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Holzheimer RG, Mannick JA, editors. Surgical Treatment: Evidence-Based and Problem-Oriented. Munich: Zuckschwerdt; 2001.
Lung cancer is the most common non-cutaneous cancer in the western Countries; in the United States, near to 30% of the cancer deaths are due to carcinoma of the lung. The age-adjusted cancer death rate is close to 30 × 105 women, and 75 × 105 men. In 1998 it has been estimated that there will be 67,000 lung cancer deaths among women and 93.000 deaths among men in the United States. In this Country, whilst the incidence in men shows a decline commencing in 1990s, since 1970 there has been a sharp increase in women. In 1987 lung cancer surpassed breast cancer as the greatest cause of female cancer death.
Risk factors
The most important risk factor for lung cancer is tobacco use. Cigarette smoking has been definitely established by epidemiological and animal experimental data as the primary cause of lung cancer (grade A).
The percentages of lung cancers estimated to be caused by tobacco smoking in males and females are 90% and 78%, respectively. Environmental tobacco smoke is also implicated in causing lung cancer. An unequivocal link between tobacco smoke and lung carcinogenesis has been established by molecular data, demonstrating genetic damage in human lung tissue (grade B). Other carcinogens, including asbestos, radon and acrylo-nitrile are associated with lung cancer in a smaller proportion of cases.
Pathology
There are two major types of lung cancer: non-small-cell (more than 80%) and small-cell. They grow and spread in a different way, and so are treated differently. Thus, it is important to obtain histopathologic evidence of the tumor in order to consider therapeutic options.
Table I demonstrates the histologic classification according to the World Health Organization histologic classification of tumors.
Table I
Lung cancer: Histologic classification.
Table II summarizes the TNM definitions; and table III includes the new concepts of pathological classification, histopathological grading; and the microscopic and macroscopic evidence of residual tumor after surgical resection, lymphatic and venous invasion.
Table II
Lung cancer: TNM definitions.
Table III
Lung cancer: Macroscopic and microscopic pathological classifications.
Stage
The stage of lung tumors has a primordial role in the selection of therapy. It is based on a combination of clinical and pathologic studies:
- Physical examination
- Radiology
- Laboratory tests
- Mediastinoscopy
- Bronchoscopy
- Biopsy
- Biopsy of lymph nodes
- and/or surgical exploration.
The clinical signs may be grouped into four categories:
- 1.
Respiratory symptoms (cough, haemoptysis, pulmonary infections)
- 2.
Signs and symptoms from the involvement of thoracic extrapulmonary structures (superior vena cavae, esophagus, chest wall, pericardium, recurrent laryngeal nerve)
- 3.
Metastases (supraclavicular nodes, liver, brain)
- 4.
Paraneoplasic syndromes: ectopic hormonal release (most frequently associated with small-cell cancer), neurologic, dermatologic.
With regard to the radiologic studies, a report evaluating the staging of 1400 patients undergoing tumor resection found that clinical staging by radiology accurately assessed T stage in 78% of patients, and the N stage in only 47%. Errors were equally divided between overstaging and understaging (grade B).
The Radiology Diagnostic Oncology Group concluded that computed tomography provides a sensitivity of 52% and a specificity of 69% in staging lung cancer; magnetic resonance imaging does not appear to improve this accuracy. Positron emission tomography, in combination with CT, may have greater sensitivity and specificity than CT alone.
Table IV shows the revised International System for Staging Lung Cancer, adopted in 1997 by the American Joint Committee on Cancer and the International Union Against Cancer. This revision was made to provide greater specificity for patients groups. Stages I and II are divided into two categories by the size of the tumor. T3 N0 has been moved from stage IIIA to stage IIIB. Satellite tumor nodules in the same lobe as the primary lesion should be classified as T4, and intrapulmonary ipsilateral metastases in a lobe other than the lobe containing the primary lesion should be classified as M1 (stage IV).
Table IV
Lung cancer: IUAC and AJCC stage groupings.
Prevention
Avoidance of tobacco use is the most effective measure for preventing lung cancer. One powerful indicator of the public benefit of smoking cessation is the decline in age-adjusted lung cancer mortality among men, which is consistent with their reduction in smoking, and in women, in whom lung cancer mortality continues to increase, the rate of increase has slowed.
Specific chemical agents have been used to reverse, suppress or prevent carcinogenesis before development of invasive malignancy. In randomized trials, isotretinoin and etretinate have shown controversial results in the reversal of metaplasia. These trials have established that retinoids have minimal or no effect on metaplasia (grade B).
