Lung cancer is the malignant transformation and expansion of lung tissue, and is the most lethal of all cancers worldwide, responsible for up to 3 million deaths annually. Although lung cancer was previously an illness that predominantly affected males, the incidence in women has been increasing in the last few decades, which has been attributed to the rising ratio of female to male smokers. Currently, lung cancer is the leading causing of cancer death in women, overshadowing breast cancer, ovarian cancer and uterine cancers combined. However, it is of note that there are certain types of lung cancers that appear in otherwise healthy patients who has never smoked.
Current research indicates that the factor with the greatest impact on risk of lung cancer is long-term exposure to inhaled carcinogens. The most common means of such exposure is tobacco smoke.
Treatment and prognosis depend upon the histological type of cancer, the stage (degree of spread), and the patient’s performance status. Treatments include surgery, chemotherapy, and radiotherapy.
Signs and Symptoms
Symptoms that suggest lung cancer include:
dyspnea (shortness of breath)
hemoptysis (coughing up blood)
chronic cough or change in regular coughing pattern
chest pain or pain in the abdomen
cachexia (weight loss), fatigue and loss of appetite
dysphonia (hoarse voice)
clubbing of the fingernails (uncommon)
If the cancer grows into the lumen it may obstruct the airway, causing breathing difficulties. This can lead to accumulation of secretions behind the blockage, predisposing the patient to pneumonia.
Many lung cancers have a rich blood supply. The surface of the cancer may be fragile, leading to bleeding from the cancer into the airway. This blood may subsequently be coughed up.
Depending on the type of tumor, so-called paraneoplastic phenomena may initially attract attention to the disease. In lung cancer, this may be Lambert-Eaton myasthenic syndrome (muscle weakness due to auto-antibodies), hypercalcemia and SIADH. Tumors in the top (apex) of the lung, known as Pancoast tumors, may invade the local part of the sympathetic nervous system, leading to changed sweating patterns and eye muscle problems (a combination known as Horner’s syndrome), as well as muscle weakness in the hands due to invasion of the brachial plexus.
In many patients, the cancer has already spread beyond the original site by the time they have symptoms and seek medical attention. Common sites of metastasis include the bone, such as the spine (causing back pain and occasionally spinal cord compression), the liver and the brain.
Performing a chest X-ray is the first step if a patient reports symptoms that may be suggestive of lung cancer. This may reveal an obvious mass, widening of the mediastinum (suggestive of spread to lymph nodes there), atelectasis (collapse), consolidation (infection) and pleural effusion. If there are no X-ray findings but the suspicion is high (e.g. a heavy smoker with blood-stained sputum), bronchoscopy and/or a CT scan may provide the necessary information. In any case, bronchoscopy or CT-guided biopsy is often necessary to identify the tumor type.
If investigations have confirmed lung cancer, scan results and often positron emission tomography (PET) are used to determine whether the disease is localized and amenable to surgery or whether it has spread to the point it cannot be cured surgically. PET is not useful as screening, as not all malignancies are positive on PET scan (such as bronchoalveolar carcinoma), and lung infections may be positive on PET Scan.
Blood tests and spirometry (lung function testing) are also necessary to assess whether the patient is well enough to be operated on. If spirometry reveals a very poor respiratory reserve, as may occur in chronic smokers, surgery may be contraindicated.
There are two main types of lung cancer categorized by the size and appearance of the malignant cells seen by a histopathologist under a microscope: non-small cell (80%) and small-cell (roughly 20%) lung cancer. This classification although based on simple pathomorphological criteria has very important implications for clinical management and prognosis of the disease.
Non-small Cell Lung Cancer
The non-small cell lung cancers (NSCLC) are grouped together because their prognosis and management is roughly identical. When it cannot be subtyped, it is frequently coded to 8046/3. The subtypes are:
(M8070/3) Squamous cell carcinoma, accounting for 20% to 25% of NSCLC, also starts in the larger breathing tubes but grows slower meaning that the size of these tumours varies on diagnosis.
(M8140/3) Adenocarcinoma is the most common subtype of NSCLC, accounting for 50% to 60% of NSCLC. It is a form which starts near the gas-exchanging surface of the lung. Most cases of the adenocarcinoma are associated with smoking. However, among non-smokers and in particular female non-smokers, adenocarcinoma is the most common form of lung cancer. A subtype of adenocarcinoma, the bronchioalveolar carcinoma, is more common in female non-smokers and may have different responses to treatment.
Large cell carcinoma is a fast-growing form that grows near the surface of the lung. It is primarily a diagnosis of exclusion, and when more investigation is done, it is usually reclassified to squamous cell carcinoma or adenocarcinoma.
