Lung Cancer
by H. Linardou, M.D., PhD, Medical Oncologist

Introduction & Epidemiology

Lung cancer is the most common cancer in men, the fifth most common in women, and the first cause of cancer-related death in both sexes. Lung cancer was an uncommon disease until the 1930s, but the use of tobacco led to a linear and rapid increase in lung cancer incidence.

Lung cancer causes more deaths in women than breast cancer, since 1987, following the popularity of the smoking habit among women. In 1952 the gender ratio of lung cancer were 13:1 for men:women, while in 2000 this ratio became 3:2. Overall, the risk for a man to develop lung cancer regardless of smoking is 1 in 13 and for a woman 1 in 17.

Lung cancer is primarily a disease of the elderly, with almost 70% of lung cancer diagnoses in people 65 years or older, while <3% of lung cancers occur in people younger than 45 years of age.

Recent public awareness efforts about the dangers of tobacco, combined with anti-smoking campaigns and cessation programs have managed to lower lung cancer rates in many developing countries.

 

Etiology and risk factors

Smoking is the main cause of lung cancer. Smoking causes more than 85-90% of chronic respiratory diseases, about 40% of acute myocardial infarctions and almost 90% of lung cancers. Cigarette smoke contains 4000 different chemicals, 55 of which are defined as known carcinogens. Smokers have 20 times more risk of developing lung cancer than never-smokers and 9 in 10 lung cancer patients are smokers.

The risk of developing lung cancer from smoking depends on the number of cigarettes and the history of smoking. This is termed as ‘pack-years’ (the number of packs of cigarettes smoked per day multiplied by the number of years smoked). For example, a 20 pack-year smoking history means that someone has smoked two packs of cigarettes per day for 10 years. People with 30-pack-year histories or more have the greatest risk for lung cancer.

Cigars and pipe smoking can also cause lung cancer, although the risk is believed to be not as high as that of cigarettes.

The exposure and inhalation of smoke by non-smokers is called ‘passive smoking’ and it can also cause lung cancer and other smoking-related diseases. Passive smoking defers a risk of 20-30% for lung cancer development.

Smoking cessation can help all current smokers reduce their long-term risk:  as cells ‘recover’ with the growth of normal cells, the risk of developing lung cancer decreases significantly every year. In former smokers, lung cancer risk drops by 30-50% after 10 years of smoking cessation and the risk of esophageal or oral cavity cancer drops by 50% after 5 years of quitting. Overall, the risk of lung cancer begins to approach that of a nonsmoker at about 15 years after quitting. Therefore, early smoking cessation can be very beneficial and anti-smoking campaigns in young people are of great importance. Smoking light cigarettes or using filters do not ‘protect’ against the risk of lung cancer.

Other established risk factors for lung cancer include:

  • exposure to asbestos, which can cause mesothelioma (a cancer of the pleura, i.e. the membrane lining of the lung)
  • radon gas
  • chronic obstructive pulmonary disease (COPD) and pulmonary fibrosis
  • air pollution
  • genetic familial predisposition, to some degree.

 

Symptoms and signs

The symptoms of lung cancer can vary and generally appear late; actually, 10-15% of patients have no symptoms at diagnosis. The location and extent of the tumor define the presence and severity of symptoms and signs.

Common symptoms include:

  • cough (which can be a new persistent cough or worsening of an existing chronic one)
  • coughed blood (haemoptysis)
  • repeated respiratory infections
  • breathing difficulties (such as shortness of breath, chest pain or wheezing).

Symptoms from other organs, such as bones, liver or brain can be present if the lung cancer has spread to these organs (metastasis).

More generalized symptoms such fatigue and weight loss can be present as well. Finally, if the cancer produces several hormone-like substances, other syndromes can complicate the picture (these syndromes are called paraneoplastic as they are not directly due to the local presence of cancer cells).

 

Diagnosis

Several diagnostic tests or procedures are used to diagnose and stage lung cancer. These procedures begin with the collection of a detailed history and a thorough clinical examination, followed by radiological tests, such as chest x-ray and CT scan. Examination of the airways by bronchoscopy, will not only give a clear picture of the respiratory tree and the location and relations of the tumor, but will also reveal areas that can be biopsied for histological diagnosis.

In recent years staging may include Positron Emission Tomography (PET) scanning, a specialized highly specific imaging technique, which measures metabolic function. If diagnosis is not possible by bronchoscopy, fine needle aspiration or biopsy is commonly performed under Computed Tomography (CT) guidance; otherwise, surgical procedures are performed, such as mediastinoscopy or thoracotomy.

 

Types of lung cancer

Lung cancers are generally classified into two categories, based on the type of small cells seen under the microscope:

  1. Small Cell Lung Cancers (SCLC)
  2. Non-Small Cell Lung Cancers (NSCLC).

Small Cell Lung Cancers (SCLC) accounts for about 20% of lung cancers, and represents an aggressive, rapidly growing cancer which is almost exclusively related to smoking.

Non-Small Cell Lung Cancers (NSCLC) is the most common type of lung cancer, covering about 80% of all lung cancers, exhibited in many different histologies. The most common histological type of NSCLC is adenocarcinoma, which includes almost half of all NSCLC diagnoses. Adenocarcinoma is observed in smokers, but is also the most common lung cancer type seen in non-smokers and women. Other NSCLC histologies include squamous cell carcinoma, large cell carcinoma, mixed types, as well as several other rarer types, such as lung carcinoids.

