Lung Cancer
Overview
Most lung cancers start in the lining of the bronchi, but they can also begin in other areas such as the trachea, bronchioles, or alveoli. Lung cancers are thought to develop over a period of many years.
There are 2 main categories of primary lung cancer: non-small cell lung cancer (NSCLC) and small cell lung cancer (SCLC). Non-small cell lung cancer accounts for approximately 80% of all primary lung cancers, making it the most common type of lung cancer.
The term secondary or metastatic lung cancer describes the situation where cancer cells have spread to the lungs from a cancer that began elsewhere in the body. Lung cancer is more commonly metastatic than primary in origin. Carcinomas and sarcomas may reach the lung from anywhere in the body by haematogenous or lymphatic spread. Mediastinal lymphomas and oesophageal carcinomas may invade into the lung directly.
Primary lung cancer
Incidence
Primary lung cancer is the leading cause of cancer-related mortality in both men and women. In 2007, an estimated 213 380 new lung cancer cases will occur in the United States (114 760 in men and 98 620 in women). Worldwide, lung cancer remains the most common malignancy, with over 1.4 million new cases each year worldwide, which accounts for 12% of new cancer cases. More than half of new lung cancer cases occur in the developing world.
Risk factors
Smoking accounts for almost 90% of all cases of lung cancer. The risk increases in proportion to the number of cigarettes smoked per day and the number of years of smoking. Women are at greater risk than men who have smoked the same amount. Passive smoking may also increase risk. Other carcinogens that can affect the respiratory tract lead to increased risk, such as asbestos, arsenic and radon. The presence of underlying diseases, namely tuberculosis and pneumonia, that cause damage to the lung tissue, and diet have also been implicated.
Prognosis
It is a highly lethal cancer, with an overall 5-year patient survival rate of 12%. Estimates suggest that approximately 160 390 lung cancer–related deaths will occur in 2007 in the United States (89 510 in men and 70 880 in women). Although the mortality rate for this disease has levelled off in men in developed countries, it is still the most common cause of cancer death in this group, and men account for about 60% of all lung cancer cases. The incidence continues to rise in women, accounting for one in six of all cancer deaths. This is directly related to the changes in smoking habits.
Small cell lung cancer
Small cell lung cancer accounts for approximately 20% of all lung cancers. SCLC has a rapid onset and aggressive clinical pattern. Median survival of untreated SCLC is 2-4 months. At the time of diagnosis, approximately 30% of patients with small cell carcinoma will have tumour confined to the hemithorax of origin, the mediastinum, or the supraclavicular lymph nodes. These patients are designated as having limited-stage disease. Patients with tumours that have spread beyond the supraclavicular areas are said to have extensive-stage disease and have a worse prognosis
The median survival for limited-stage disease (LD) SCLC is 14–20 months, and the 2- and 5-year survival rates are approximately 20%–30% and 10%, respectively. The median survival for extensive stage disease (ED) is 9–12 months, but survival after 2 years is rare (<5%). The correlation between disease stage and survival rate could be biologically explained by the fact that SCLC has a large growth fraction, with a rapid growth rate and early metastases.
Treatment
In limited stage disease, surgery is reserved for selected patients. Adjuvant chemotherapy is recommended for patients who have undergone resection. Chemotherapy is presently the cornerstone of treatment of SCLC in most patients, and it is routinely recommended for patients with good performance status, with or without radiation to the chest.
Non-small cell lung cancer
NSCLC is a heterogeneous aggregate of several distinct histologies of lung cancer, the three major ones being squamous carcinoma, adenocarcinoma, and large cell carcinoma. These histologies are often classified together because, when localized, they have the potential for cure with surgical resection. Systemic chemotherapy can produce objective partial responses and palliation of symptoms for short durations in patients with advanced disease. Local control can be achieved with radiation in a large number of patients with unresectable disease, but cure is seen only in a small number of patients.
NSCLC is diagnosed in approximately 80% of patients with primary lung cancer. Of these patients, 30-35% present with localised disease (stage I & II), and 65-70% patients present with advanced disease (stage III & IV) and are generally not eligible for surgery, and overall five-year survival is poor.
Prognosis
At diagnosis, patients with NSCLC can be divided into 4 stages that reflect the extent of the disease and, consequently, the treatment approach.
Patients with stage 1 disease have the best prognosis, with a 5 year survival rate of 60% or better. Stages II and IIIA include patients with either locally or regionally advanced lung cancer. Five year survival in these patients can range between 10 and 50%.
The final group includes patients with advanced disease with or without distant metastases (stages IIIB and IV) has few (<10%) 5 year survivors.