Small Cell Lung Cancer
(M8041/3) Small cell carcinoma (SCLC, also called “oat cell carcinoma”) is the less common form of lung cancer. It tends to start in the larger breathing tubes and grows rapidly becoming quite large. The oncogene most commonly involved is L-myc. The “oat” cell contains dense neurosecretory granules which give this an endocrine/paraneoplastic syndrome association. It is initially more sensitive to chemotherapy, but ultimately carries a worse prognosis and is often metastatic at presentation. This type of lung cancer is strongly associated with smoking.
Adenoid cystic carcinoma
The lung is a common place for metastasis from tumors in other parts of the body. These cancers, however, are identified by the site of origin, i.e., a breast cancer metastasis to the lung is still known as breast cancer. The adrenal glands, liver, brain, and bone are the most common sites of metastasis from primary lung cancer itself.
Exposure to carcinogens, such as those present in tobacco smoke, immediately causes cumulative changes to the tissue lining the bronchi of the lungs (the bronchial mucous membrane) and more tissue gets damaged until a tumor develops.
There are four major causes of lung cancer (and cancer in general):
Carcinogens such as those in cigarette smoke
The Role of Smoking
Smoking, particularly of cigarettes, is by far the main contributor to lung cancer, which at least in theory makes it one of the easiest diseases to prevent. In the United States, smoking is estimated to account for 87% of lung cancer cases (90% in men and 79% in women), and in the UK for 90%. Cigarette smoke contains 19 known carcinogens including radioisotopes from the radon decay sequence, nitrosamine, and benzopyrene. Additionally, nicotine appears to depress the immune response to malignant growths in exposed tissue. The length of time a person continues to smoke as well as the amount smoked increases the person’s chances of contracting lung cancer. If a person stops smoking, these chances steadily decrease as damage to the lungs is repaired and contaminant particles are gradually vacated. More recent work has shown that, across the developed world, almost 90% of lung cancer deaths are caused by smoking.
Passive smoking – the inhalation of smoke from another’s smoking – is claimed to be a cause of lung cancer in non-smokers. Studies from the USA (1986, 1992, 1997, 2001, 2003), Europe (1998), the UK (1998), and Australia (1997) have consistently shown a significant increase in relative risk among those exposed to passive smoke.
The EPA in 1993 claimed that about 3,000 lung cancer-related deaths a year were caused by passive smoking. However, since this report was based on a study that was alleged to be heavily biased and was ruled by a federal judge to be “unscientific”, the EPA report was declared null and void by a federal judge in 1998.
Percentage of lung cancer deaths attributable to smoking in the developed world:
35-69 Years 70 Years+ All Ages
Men 93.9 90.3 92.5
Women 68.8 68.9 68.8
Both 88.7 84.3 86.6
The extensive attempts made by Philip Morris to delay the release of the 1997 IARC study, to affect the wording of its conclusions, to neutralize its negative results for their business, and to counteract its impact on public and policymakers’ opinion have been documented by Ong & Glantz in The Lancet journal. Their work was based on 32 million pages of documents made public as part of the settlement of the 1998 legal case of State of Minnesota and Blue Cross/Blue Shield of Minnesota vs Philip Morris Inc, et al. and available at Philip Morris’ own website.
Recent investigation of side stream smoke suggests it is more dangerous than direct smoke inhalation.
Asbestos can cause a variety of lung diseases. It increases the risk of developing lung cancer. There is a synergistic effect between tobacco smoking and asbestos in the formation of lung cancer.
Asbestos can also cause cancer of the pleura, called mesothelioma (which is distinct from lung cancer).
Radon is a colorless and odorless gas generated by the breakdown of radioactive radium, which in turn is the decay product of uranium, found in the earth’s crust. Radon exposure is the second major cause of lung cancer after smoking. The radiation decay products ionize genetic material, causing mutations that sometimes turn cancerous. Radon gas levels vary by locality and the composition of the underlying soil and rocks. For example, in areas such as Cornwall in the UK (which has granite as substrata), radon gas is a major problem, and buildings have to be force-ventilated with fans to lower radon gas concentrations. In the US, the EPA estimates that one in 15 homes has radon levels above the recommended guideline of 4 pCi/L (150 Bq/m3). Iowa has the highest average radon concentrations in the United States. Studies performed by R. William Field, Daniel J. Steck, Charles F. Lynch, Brian J. Smith and colleagues at the University of Iowa have demonstrated a 50% increased lung cancer risk with prolonged radon exposure at the EPA’s action level of 4 pCi/L. Recent pooled epidemiologic radon studies by Dan Krewski et al. (2005; 2006) and Sarah Darby et al. (2005) have also shown an increased lung cancer risk from radon below the U.S. EPA’s action level of 4 pCi/L.
Radon causes lung cancer because it causes arbitrary damage to the chromosomes and DNA molecules contained in the nucleus of the cell.