The Beta-carotene and Retinol Efficacy Trial, involving smokers, former smokers and asbestos-exposed workers was terminated early because its results confirmed a harmful effect of beta-carotene, increasing lung cancer incidence.
Many randomized screening trials have been conducted with the aim to reduce lung cancer mortality, as the Mayo Lung Project. There is not good evidence that these trials achieved a reduction in lung cancer mortality, but cancer cases discovered in screened patients were diagnosed in earlier stages than those in control group. The interpretation of results from these studies has led to conflicting positions in the medical community and confusion in population at risk regarding the value of chest X-ray screening.
Non-small-cell lung cancer (NSCLC)
Treatment options
Current therapeutic areas under evaluation are: Local (surgery), Regional (radiotherapy), and Systemic (chemotherapy and immunotherapy).
Occult carcinoma
The recommended management is diagnostic evaluation, with close follow-up, to define the site and nature of the tumor. When discovered, they are early stage and curable by surgery.
Stage 0
They are carcinomas in situ of the lung, noninvasive and nonmetastasizing. They should be curable with surgical resection. An alternative treatment to surgical resection exists: endoscopic phototherapy with a hematoporphyrin derivative, specially for very early central tumors that extend less than 1 cm within the bronchus; but there is no evidence on the efficacy of this modality of therapy.
Stages IA-IB
Surgery is the treatment of choice. Postoperative mortality is age-related, but less than 5% can be expected with lobectomy. The 5-year survival rates are more than 60% in this stage after resection. Patients with impaired pulmonary function may be considered for segmental or wedge resection, and these cases may be operated on video-assisted thoracoscopy technique. Randomized trials, comparing lobectomy with limited resections show no difference in overall survival, but a reduction in local recurrence was noted in patients treated with lobectomy (grade B).
In patients who are medically inoperable or refused surgery, radiation therapy may be considered as curative intent. In some retrospective radiation therapy series, inoperable patients treated with definitive radiotherapy achieved 5-year survival rates of 10% to 27%, and in the subgroup T1 N0 these series found survival rates of 32% to 60%. Primary radiation therapy consists of 6000 cGy delivered with megavoltage equipment.
It has been reported higher risk of second tumors in long-term survivors, with rates of about 10%. A randomized trial of vitamin A administration in resected stage I patients showed a trend toward decrease second primary lung cancers, but with no difference in overall survival rate.
Stages IIA-IIB
The treatment of choice is surgical resection. Careful preoperative assessment of the patient's overall medical condition is critical in considering the benefits of surgery. Postoperative mortality, age-related, is up to 5–10% with pneumonectomy or 4–6% with lobectomy.
Inoperable patients may be considered for radiation therapy, with a 20% 3-year survival rate, and 10% 5-year survival rate.
The role of postoperative radiotherapy has been evaluated in individual trials: they showed inconclusive and conflicting results. In a meta-analysis including 2128 patients from 9 eligible trials, the conclusion was that postoperative radiotherapy is detrimental to patients with early-stage (I-II) completely resected NSCLC and should not be used for such patients (grade A).
Stage IIIA
The three principal forms of treatment are under consideration: radiation therapy, chemotherapy, surgery, and combinations of them.
- Radiation therapy: the majority of these patients do not achieve a complete response but there is a long-term survival benefit in 5–10%. One prospective randomized trial showed that radiation therapy given as three daily fractions improved overall survival compared to radiotherapy given as one daily fraction (grade B). The addition of chemotherapy resulted in 10% reduction in the risk of death.
- The use of preoperative (neoadjuvant) chemotherapy has been shown to be effective in patients with N2 disease: in two randomized studies, cisplatin-based chemotherapy followed by surgery had a median survival more than three times as long as patients treated with surgery but no chemotherapy (grade B).
- Combination of chemotherapy plus chest irradiation for 211 patients with N2 stage IIIA has shown that near to 75% of patients were able to have a resection of their cancer, and 27% were alive at 3 years.
- The use of postoperative irradiation in patients with completely resected stage IIIA squamous cell lung cancer failed to demonstrate any survival benefit (grade A). At least, its role in the treatment of N2 tumors is not clear and may warrant further research with more modern radiotherapy techniques as conformal or hyperfractionated radiotherapy.
- In selected patients with chest wall tumors (including superior sulcus tumor), surgical management may be curative, with a 5-year survival rate of 20%, provided that their tumor is completely resected. Patients with more invasive tumors (true Pancoast tumor) have a worse prognosis and do not benefit from primary surgical management.
- Immunotherapy, in any form, has demonstrated no consistent benefit.