Factors that have correlated with adverse prognosis include advanced stage of disease, performance status and weight loss and molecular prognostic markers. Within a given disease stage, the next most important prognostic factors are performance status and recent unexplained weight loss. Several studies published over the past decade have indicated that mutations of ras proto-oncogenes, particularly K-ras, portend a poor prognosis in individuals with stage IV NSCLC.
Treatment
Determination of stage is important in terms of therapeutic and prognostic implications. Careful initial diagnostic evaluation to define the location and to determine the extent of primary and metastatic tumour involvement is critical for the appropriate care of patients. Current areas under evaluation include combining local treatment (surgery), regional treatment (radiation therapy), and systemic treatments (chemotherapy, immunotherapy, and targeted agents) and developing more effective systemic therapy.
In operable candidates, clinically staged IA, IB, IIA, and IIB NSCLC should undergo anatomic complete surgical resection. Primarily, patients with stage IIIB and IV disease are treated non-operatively. Although multimodality therapy is routinely recommended for stage IIIA disease, it is recommended that it be performed within a clinical trial.
Only 30-35% of patients with NSCLC present with sufficiently localised disease at diagnosis to attempt curative surgical resection. Approximately 50% of patients who undergo surgical resection experience local or systemic relapse; thus, approximately 80% of all patients with lung cancer are considered for other therapies at some point during the course of their illness.
Selected patients with good responses to first-line chemotherapy, good performance status, and a long disease-free period between initial chemotherapy and relapse may be candidates for second-line chemotherapy.
Because most lung cancers cannot be cured with currently available therapeutic modalities, the appropriate application of skilled palliative care is an important part of the treatment of patients with NSCLC.
Surgery
Surgical resection provides the best chance of long-term disease-free survival and possibility of a cure. In stages I and II NSCLC, surgical resection is almost always possible unless comorbid medical conditions are present or the patient's respiratory reserve is so low that the intended resection will leave the patient with crippling respiratory dysfunction.
The role of surgery for stage IIIA disease is controversial – surgery alone is recommended in operable patients without bulky lymphadenopathy.
Patients with stage IIIB or IV tumours are generally not surgical candidates.
Radiotherapy
Radiation therapy can produce a cure in a small number of patients and can provide palliation in most patients. In the treatment of stage I and stage II NSCLC, radiation therapy alone is considered only when surgical resection is not possible because of limited pulmonary reserve or the presence of comorbid conditions. The role of radiation therapy as surgical adjuvant therapy after resection of the primary tumour is controversial. Radiation therapy reduces local failures in completely resected (stages II and IIIA) NSCLC but has not been shown to improve overall survival rates.
Chemotherapy
Adjuvant chemotherapy may provide an additional benefit to patients with resected NSCLC. At present, chemotherapy alone has no role in potentially curative therapy for NSCLC. Although the relapse rate after surgical resection of localised NSCLC is high, multiple randomised trials have failed to detect a benefit of adjuvant chemotherapy (ie., chemotherapy given after surgery).
Chemotherapy may be considered as part of multimodality therapy for locally advanced NSCLC and is used alone in the palliative treatment of stage IIIB NSCLC (owing to malignant pleural effusion) and stage IV NSCLC. In advanced-stage disease, chemotherapy offers modest improvements in median survival, although overall survival is poor. Palliative chemotherapy with a cisplatin-based or carboplatin-based regimen has been associated with objective and subjective responses for patients with metastatic NSCLC.
Some newer agents (eg, gemcitabine, paclitaxel, docetaxel, vinorelbine) have shown promising single-agent activity, with response rates in patients with metastatic NSCLC from 20-25%. Combination chemotherapy regimens have been reported to achieve response rates as high as 50%, especially when newer agents are included.
Multimodality therapy
Depending on clinical circumstances the principal forms of treatment that are considered for patients with stage IIIA NSCLC are radiation therapy, chemotherapy, surgery and combinations of these modalities.
Patients with stage IIIB NSCLC do not benefit from surgery alone and are best managed by initial chemotherapy, chemotherapy plus radiation therapy, or radiation therapy alone, depending on the sites of tumour involvement and their performance status.
Metastatic lung cancer
The treatment of metastatic cancer depends on where the cancer started. When breast cancer spreads to the lungs, for example, it remains a breast cancer and the treatment is determined by the tumour’s origin within the breasts, not by the fact that it is now in the lung. About 5 percent of the time, metastases are discovered but the primary tumour cannot be identified. The treatment of these metastases is dictated by their location rather than their origin.
The treatment of lung metastases of solid tumours is still a major problem, as many patients manifest extensive unresectable disease or pulmonary recurrence in the resected or contralateral side after complete resection. The use of intravenous chemotherapy is primarily limited because of systemic toxicity and so far has not achieved a curative effect in patients with unresectable pulmonary metastases. As with neoadjuvant or palliative treatment of liver metastases, the regional application of cytotoxic agents might also be a method for improving the therapy of unresectable lung metastases.