart, great vessels, trachea, esophagus, vertebral bodies, carina, or

Malignant pleural effusion • tumor (Note 2) or

• satellite tumor nodules in the lung lobes are the primary tumor. (Note 3)

Regional lymph nodes (N)

Nx – regional lymph nodes cannot be assessed

N0 – no regional lymph node metastases

N1 – peribronchial lymph node metastases, and / or ipsilateral hilar lymph nodes and lymph nodes intrapulmonarily invaded by direct extension of the primary tumor

N2 – ipsilateral mediastinal lymph node metastasis and / or subcarinal lymph nodes.

N3 – hilar lymph node metastases and mediastinal controlateral, ipsilateral scalene and supraclavicular lymph nodes or controlateral

Distant metastasis

Mx – this distant metastasis cannot be evaluated

M0- without distant metastases

M1 – distant metastases shows

M1a- separate nodules controlateral lobe; tumor with pleural nodules or malignant pleural (or pericardial effusion)

M1B-distant metastasis

 

Note 1.

The tumor with unusual superficial dissemination of any size, invasive component limited to the bronchial wall, which may extend proximally until the main bronchitis is also classified as T1.

Note 2. Most pleural effusions are due to tumors. The few patients multiple cytopathological exams are negative for tumor, fluid exudation and is not bleeding. When there are these elements and clinical judgment dictate that the effusion is not related to the tumor, the effusion should be excluded as a staging element and the patient should be classified as T1, T2 or T3.

Note 3. Separate tumor nodules in the same lobe are classified as T4 tumor and lymph synchronous separated in a different lobe (ipsilateral or controlateral is classified as M1).

pTNM – pathologic classification

Categories pT, pN and pM categories correspond to the T, N, M.

pN- histological examination of hilar and mediastinal lymph will usually include 6 or more lymph.

 

Stages:

N0 M0 occult carcinoma Tx

Tis N0 M0 Std.0

Stg.IA T1a / b N0 M0

Stg.IB N0 M0 T2a

Stg.II A T2b N0 M0

T1a N1 M0

N1 M0 T1b

N1 M0 T2a

Stg.II B T2b N1 M0

T3 N0 M0

Stg.III A T1a N2 M0

N2 M0 T1b

N2 M0 T2a

T2b N2 M0

T3 N1 Mo

T3 N2 M0

T4 N0 M0

T4 N1 M0

Stg.III B T1-3 N3 M0

N 2-3 M0 T4

Stg.IV any T any N M1a

Any T Any N M1B

 

Cancer treatment with non-small cell lung (NSCLC)

Therapeutic Indication

Stg.IA (T1N0M0) and IB (T2N0M0) and IIA (T1-2, N1)

The recommended treatment is surgical resection. Survival at 5 years for patients completely resected is 65-70% to 45-55% for T1N0M0 and T2N0M0.

Postoperative chemotherapy is not recommended for stage IA In stage IB effectiveness of chemotherapy is controversial. Current data suggest that no survival benefit except with tumors> 4.5 cm. Age is not a contraindication for chemotherapy.

Radiation therapy is recommended in patients with a contraindication to surgery or who refuse surgery. The survival to 5 years for patients treated with radiation therapy is 15-25%.

 

Stg.II A (T1N1M0) Std. IIB (T2N1M0, T3N0M0) recommend surgical resection is associated with systematic lymph node dissection. For T1N1M0 and T2N1M0 tumors survival at 5 years by surgery is between 35-50%. For T3N0M0 tumors survival at 5 years it is between 26-40%. For patients with completely resected stage II or N2 disease discovered microscopic histopathological examination is recommended postoperative adjuvant chemotherapy. There is no indication that postoperative radiotherapy improves outcomes in patients with N0 or N1 disease completely resected. For patients with lymph node metastases to lymph node dissection is not carried out or patients with positive resection margins, ie incomplete surgical resection (R1) locoregional radiation therapy is recommended.

In patients with stage IIB (T3, N0) with superior sulci tumors preoperative concurrent chemoradiotherapy followed recommend surgical resection and chemotherapy.

Current data suggest a poor survival by using inhibitors of EGFR tyrosine kinase, gefitinib versus placebo in the adjuvant situation even in the subgroup with mutant EGFR. Therefore it is currently not recommended with molecular target agents in adjuvant situation.

Medical contraindication:  for patients that refuse surgery or radiotherapy is recommended. The 5-year survival of patients treated by radiotherapy is between 10-22%. Patients with T1N1M0 have local recurrence rate of 12% and the rate of distant metastasis and 33% for patients with T2N1M0 local recurrence rate is 14% and distant metastases by 36%.

Std. IIIA (T3, N1, M0, T1-3, N2, M0)

In patients with stage IIIA (T3, N1) with superior sulci tumors preoperative concurrent chemoradiotherapy followed recommend surgical resection and chemotherapy.

In patients with IIIA tumors (T4 extended N1) is recommended concurrent chemoradiotherapy followed by final 4 courses of chemotherapy.

In patients with stage IIIA tumors (T3-4, N0, N1) of the chest wall and mediastinum proximal airway there are several options:

1. Surgical resection is the preferred treatment

2. Chemotherapy before surgery or chemoradiation

3. Concomitant chemoradiotherapy final T4 tumors, N0-1 without pleural effusion, followed by four courses of chemotherapy if not previously received.

In patients with stage IIIA (T1-3, N2) is based on data evaluation treatment of pathological mediastinal lymph. Patients with mediastinal lymph node negative biopsy are candidates for surgery. For patients with resectable lesions, mediastinal lymph node dissection or mediastinal lymph node biopsy should be performed during surgery. For patients with T1-3, N2 positive lymph node disease concomitant chemoradiotherapy is recommended final. Another option for patients with N2 lymph node positive disease is induction chemotherapy with or without radiotherapy.