Stage IIIB
These patients do not benefit from surgery alone and are best managed by initial chemotherapy plus radiation therapy. A meta-analysis of patient data from 11 randomized clinical trials showed that cisplatin-based combinations plus radiation therapy resulted in 10% reduction in the risk of death compared with radiation therapy alone.
Because of the poor overall results, those patients should be considered for clinical trials.
Stage IV
Meta-analyses have demonstrated that chemotherapy produces modest benefits in short-term survival compared to supportive care alone. Chemotherapy should be given only to patients with good performance status and evaluable tumor lesions who desire such treatment after being fully informed of its anticipated risks (myelosuppresion, sepsis, drug specific toxicities and death are potential complications of chemotherapy) and limited benefits. Absolute benefit is 10% at 1 year.
Regimens used: cisplatin-containing and carboplatin-containing combinations, vinorelbine, paclitaxel (Taxol). The combination of cisplatin and paclitaxel has shown to have a higher response rate than the combination of cisplatin and etoposide. A meta-analysis including 25 trials, with a total of 5156 patients, concluded that combination chemotherapy increased objective response and toxicity rates compared with single-agent chemotherapy. However, when a platinum analogue or vinorelbine are used as single agents, the difference was not statistically significant (grade A).
Radiotherapy may be effective in palliating symptomatic local involvement, such as tracheal or esophageal compression, bone or brain metastasis, and superior vena cava syndrome.
Endobronchial laser therapy has been used to alleviate proximal obstructive lesions.
Prognostic factors
The main factor in the outcome of patients is TNM stage, with some different prognosis according to histopathology: bronchoalveolar adenocarcinomas and large-cell carcinomas have worse survival rates.
In operable patients with stages I-II, prognosis is influenced by biological factors, which possess great interest for establishing the risk of recurrences, the need of complementary therapies and the stratification of results. In different series of patients with resected NSCLC, the following factors have demonstrated independent predictive value in multivariate analysis (grade B) indicating worse prognosis:
- high cytosolic CA-125, specially in adenocarcinomas
- high cytosolic SCC in epidermoid carcinomas
- aneuploidy in epidermoid and adenocarcinomas
- mutations in the codon 12 of the oncogen K-ras, in adenocarcinomas
- increased tumoral expression of p185 neu, codified by the oncogen C-erb B2
- mutations in the exon 5 of chromosome 17p, codifying the suppressor oncoprotein p53
- increased telomerase activity
Actually, several research groups are devoted to establish in vitro cellular lines for the study of individual growth factors, antigen expression and chemosensitivity of lung cancer.
Small-cell lung cancer
This tumor has the most aggressive clinical course of any type of pulmonary tumor and a greater tendency to be widely disseminated by the time of diagnosis (median survival from that time is only 3–5 months), but is much more responsive to chemotherapy and irradiation.
Staging procedures are important in distinguishing patients whose disease is limited to the thorax from those with distant metastasis; the choice of treatment is influenced by this stage. Staging procedures used to document distant metastases include marrow examination, CT or MRI scans of the brain, CT scans of the chest and the abdomen, and radionuclide bone scans.
Limited stage small-cell lung cancer
- Combination chemotherapy containing two or more drugs are needed for maximal effect. Two meta-analyses have shown an improvement in 3-year survival rates for those receiving chemotherapy and radiation therapy compared to those receiving chemotherapy alone.
- The combination of etoposide and cisplatin chemotherapy with chest radiation therapy has now been used in cooperative group studies, which have achieved median survivals of 18–24 months and 40–50% 2-year survival with less than 3% treatment-related mortality (grade A).
- Patients with the tumor confined to the lung and ipsilateral hilar lymph nodes, may benefit from surgical resection with adjuvant chemotherapy (grade C).
- Patients treated with chemotherapy, with or without chest irradiation who have achieved a complete remission can be considered for administration of prophylactic cranial irradiation. A meta-analysis of 7 randomized trials has reported improvement in brain recurrence, diseasefree survival and overall survival with this approach (grade A).
Extensive stage small-cell lung cancer
- Combination chemotherapy includes several regimens, which produce similar survival rates:
- cyclophosphamide + doxorubicin + vincristine; etoposide + cisplatin; ifosfamide + carboplatin + etoposide
- Under clinical evaluation are new drug regim ens, dose intensity, alternative drug schedules and highdose chemotherapy with stem cell transplant. A meta-analysis did not show evidence for improved response rates or survival for more intense chemotherapy regimens (grade A).
- Chest irradiation is sometimes given for superior vena cava syndrome; brain metastases are treated with wholebrain radiation therapy.
- Interleukin-2 as initial therapy for patients with extensive small-cell lung cancer is under investigation.
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