Genetics and Viruses
Oncogenes are genes that are believed make people more susceptible to cancer. Proto-oncogenes are believed to turn into oncogenes when exposed to particular carcinogens. Viruses are also suspected of causing cancer in humans, as this link has already been proven in animals. Genetic susceptibility and viral infection are not of major importance in lung cancer, but they may influence pathogenesis.
Lung Cancer Staging
Lung cancer staging is an important part of the assessment of prognosis and potential treatment for lung cancer.
Treatment for lung cancer depends on the cancer’s specific cell type, how far it has spread, and the patient’s performance status. Common treatments include surgery, chemotherapy, and radiation therapy.
Surgery is usually only an option in non-small cell lung cancer (NSCLC) and if the disease is limited to one lung and has not spread beyond its confines. This is assessed with medical imaging (computed tomography, positron emission tomography). Furthermore, as stated, a sufficient respiratory reserve needs to be present to allow for the removal of lung tissue. Procedures performed include lobectomy (removal of one lobe), bilobectomy (two lobes) or pneumonectomy (removal of a whole lung). Smaller resections include wedge excision or segmentectomy (part of a lobe).
The role of sub lobar resection (extended wedge resection) continues to be debated for the primary management of NSCLC. Although overall survival appears to be equivalent to that of lobectomy resection, the local recurrence rate has been documented to be over three times more common (19% compared to 5%). Accordingly, sub lobar resection has historically been used as a “compromise resection” approach for the management of small (less than 3 centimeters diameter) stage I peripheral NSCLC identified in patients with impaired cardiopulmonary reserve. Recent reports of the use of intraoperative radioactive iodine brachytherapy implants at the margins of sublobar resection suggest that local recurrence can be reduced to that of lobectomy when this is used as a surgical adjunct to sublobar resection.
The role of anatomic segmentectomy (a larger sublobar resection) with complete lymph node staging has also been found to have potential survival benefits similar to lobectomy. Such resections should be limited to peripheral small (less than 2 cm diameter) stage I NSCLC where a margin of resection equivalent to the diameter of the tumor can be achieved.
Five-year prognosis is often as good as 70% following complete resection of limited (lesions limited to the lung tissue without lymph node spread – stage I) disease.
After surgery, adjuvant chemotherapy may be recommended if lymph nodes within the lung tissues resected (stage II) or the mediastinum (lymph nodes in the peri-tracheal region, stage III) are found to be positive for cancer spread. Survival may be improved by up to 15% above patients receiving only surgical resection in these circumstances. The role of adjuvant chemotherapy for patients with large stage I NSCLC (tumor diameter greater than 3 cm without lymph node involvement, stage IB) remains controversial.
The NCI Canada study JBR.10 treated patients with stage IB to IIB NSCLC with vinorelbine and cisplatin chemotherapy and showed a significant survival benefit of 15% over 5 years. However subgroup analysis of patients in stage IB showed that chemotherapy did not result in any survival gain in them. Similarly, while the Italian ANITA study showed a survival benefit of 8% over 5 years with vinorelbine and cisplatin chemotherapy in stages 1B to 3A patients, subgroup analysis also showed no benefit in the IB stage.
The Cancer and Leukemia Group B (CALGB) study was a randomized study which examined the use of carboplatin and paclitaxel chemotherapy in patients with stage 1B disease. Unfortunately, although initial results in 2004 were encouraging, an update at the recent American Society of Clinical Oncology meeting (June 2006) reported that the findings are now negative with no survival advantage with the use of adjuvant chemotherapy in patients with this stage of disease. However, exploratory analysis of patients in the CALGB study suggested that perhaps those with tumors equal or greater than 4 cm in size may still benefit.
At present, it is standard practice to offer patients with resected stage II-IIIA NSCLC adjuvant third generation platinum-based chemotherapy (e.g. cisplatin and vinorelbine). Adjuvant chemotherapy for patients with stage 1B remains controversial as clinical trials have not clearly demonstrated a survival benefit.
Small-cell lung cancer is treated primarily with chemotherapy, as surgery has no demonstrable influence on survival. Primary chemotherapy is also given in metastatic NSCLC.
The combination regimen depends on the tumor type:
-NSCLC: cisplatin or carboplatin, in combination with gemcitabine, paclitaxel, docetaxel, etoposide or vinorelbine. In metastatic lung cancer, the addition of bevacizumab when added to carboplatin and paclitaxel was found to improve survival (though in this study, patients with squamous cell lung cancer were excluded because of problems with pulmonary hemorrhage in this group in the past).
-SCLC: cisplatin or carboplatin, in combination etoposide or ifosfamide; combinations with gemcitabine, paclitaxel, vinorelbine, topotecan and irinotecan are being studied.