 

Stages of lung cancer

Stages of Non-Small Cell Lung Cancer (NSCLC)

For NSCLC, staging is based on the extension of the disease with four stages, defined by 3 characteristics:

  • the tumor (T)
  • the presence and extent of mediastinal lymph node involvement (N)
  • metastasis (M).

In general:

  • Stage 1 disease refers to lung cancer confined to the lung
  • Stage 2 & Stage 3 represent disease that is more extensive but is still within the anatomical limits of the chest
  • Stage 4 refers to cancer which has spread to other organs or parts of the body (metastatic).

 

Stages of Small Cell Lung Cancer (SCLC)

For SCLC a more general staging is utilized, which recognizes only two stages:

  • a limited disease stage, which refers to disease that could be limited within a single radiotherapy field in the chest
  • an extensive-disease stage, when metastasis beyond the chest is present.

 

Treatment of lung cancer

The therapeutic management of lung cancer is based on the type of cancer, the stage of the disease, as well as the general condition of the patient.

Treatment choices include surgery, chemotherapy, radiotherapy, or combinations of these treatment modalities. Treatment is with curative intent when the cancer can be completely removed; otherwise, treatment is intended to relieve symptoms and palliate.

Adjuvant therapy (i.e. following primary therapy) is indicated for disease in stage 2 or in early stage 3. It involves chemotherapy administered after surgery in order to eradicate micro-metastases, i.e. any cancer cells that might have remained following surgery.

 

Surgery

Surgery is not offered for Small Cell Lung Cancer (SCLC), except in very rare cases of early stage disease, because SCLC presents commonly as a systemic disease, after it has spread in the body.

For Non-Small Cell Lung Cancer (NSCLC), surgery is offered for early stages (stage 1 and some stage 2). The choice of surgical procedure is dependent upon the size and location of the tumor, and it ranges from a limited removal of part of one lobe, to lobectomy (removal of a lobe), or pneumonectomy (removal of entire lung), usually complemented by regional or distant mediastinal lymphadenectomy.

In some cases when the tumor is extended locally, chemotherapy alone or combined with radiotherapy is offered prior to surgery (i.e. neoadjuvant treatment), in an attempt to reduce the tumor and achieve a successful surgical removal.

 

Radiotherapy

Radiotherapy is a treatment option for both Non-Small Cell Lung Cancers (NSCLC) and Small Cell Lung Cancer (SCLC).

It can be offered in cases where surgery is not possible due to serious comorbidities (other illnesses), or when surgery is not possible because of tumor spread to lymph nodes or major vessels or the trachea. The combination of radiotherapy with chemotherapy can further improve survival.

The radiotherapy course is usually on an outpatient basis, 5 days a week for 3-4 weeks, with little toxicity. Radiation can cause inflammation to the skin, can affect the blood count or cause irritation in the esophagus, or nausea.

In SCLC, prophylactic radiotherapy to the brain is a common practice after the end of chemotherapy.

 

Chemotherapy

Both Non-Small Cell Lung Cancers (NSCLC) and Small Cell Lung Cancer (SCLC) may be treated with chemotherapy.

Chemotherapy is the administration of cytotoxic drugs that kill rapidly dividing cells, such as cancer cells. It is usually administered as an intravenous infusion, but it may also be given as pills or as a combination of the two, and is usually given on an outpatient setting. Chemotherapy may be given alone or in combination with radiotherapy.

The most commonly utilized and effective drug combinations for lung cancer include a platinum drug, although several different classes of cytotoxics have shown significant efficacy in Non-Small Cell Lung Cancer (NSCLC). One or two lines of chemotherapy can be offered for NSCLC that relapses, providing options for modest survival extension, but most importantly significant palliation.

For Small Cell Lung Cancer (SCLC) the most effective combination is the well-established platinum-etoposide combination which achieves very high response rates.

Chemotherapy has side effects that vary according to the drug, dose or combination and should be administered in experienced centers by certified specialists in medical oncology. The main side effects include

  • susceptibility to infections (due to suppression of the blood cells)
  • bleeding or bruising (due to problems in blood clotting)
  • hair loss
  • nausea
  • vomiting
  • diarrhea
  • kidney or liver problems
  • fatigue.

There are many supportive medications which can be given in order to prevent or treat these chemotherapy side effects.

 

Targeted therapy

Certain patients with Non-Small Cell Lung Cancer (NSCLC), approximately 15% of the adenocarcinoma histology, have specific alterations (mutations) in a gene involved in the development and promotion of lung cancer (called Epidermal Growth Factor Receptor, or EGFR).

These mutations confer significant sensitivity to certain targeted drugs, called EFGR inhibitors. These drugs (gefitinib, erlotinib, afatinib) target specifically the cancer cells that have these molecular alterations, resulting in significantly greater effect and response and also less toxicity to normal cells than standard chemotherapy.

Similarly, ALK inhibitors (like crizotinib) are drugs that target the ALK-EML4 fusion which appears in certain patients with adenocarcinoma.

Lung cancer treatment options also include targeted agents against the development of new vessels within or around a cancer, called antiangiogenic drugs. For example, the drug bevacizumab (Avastin) is used in combination with chemotherapy and has been shown to improve survival.

 

Immunotherapy

Intensive research is being conducted during the recent years to discover drugs which may benefit Non-Small Cell Lung Cancer (NSCLC) patients by activating immune response. Ipilimumab, nivolumab and other novel agents are very promising.

 

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