5-year survival after complete resection T3N1M0 disease is 20% and for T1-3N2M0 is 10-20%.

In patients with pulmonary nodules in the same lobe separated or ipsilateral lung without other systemic metastases surgery is recommended. After surgery in patients with positive surgical margins is recommended chemoradiotherapy and those with negative surgical margins is recommended chemotherapy alone.

In patients with synchronous solitary nodules in the lung contralateral recommend treating them as two primary lung tumors if both are curable, even if the 2 tumor histology is similar.

Multiple lung cancers is important to determine whether multiple lung cancers are metastatic or separate primary lung tumors (synchronous or metachronous). Martini and Melamed criteria are used to diagnose multiple lung cancers: 1). Different histology, 2). But there are similar histology invasion and lymph node metastasis extrathoracic. In patients who are eligible for permanent therapy with sparing resection prefer local parenchyma.

Patients with stage IIIB include 2 groups: 1). Patients with tumors T1-3, N3 that are unresectable mediastinal lymph and include controlateral (T4, N3). Surgical resection is not recommended in patients with T1-3, N3. In patients suspected N3 disease recommend pathologic confirmation. If confirmed N3 disease concomitant chemoradiotherapy is recommended followed by four courses of chemotherapy if given initially. 2). For patients with stage IIIB (T4, N2-3) is not recommended surgery. We recommend biopsy lymph N2 and N3. If biopsies are negative therapeutic options are as Category IIIA (T4, N0-1). Ipsilateral mediastinal lymph or contralateral; if positive then definitive chemoradiotherapy is recommended followed by four courses of chemotherapy if given initially.

 

Stage IV (any T, any N, M1)

The management strategy should take into account the histology, molecular pathology, age, performance status, comorbidities, and patient preference. Systemic therapy should be offered to all patients with stage IV NSCLC with performance status 0-II. In every stage of NSCLC smoking cessation should be encouraged because it improves outcomes and smoking can interact with systemic therapy. For example smoking reduces the bioavailability of erlotinib.

a) In patients with good performance status polichemotherapy is recommended.

b) In patients with bad performance status supportive treatment is recommended

The multi-agent chemotherapy treatment demonstrated a survival advantage compared to patients treated with supportive therapy only. In patients treated with multi-agent chemotherapy median survival was 9.8 months with a survival rate of 33-39% at 1 year.

Through supportive treatment median survival was 4-5 months and 1 year survival rate was 10-14%.

Cisplatin-based combinations have generated an overall response rate of 25% -35%, a time until disease progression of 4-6 months, average survival of 8-10 months to 1 year survival rate of 30% -40 % and the survival rate at 2 years of 10% -15% in patients with PS 0-2. PS 3-4 patients not getting chemotherapy treatment except erlotinib in patients positive for EGFR mutations.

 

I line treatment

Cisplatin-based chemotherapy prolongs survival and improves quality of life in patients with performance status 0-2. For most patients four cycles of chemotherapy, are recommended up to a maximum of 6 cycles of chemotherapy when maintenance is expected. Meta-analyzes showed higher response rates than combination with cisplatin combination with carboplatin. Survival was superior to cisplatin in tumor subgroup nonscuamous and patients treated with regimens that included third generation gemcitabine and taxanes.

Pemetrexed based Chemotherapy is used in patients with nonscuamos NSCLC in any treatment line.

Bevacizumab improves overall survival when administered in combination with taxol plus carboplatin regimen in patients with nonscuamouas histology and performance status 0-1.

Chemotherapy agents based on third generation (gemcitabine, taxotere) should be considered only in cases of contraindications to platinum. Several meta-analyzes have shown lower response rates and lower survival.

In patients with performance status ≥ 2 chemotherapy prolongs survival and quality of life compared with best supportive care. Chemotherapy with a single agent such as gemcitabine, vinorelbine, taxanes remains an option.

The superiority of the combination versus carboplatin-based monochemotherapy with acceptable toxicity profile has been found in a subset of patients with PS 2.

Patients with bad performance status of 3-4 should receive BSC (best supportive care which) in the absence of activating mutations (sensitizing) EGFR

Older patients

Chemotherapy is the standard single-agent treatment as first-line therapy for older patients with NSCLC. A randomized trial comparing carboplatin administration of taxol monthly versus weekly vinorelbine or gemcitabine single agent in patients aged 70-89 years with PS of 0-2 and reported a survival advantage for combination therapy but also a high toxicity. Cisplatin-based chemotherapy is preferred to the older patients with PS 0-2 with suitable organic functions, while monochemotherapy remains the recommended treatment for patients with comorbidities.

 

Use of tyrosine kinase inhibitors

In patients with activating mutations (sensitizing) of EGFR TK inhibitor therapy significantly delays progression of EGFR and should be considered as a first line therapy. Patients with NSCLC should be screened for EGFR mutations before initiation of first-line therapy. First-line treatment with TKI (afatinib, erlotinib or gefitinib) was associated with longer PFS with a higher RR and a better life quality possible. PS 3-4 Patients may also receive EGFR TKI. In patients with EGFR wild type (unmutated) tyrosine kinase inhibitors is not recommended frontline chemotherapy because it is inferior and as effective as placebo therapy.

Patients with NSCLC ALK gene rearrangements are to be considered for therapy with Crizotinib a dual ALK and MET TKI (epithelial mesenchyme transition factor). All patients will eventually present progression through primary or secondary resistance.

In conclusion:

Bevacizumab plus chemotherapy or chemotherapy is alone in…