In recent years, various molecular targeted therapies have been developed for the treatment of advanced lung cancer. Gefitinib (Iressa) is one such drug, which targets the epidermal growth factor receptor (EGF-R) which is expressed in many cases of NSCLC. However despite an exciting start it was not shown to increase survival, although females, Asians, non-smokers and those with the adenocarcinoma cell type appear to be deriving most benefit from gefitinib.
A newer drug called erlotinib (Tarceva), another EGF-R inhibitor, has been shown to increase survival in lung cancer patients and has recently been approved by the FDA for second-line treatment of advanced non-small cell lung cancer.[Similar to gefitinib, it appeared to work best in females, Asians, non-smokers and those with the adenocarcinoma cell type.
A number of targeted agents are at the early stages of clinical research, such as cyclo-oxygenase-2 (COX-2) inhibitors, the pre-apoptic inhibitor exisulind, proteasome inhibitors, bexarotene (Targretin) and vaccines.
Treatment of non-small cell lung cancer is evolving.
Radiotherapy is often given together with chemotherapy, and may be used with curative intent in patients who are not eligible for surgery. A radiation dose of 40 or more Gy in many fractions is commonly used with curative intent in non-small cell lung cancer; typically in North America, the dose prescribed is 60 or 66 Gy in 30 to 33 fractions given once daily, 5 days a week, for 6 to 6½ weeks. For small cell lung cancer cases that are potentially curable, in addition to chemotherapy, chest radiation is often recommended. For these small cell lung cancer cases, chest radiation doses of 40 Gy or more in many fractions are commonly given; typically in North America, the dose prescribed is 45 to 50 Gy and can be given in either once daily treatments for 5 weeks or twice daily treatments for 3 weeks.
For both non-small cell lung cancer and small cell lung cancer patients, radiation of disease in the chest to smaller doses (typically 20 Gy in 5 fractions) may be used for symptom control.
Radiofrequency ablation is increasing in popularity for this condition as it is nontoxic and causes very little pain. It seems especially effective when combined with chemotherapy as it catches the cells inside a tumor – the ones difficult to get with chemotherapy due to reduced blood supply to the inside of the tumor. It is done by inserting a small heat probe into the tumor to cook the tumor cells. The body then disposes of the cooked cells through its normal eliminative processes.
Prevention is the most cost-effective means of fighting lung cancer on the national and global scales. While in most countries industrial and domestic carcinogens have been identified and banned, tobacco smoking is still widespread. Eliminating tobacco smoking is a primary goal in the fight to prevent lung cancer, and smoking cessation is the most important preventative tool in this process.
Policy interventions to decrease passive smoking (e.g. in restaurants and workplaces) have become more common in various Western countries, with California taking a lead in banning smoking in public establishments in 1998, Ireland playing a similar role in Europe in 2004, followed by Italy and Norway in 2005 and Scotland as well as several others in 2006. New Zealand has also recently banned smoking in public places. (See Smoking ban).
Only the Asian state of Bhutan has a complete smoking ban (since 2005). In many countries pressure groups are campaigning for similar bans. Arguments cited against such bans is criminalization of smoking, increased risk of smuggling and the risk that such a ban cannot be enforced.
Screening and Secondary Prevention
Regular chest radiography and sputum examination programs were not effective in reducing mortality from lung cancer. Earlier studies (Mayo Lung Project and Czechoslovakia lung cancer screening study, combining over 17,000 smokers) showed earlier detection of lung cancer was possible but mortality was not improved. Simply detecting a tumor at an earlier stage may not necessarily yield improved mortality. For example, plain radiography resulted in increased time from diagnosis of cancer until death and those cancers being detected by screening tended to be earlier stages. However, these patients continued to die at the same rate as those who are not screened. At present, no professional or specialty organization advocates screening for lung cancer outside of clinical trials.
A computed tomography (CT) scan can uncover tumors not yet visible on an X-ray. CT scanning is now being actively evaluated as a screening tool for lung cancer in high risk patients, and it is showing promising results. The USA-based National Cancer Institute is currently completing a randomized trial comparing CT scans with chest radiographs. Several single-institution trials are ongoing around the world. The International Early Lung Cancer Action Project published the results of CT screening on over 31,000 high-risk patients in late 2006 in the New England Journal of Medicine. In this study 85% of the 484 detected lung cancers were stage I and thus highly treatable. Mathematically these stage I patients would have an expected 10-year survival of 88%. However, there was no randomization of patients (all received CT scans and there was no comparison group receiving only x-rays) and the patients were not actually followed out to 10 years post detection (the median follow-up was 40 months). Other studies are underway in this area to see if decreased long-term mortality can be directly observed from CT screening.
It should be noted that screening studies have only been done in high risk populations, such as smokers and workers with occupational exposure to certain substances. This is important when one considers that repeated radiation exposure from screening could actually induce carcinogenesis in a small percentage of screened subjects, so this risk should be mitigated by a (relatively) high prevalence of lung cancer in the population being screened.